Potential role of immunotherapy and targeted therapy in the treatment of cancer: A contemporary nursing practice.

Abbreviations

Adverse events

Acute lymphoblastic leukemia

Acute myeloid leukemia

Advanced renal cell carcinoma

Aggressive systemic mastocytosis

Basal cell carcinoma

Chimeric antigen receptor

Classical hodgkin lymphoma

Chronic lymphocytic leukemia

Chronic myelogenous leukemia

Colorectal cancer

Cutaneous T-cell lymphoma

Dendritic cells

Differentiated thyroid cancer

Esophageal squamous cell carcinoma

Follicular lymphoma

Germline BRCA-mutated

Hepatocellular carcinoma

Human epidermal growth factor receptor 2

Hand foot skin reaction

Head and neck squamous cell cancer

Hormone receptor

Hypertension

Immune checkpoint inhibitors

Indoleamine 2,3-dioxygenase

Interleukin-2

Large B-cell lymphoma

Mitogen-activated protein kinase

Multinational association of supportive care in cancer

Mantle cell lymphoma

Metastatic colorectal cancer

Metastatic non-small cell lung cancer

Monoclonal antibodies

MASCC Oral Agent Teaching Tool

Microsatellite instability-high

Mammalian target of rapamycin

Non-Hodgkin lymphoma

Non-small cell lung cancer

Primary mediastinal B-cell lymphoma

Pancreatic neuroendocrine tumors

Palmar-plantar erythrodysesthesia syndrome

Peripheral T-cell lymphoma

Phosphatase and tensin homolog

Renal cell carcinoma

Small cell lung cancer

Small lymphocytic lymphoma

Systemic mastocytosis with associated hematological neoplasm

Soft tissue sarcoma

Tyrosine kinase inhibitors

Upper respiratory infection

Urinary tract infection

Introduction

The term cancer involves numerous different types of malignancy that share some common features including abnormal cells that exhibit uncontrolled cell division and can evade apoptosis or programmed cell death [ 1 ]. Cancer is a leading public health problem around the world and tens of millions of people are diagnosed with cancer each year worldwide [ 2 ]. After cardiovascular diseases, cancer is the second leading cause of death in many countries. Furthermore, it has been reported that the number of deaths and new cases of cancer will continue to increase because of the increasing aging population and the adoption of lifestyle behaviors that elevate cancer risk [ 3 ]. Over the past half-century, treatment options for cancer have advanced from a highly toxic, single chemotherapeutic drug (for example-nitrogen mustard) to targeted therapies that interrupt specific signaling mechanisms and are more tolerable as compared to conventional anticancer drugs. Moreover, current cancer therapies include immunotherapy, biotherapy, adjuvant chemotherapy, surgery, combined modalities including concurrent chemotherapy and radiation or sequential neoadjuvant chemotherapy, and combinations of drugs [ 4 ]. Unfortunately, still chemotherapy resistance and recrudescence remain a great challenge [ 5 ]. Therefore, novel therapies are urgently needed to treat cancer [ 6 ].

The immune system is capable of detecting non-self versus self, thus providing protection to the human body from diseases of endogenous and exogenous origins. The immune system involves white blood cells and lymphoid tissues and organs, such as bone marrow, lymph vessels, lymph nodes, tonsils, spleen, and thymus, which eventually detects many threats and eradicates them to maintain homeostasis. A comprehensive knowledge of the interaction between the immune system and cancer cells is important to appreciate the important role of immunotherapy in cancer therapy. Chemotherapy kills cancer cells through their cytotoxic activities, whereas immunotherapies utilize the host immune system to destroy tumor cells [ 7 ]. On the other hand, targeted therapies specifically attack various targets in the cell that consequently interfere with a growth pathway. Improvements in genomic sequencing technology and molecular biology have resulted in the detection of numerous therapeutic targets within cancer cells and the development of therapies to interfere with them. It has been reported that these novel therapies possess fewer toxic side effects owing to their capacity to act precisely on precise targets in the growth pathways with minimum collateral injury to healthy tissues and cells [ 4 ].

Chemotherapy or cytotoxic therapy is a traditional or conventional mode of cancer treatment, however chemotherapy is now not regarded as a mandatory therapeutic option for several malignancies. Chemotherapy also involves collateral damage to healthy cells. As compared to chemotherapy, very little cytotoxic side-effects are observed with immunotherapy and targeted therapy [ 8 ]. Nurses are the interface between physicians and patients, therefore it is crucial that they have a comprehensive understanding of how newer anticancer drugs affect patients and patient care. There are two major factors that need to be carefully considered in the case of any anticancer drug including adherence to treatment and proper understanding of the adverse events (AEs) of a therapy. The knowledge regarding the AEs of therapy includes an understanding of the management of each AE and assisting effective care coordination. Various other factors that need to be considered involve current medications, co-morbid factors, the patient's performance status, patient suitability for the anti-cancer agent, and the timing of drug administration with respect to consumption of/interaction with food. All these aforesaid factors can affect the efficacy of the anticancer drugs or the capacity of the patients to deal with AEs. In addition, effective management of AEs might ameliorate the health-associated quality of life of patients and maximize their responsiveness to therapies. Patient education is another crucial competency offered by nurses to patients. The definition of patient education includes counseling and training patients [ 9 ]. Indeed, patient education is important for the exchange of knowledge and for the active participation of patients in the health care system. Oncology nurses are responsible for providing treatment to a wide range of patients with varying levels of health literacy. Thus, nurses need to utilize specific approaches to confirm useful patient education and techniques that are customized to the patient's preferred method of teaching and level of health literacy. This article provides an overview of the potential role of immunotherapy and targeted therapy as promising therapeutic options for cancer patients. Moreover, this article has broadly covered the role of nursing assessment and management of adverse events in cancer treatment with immunotherapies and targeted therapies, strategies of nurse-led patient education in immunotherapies and targeted therapies, and challenges of combining immunotherapy and targeted therapy.

Search strategies

A search was performed in Embase Cochrane Central, Google Scholar, Web of Science, ScienceDirect, PubMed, and Scopus databases. The terms or combination of terms used for the search include nursing, immunotherapy, cancer, cancer treatment, nursing practice, oncology; oncology nursing, targeted therapy; and adverse events from 2004 to December 2023. The articles that satisfied the inclusion criteria were fully reviewed and references from the selected literature have been cited where appropriate.

Targeted therapy

Targeted therapies have the capacity to directly act on cancerous cells via suppressing cell migration, differentiation, and proliferation [ 10 ]. The composition of the tumor microenvironment includes immune cells and local blood vessels, which may be changed by targeted drugs to hinder tumor growth and ratify powerful immune surveillance and attack ( Fig. 1 ). In targeted therapies, small molecules including monoclonal antibodies (MoAbs) play significant roles [ [11] , [12] , [13] ]. It has been observed that small molecules with molecular weights less than 900 Da may penetrate into cells and then work within cells to deactivate certain enzymes, which further interferes with tumor cell growth and eventually induce apoptosis. Most of the molecular targets involve proteasomes, poly ADP-ribose polymerase, and cyclin-dependent kinases. For example, ribociclib for metastatic breast cancer, rucaparib for BRCA-positive ovarian cancer, and carfilzomib for multiple myeloma [ 14 ]. On the other hand, for targets outside cells including therapeutic antibodies or MoAbs, membrane-bound sites or cell surface receptors can detect and bind with them to directly control downstream cell death and cell cycle progression. Moreover, specific MoAbs act on cells instead of cancerous cells including immune cells, which can further aid the manipulation of the immune system to attack human cancer [ 15 ].

Three major types of targeted therapies include MoAbs, small molecule tyrosine kinase inhibitors (TKIs), and vaccines. It has been observed that vaccines do not work particularly on signaling pathways in cancer cells, however mostly play a role to cause activation of the immune system of the body to detect and attack cancer cells. It is now well known that small molecules can effectively cross cell membranes. The suffix “nib" is present in small molecule TKIs, for example sorafenib, sunitinib, pazopanib, imatinib, and erlotinib. Since small-molecule drugs are administered orally, therefore food-drug and drug-drug interactions need to be considered. Most of the patients obtain their treatment at home, therefore oncology nurses adopt approaches to ensure adherence to time and dose requirements as well as management of side effects. MoAbs act outside of the cell to prevent receptors and signaling molecules from interacting. Furthermore, MoAbs have the capacity to transport toxins or radioactive molecules to cancer cells. Once within the cells, the cytotoxin is secreted which results in cell death. MoAbs have the capacity to play roles outside the cells to induce immune responses and eliminate cancer cells. In addition, MoAbs are derived from human, chimeric, or mouse antibodies and are intravenously administered [ 4 ]. Interestingly, MoAbs derived from human antibodies are more tolerable and generate fewer infusion reactions. Examples of such antibodies include bevacizumab, panitumumab, trastuzumab, rituximab, and tositumomab [ 16 ].

In general, the suffix "-mab" is used to denote monoclonal antibodies. Mo before mab is used to denote mouse-derived MoAbs, for example tositumomab. Xi before mab is used to indicate a cross or chimeric between a human and a mouse, for example rituximab. On the other hand, Zu before mab indicates humanized antibodies (for example bevacizumab or trastuzumab), while mu before mab denotes fully human-derived antibodies, for example panitumumab. Indeed, fewer infusion reactions can be anticipated if the antibodies are more humanized. Tu is used prior to the type of antibody to indicate that the tumor is the target, for example panitumumab or trastuzumab, Ci denotes a circulatory target (for example bevacizumab), and Li is used to denote that the MoAb is an immunomodulatory, for example ipilimumab. In order to have better command regarding cancer therapies, oncology nurses need to understand the naming conventions, routes of administration, and management of side effects [ 17 ]. Current targeted therapies for cancer have been summarized in Table 1 . The nurses are required to have good knowledge regarding the important and common adverse effects to intervene and educate the patients about the self-care measures since some of the adverse effects could be dangerous.

Nursing assessment and management of adverse events in cancer treatment with targeted therapies

In general, all the drugs that belong to the same class share a common mechanism of action, therefore some of the adverse effects are predictable. With the proper knowledge regarding the class effects, drugs and their mechanisms of action, and predicted adverse effects, the nurses can evaluate the patients for possible toxicity, collaborate with practitioners/physicians and intervene, as well as can provide correct patient education in self-care. Indeed, nurses need to have a better understanding regarding each drug prior to administering it, since numerous drugs sound alike to recognize drug-specific nursing care management approaches. The nurses should have the capacity to evaluate hypersensitivity reactions and intervene in an emergency. Furthermore, all symptoms and signs are not the same. In this regard, for instance the nurses need to know that erlotinib (an EGFR inhibitor) associated diarrhea is very different from nivolumab (a PD-1 inhibitor) associated diarrhea, which might be symptomatic of immune-mediated colitis and might be life-threatening [ 108 ]. The nursing care plan should be updated and evidence-based [ 109 ]. Immunotherapies are being developed rapidly and guidelines are still being written [ 109 ]. Cytokine release syndrome associated with CAR-T cell therapy might be fatal and severe, and nurses need to have a better understanding regarding the treatment implications. Most of the drugs have the potential to cause embryo-fetal developmental toxicity, therefore it is crucial to educate female patients of child-bearing age to utilize very effective contraception. Moreover, since the costs of most of these therapies are important, therefore nurses should assist the patients or involve others in findings resources to help the patients to receive these therapies [ 109 ].

Immunotherapy

Immunotherapy involves the usage of materials that enhance and/or reestablish the ability of the immune system to avert and fight diseases [ 110 ]. The aim of immunotherapy is to balance the immune system to eradicate cancer cells ( Fig. 2 ), while not generating unchecked autoimmune inflammatory reactions that can cause therapeutic restrictions of immunotherapies [ 111 ]. The innate immune responses are restricted to the secretion of cytokines that involve immune cells to instigate non-specific immune responses. On the other hand, adaptive immune responses have a significant contribution in the immune response to cancer cells owing to their capacity to precisely target non-self antigens [ 110 , 111 ]. In the tumor microenvironment, cancer-specific antigens generated during oncogenesis are processed and captured via dendritic cells (DCs) [ 111 ]. These DCs are activated and move to tumor-draining lymph nodes, after additional pro-inflammatory signals, where they induce the activation and also differentiation of naïve T cells to become effector T cells that have the capacity to kill cancer cells. Furthermore, activated effector T cells move from the lymph nodes via blood vessels to the tumor and infiltrate into the tumor bed via a multistep procedure that includes preliminary adhesive interactions between the vascular endothelial cells and T cells, after that transendothelial migration into the tumor [ 112 , 108 ]. After the tumor bed infiltration by T cells, identification of certain tumor antigens results in T cell killing of cancer cells, which can further induce additional antigen secretion and successive stimulation of extra rounds of the cancer-immunity cycle ( Fig. 2 ) [ 109 ].

Immune therapies include MoAbs, oncolytic virus therapy, cancer vaccines, cytokine drugs, checkpoint inhibitors, and chimeric antigen receptor (CAR) T-cell therapy. Immunotherapies aim to elevate immune activity and they are classified based on their mechanisms of action. In addition, immunotherapies can be grouped into passive and active immunotherapies. Active immunotherapies directly induce immune responses, lasting responses, and immune memory [ 114 ]. Oncolytic vaccines are examples of active immunotherapies. Passive immunotherapies (for example MoAbs) can generate precise but often short-lived responses; therefore these agents need to be regularly administered. Moreover, there can be an interruption in radiologic and clinical response to immunotherapies. This can take place owing to the time requires for an immune response to take place and then the time requires for the T cells to eliminate the tumor. There are several advantages of using immune therapy owing to their immune memory properties including prolonged immune action following termination of therapy, which might result in sustained antitumor activities and long-term overall survival [ 114 ]. However, some reports indicate that tumors that primarily respond to immune therapy might eventually become resistant. Multiple studies are ongoing to evaluate the effects of therapies to fight against immunotherapy resistance [ 6 , 115 ]. Approved immunotherapies that are approved for cancer treatment have been summarized in Table 2 .

FDA approval of immune checkpoint inhibitors (ICIs) has significantly transformed the cancer treatment strategy for multiple diseases that were once thought incurable. Now, individuals with renal cell carcinoma (RCC), metastatic melanoma, and lung cancer have hope and active therapies are playing role in extending their life. Another important discovery in cancer treatment is chimeric antigen-receptor T-cell (CAR T-cell) therapies. In the treatment of certain hematologic malignancies, two different CAR T-cell therapies including axicabtagene ciloleucel and tisagenlecleucel were approved [ 142 ]. Other important immunotherapies include modified viral targets and oncolytic vaccines. A number of vaccine candidates were found effective in animal studies, however their effectiveness was not confirmed in clinical studies. The reason for the failure of cancer vaccines in the metastatic setting was mainly because of the immune systems of patients being in a state of chronic inflammation, which further results in T-cell exhaustion [ 143 ]. However, studies are ongoing in exploring the usage of vaccines in cancer recurrence following complete surgical resection. Another promising immunotherapy is modified viral targets. Talimogene laherparepvec (T-VEC) was the first FDA-approved oncolytic virus therapy. T-VEC contains a genetically engineered herpes virus (an oncolytic herpes virus) that is used in the treatment of surgically unresectable melanoma [ 144 , 145 ].

Still, cytotoxic chemotherapy is considered as the first line of treatment for advanced-stage head and neck cancers. Moreover, second-line therapeutic options were also limited, up until the arrival of ICIs. In the treatment of head and neck cancers, nivolumab was the first immunotherapy approved by FDA based on the findings obtained from a clinical trial [ 146 ], while pembrolizumab obtained FDA approval as second-line therapy based on the findings obtained from another clinical trial [ 147 ]. Esophageal cancer can be treated, however it is rarely curable in metastatic or advanced disease. At 5 years, survival rates for advanced stages esophageal cancer are usually 5–20 %. Results obtained from a clinical trial confirmed the ability of pembrolizumab in improving the overall survival rate in patients with programmed death ligand-1 (PD-L1) and PD-L1 combined positive score (CPS) > 10 [ 148 ]. This CPS was established to assess the number of PD-L1 staining cells as compared to all viable tumor cells, and it has become a surrogate marker for individuals who might benefit from pembrolizumab treatment. In addition, it has been confirmed by a clinical trial that the addition of pembrolizumab to chemotherapy and trastuzumab markedly ameliorated objective response rate, induced complete responses in some participants, and significantly decreased the tumor size in case of unresectable or metastatic, HER2-positive gastric or gastro-esophageal junction adenocarcinoma [ 149 ].

As mentioned before, ipilimumab (anti-CTLA-4 inhibitor) is the first FDA-approved ICI that is used to treat metastatic melanoma [ 150 ]. After ipilimumab, several anti-PD-1/PD-L1 inhibitors have been developed that have been approved by FDA in the treatment of several diseases [ [151] , [152] , [153] , [154] , [155] , [156] , [157] , [158] ]. Following the success of therapy with single-agent ICI resulted in dual combination ICI therapy has been introduced to ameliorate therapeutic outcomes. Ipilimumab/nivolumab obtained its first approval as dual ICI therapy to treat metastatic melanoma [ [159] , [160] , [161] , [162] , [163] ]. Owing to the success of treatment with ICI in metastatic settings, various studies are now evaluating their effects in adjuvant settings. Former studies have compared ipilimumab versus placebo in high-risk (stage III) resected melanoma patients. Because of the improvement observed in the case of overall survival and relapse-free survival resulted in the approval of ipilimumab as adjuvant therapy [ 164 ]. Pembrolizumab and nivolumab also have been approved as adjuvant therapy in case of melanoma [ 165 , 166 ]. Unfortunately, this achievement came with the consequences of elevated levels of autoimmune toxicity. Nonetheless, researchers are currently studying to explore approaches to control the immune system of the body to maximize efficacy and regulate the often severe and unpredictable immune-related adverse events (irAEs) associated with therapies. Furthermore, researchers are still exploring the potential of ICIs in combination with chemotherapy and other targeted therapies [ 167 ].

Nursing assessment and management of adverse events in cancer treatment with immunotherapies

Indeed, immunotherapies have changed the paradigm of cancer treatment with lesser side effects and better outcomes. However, adverse events are observed along with their use. Because of the elevated level of immune system stimulation, the normal homeostatic control mechanisms providing protection to the body from its own immune response can become disturbed, which can further result in various side effects known as irAEs. It has been reported that irAEs can play role in morbidity and in numerous cases can result in the discontinuation of therapies with unpredictable effects on the course of the disease of patients. Oncology nurses ought to have a good understanding regarding the mechanisms and adverse events linked with such therapies. Nurses play a significant role in the identification of irAEs. Furthermore, irAEs might include several systems and therefore it is important to detect and manage these adverse events as soon as possible. Different irAEs and the recommended management strategies along with the extent of toxicity have been summarized in Table 3 .

Combinations of immunotherapies and targeted therapies in cancer treatment

Cancer therapy involving the combinations of immunotherapies and targeted therapies can play synergistic roles in cancer treatment. Moreover, targeted therapies can rapidly induce tumor regressions and thus can reduce tumor-related immunosuppression, which can further facilitate immunotherapies to exert more stronger cytotoxicity [ 169 ]. Success has been obtained in cancer treatment by using monotherapy, however there are major limitations in terms of the duration of therapy and response rates [ 170 ]. Because of these limitations and promising preclinical evidence regarding the effectiveness of combinations of immunotherapies with other cancer therapies, there is a growing interest in the combinations of immunotherapies and targeted therapies in cancer treatment [ 171 ]. Nonetheless, the rational design of these combined approaches needs an improved understanding of the effects of each anticancer therapy on host antitumor immunity [ 172 ]. Various preclinical studies have already confirmed the combined effects of immunotherapy and histone deacetylase (HDAC) inhibitors. These enhanced combinatorial activities were facilitated via improved antigen presentation by tumor cells and elevated activity of immune cells, both resulted in an elevated level of antitumor effect [ 173 ].

Furthermore, HDAC inhibitors were combined with various immune-activating antibodies including anti-CD40 and anti-CD137, which treated previously established subcutaneous tumors [ 174 ]. In this model, the mechanism was found to be reliant on HDAC inhibitor therapy-mediated tumor cell apoptosis, which induced antigen-cross-presentation to increase the survival and proliferation of CD8 + cytotoxic T lymphocytes [ 174 ]. In combination with immunotherapy, the potentially useful actions of HDAC inhibitors need to be balanced with the results that confirm the immune suppressive functions of HDAC inhibitors [ [175] , [176] , [177] ], particularly via elevating the inhibitory functions of T regulatory cells [ 178 , 179 ]. In lymphocytes, HDAC inhibitors are also strong suppressors of cell cycle proliferation [ 177 ]. Thus, intense mechanistic studies are needed if such combinations are evaluated in the clinic [ 180 ]. Specific pharmacologic effects of type I RAF inhibitors might further affect the capacity of targeted therapies to interact with the immune systems. It has been observed that RAF inhibitors induced paradoxical effects in wild-type BRAF cells, which further activated mitogen-activated protein kinase (MAPK) signaling pathway. This mechanism depends on the CRAF transactivation via a partly blocked wild-type CRAF:BRAF dimer, especially when the upstream activating signals are strong [ [181] , [182] , [183] ]. Interestingly, this contradictory activation of MAPK is the foundation for the discovery of cutaneous squamous cell carcinoma and various other RAS-mediated secondary cancers in individuals receiving BRAF inhibitors [ [184] , [185] , [186] ]. T cells are wild-type for BRAF and their induction of TCR causes activation of the MAPK signaling pathway, therefore BRAF inhibitors might directly cause activation of lymphocytes via contradictory activation of MAPK [ 187 ].

Moreover, in this model, vemurafenib did not alter the distribution or expansion of the adoptively transferred cells and also did not elevate the expressions of tumor antigens, which is indicating that the enhanced combined effect took place not because of a direct rise in the expressions of tumor antigens. Nonetheless, vemurafenib caused contradictory activation of MAPK that resulted in an elevated level of in vivo cytotoxic function and intratumoral cytokine release via adoptively transferred cells. In addition, the same mouse model was utilized to explore the role of alterations in chemokine signaling mediated via BRAF suppression in cancer cells and the combined activities with immune modifying antibody therapy [ 180 ]. It was also revealed that CD8 + T cells were partly needed for the antitumor function of BRAF inhibitors, which was found to be associated with the downregulation of tumor CCL2 generation after the oncogenic BRAF suppression. Combined therapy with agonistic anti-CD137 antibodies and BRAF inhibitors showed marked antitumor properties [ 180 ].

PI3K/AKT/mTOR signaling pathway is another important target for anticancer drug development because of its important contribution in the oncogenic signaling pathway in several histologies. Drug candidates that block this signaling at different stages are in clinical development and mammalian target of rapamycin (mTOR) inhibitors obtained approval for use in advanced RCC (aRCC) patients. Moreover, mTOR plays a crucial role in controlling the activities of immune cells, and inhibitors of mTOR are utilized for suppression of the immune system after organ transplantation. Nevertheless, suppression of mTOR signaling pathway has contradictory immune-stimulating activities, which can lead to the production of long-lived memory CD8 + T cells [ [188] , [189] , [190] ]. Extra useful activities of mTOR suppression were detected with hematopoietic stem cells and DCs, which is indicating that mTOR inhibitors might function via triggering promising immune cell alterations beyond their direct oncogene-targeting activities in cancer cells [ 191 ]. Additional use of targeted inhibitors of the PI3K/AKT/mTOR signaling is associated with the expressions of the immune suppressive membrane receptor PD-L1, which might have substantial uses for PD-1/PD-L1 blockade therapy. Phosphatase and tensin homolog (PTEN) loss can lead to PI3K pathway activation, which is a commonly seen event in glioblastoma multiforme (GBM). In addition, deficiency of PTEN within GBM cells was found to be linked with elevated PD-L1 expression and resulted in immune evasion, which might be reversed with inhibitors of PI3K [ 192 ]. PI3K inhibitors in combination with agonists of Toll-like receptor (TLR) were studied in a preclinical model, which showed better-combined activities against various murine tumors. Collectively, these beneficial properties were facilitated via the certain increase of polyfunctional T responses releasing IL-17 and IFN-γ [ 193 ].

Imatinib and various other c-kit and ABL inhibitors were found to successfully treat chronic myelogenous leukemia and gastrointestinal stromal tumors (GIST). Various studies have indicated that part of this success might be facilitated via triggering antitumor immune responses. Imatinib might also have off-target properties on immune effectors, regardless of its functions on tumor cells. Indeed, this activity was facilitated via the activation of promising cross-talk between NK cells and DCs [ 194 , 195 ]. The antitumor property of imatinib was found to be lost along with the depletion of CD8 + T cells and was increased via the blockade of CTLA-4 with monoclonal antibody therapy in a mouse model of spontaneous GIST development in transgenic mouse models carrying activating KIT mutation [ 196 ]. Moreover, in this model, imatinib decreased the expressions of the immune suppressive enzymes indoleamine 2,3-dioxygenase (IDO) via GIST tumor cells, which further mediated an increased level of the immune responses. In a different mouse model, the therapeutic function of dasatinib (a tyrosine kinase inhibitor) was significantly increased via immune induction with agonist anti-OX40 antibody therapy [ 197 ].

Challenges for combination approaches

Targeted therapies are highly effective in increasing responses with immunotherapy, however proper sequencing, dosage and timing of these agents will possibly be important for the success of combinatorial techniques. In addition, some targeted therapies containing immunostimulatory effects show immunosuppressive functions. For instance, even though inhibitors of HSP90 might elevate CTL-induced tumor cell lysis via increased antigen presentation on MHC class I molecules, they might also reduce some DCs and macrophage effects [ 198 , 199 ]. In a similar manner, temsirolimus (an mTOR inhibitor) might reduce the capacity of DCs to induce tumor-specific T cells [ 200 ], while HDAC inhibitors and bortezomib might hinder the activities of some NK cells [ [201] , [202] , [203] ]. Another important factor for combinatorial therapies is whether increased antitumor activities can be obtained without a corresponding rise in the level of severe toxicities. Inflammatory pathologies are major adverse events observed with some immunomodulatory agents including PD1 antibodies and ipilumimab, and combining therapies that influence different stages in immune responses may be expected to raise the chance of these side effects. Even though preclinical studies exploring these toxicities are very important, they might not completely anticipate the range of pathology that is seen in humans. For instance, inflammation of the pituitary gland is a common side effect of ipilimumab, however it was not predicted from experimental studies in mouse models [ 204 ]. Some preclinical studies also increased the chance that combination therapies including a 4-1BB agonist antibody and CTLA4 blockade may reduce instead of exacerbation of inflammatory toxicities [ 205 ].

Nursing and patient education on immunotherapy

Patients need continuous education regarding their clinical needs [ 206 ]. Therefore, individualized patient education needs to be provided by nurses including learning methods and consideration of barriers. Detection of irAEs by the patients and caregivers will permit the prompt and early intervention of irAEs, which is crucial for effective outcomes and continuance of therapy [ 207 ]. Overlooked symptoms linked with immunotherapy can result in devastating consequences for the health of patients, such as potentially life-threatening outcomes and permanent disability. Nurses need to be committed and competent to deliver useful educational opportunities to confirm quality and safe patient care [ 208 ]. Continuous research in the oncology field is leading to the development of new therapies. Thus, as new therapies come out, nurses are always at the front line of educating caregivers and patients while providing compassionate and holistic care [ 206 ]. Immunotherapy might or might not be the first line of treatment for patients. Therapies are customized by the types and stages of cancers. For patients receiving immunotherapies as their first, second or third line of therapy, it is important for caregivers and patients to appreciate and comprehend the differences between immunotherapy and cytotoxic chemotherapy. Immunotherapies target the stimulation of anticancer immune responses, while cytotoxic drugs interfere with DNA synthesis and cell division.

The effectiveness of cytotoxic chemotherapies relies on tumor shrinkage, while in individuals receiving immunotherapies, new lesions might develop or metastasis might grow prior to the reduction in total tumor burden owing to the infiltration of lymphocytes into tumors. When teaching patients on immunotherapy, an important teaching point is that immunotherapy-associated side effects take place due to dramatically different mechanisms as compared to cytotoxic chemotherapy-associated adverse events. Even though the presenting symptoms might be similar, knowledge regarding the mechanisms of action of CAR T-cell therapy, ICIs, and oncolytic viral therapies is important in comprehending the toxicity profiles and using different techniques to minimize or reverse their effect [ 209 ]. One analogy that can be utilized to elucidate the mechanisms of action of these drugs and difficult immunologic theories is to equate the immune system of patients to a car. For example, depressing the accelerator in a car (equivalent to activating T cells) is important for a car to move forward, which is comparable to an effective immune response against the tumor. Providing this analogy will help patients to better understand the mechanism of action of drugs and are frequently motivated by the idea that their own body is fighting against cancer [ 210 ]. Moreover, nurses have a significant contribution in understanding their therapeutic options, evaluating the knowledge of patients, and supporting while patients consider these treatment options ( Fig. 3 ).

Creating strong relationships between caregivers and patients can encourage honest and open communication. Thus, it is crucial to emphasize that new symptoms always need to be reported to the practitioner. This education will be particularly useful for patients who might have doubts in reporting a change because of the fear that treatment might be discontinued. In addition, they need to know that continuation of a certain treatment with associated side effects might lead to more severe toxic effects and treatment might be on hold but not discontinued [ 211 ]. Patients ought to be educated that irAEs might take place at any time after the initiation of therapy or even after several months [ 211 ]. Verbal instruction is another important step in patient education [ 212 ]. However, verbal instruction should not be the only source of patient education and need to be associated with educational guides including written instructions. Furthermore, instructional guides must include and specify how and when to report any symptoms. Nurses also need to provide the patient with segmented and shorter education prior to moving on to another topic, if a patient struggles with any content [ 212 ]. Caregivers need to be involved in the educational process, since they can provide support to the patients through their duration of treatment and are reliable in mediating effective patient education. Moreover, this permits the patients to follow along with the verbal instructions. The teach-back method is a useful method to ensure whether the patients have successfully retained the information or not. This method also helps the nurses in assessing the level of patient knowledge regarding educational instructions via asking the patients to respond and confirm their understanding, using their own words [ 206 ].

For instance, nurses can ask the patients to restate the steps regarding what to do if diarrhea takes place. This method will ensure effective education and offer chances for clarification of misinterpretations. The teaching methods need to change along with the change in therapies. For instance, visual applications, web-based patient portals, and telemedicine give nurses remote access while increasing communication to further ameliorate the management of symptoms of patients via elevating the opportunity for educational experiences [ 213 ]. Telemedicine can enable patients living in rural areas far from healthcare centers to receive timely management [ 213 ]. Although various opportunities are growing, still nurses should cater to learner preferences, the age of the learner, and evaluate whether the methods are appropriate for the content or not. Nurses also should be attentive in understanding how patients are retrieving treatment information in a technologically advanced healthcare system. The internet has transformed how medical knowledge is exchanged between patients and nurses by permitting patients access to several forms of information [ 214 ]. Furthermore, patients use Internet resources as an approach to learn regarding their diseases and therapies [ 215 ]. Patients have access to numerous social media platforms, however the safest and best information comes from the healthcare team. Various other trustworthy sources for information come from drug manufacturers, peer-reviewed journals, and organization websites. It is important to advise patients against looking for clarification on treatment-associated side effects from social media platforms [ 206 ].

Nursing and patient education on targeted therapies

Cancer treatment was previously disease-focused and was dependent on a pathologic diagnosis. Nowadays, therapeutic choices are dependent on the findings of molecular testing and targeted therapies are focused on certain mutations along the signaling pathways. Therefore, nurses need to have knowledge regarding the genetic mutations and signaling mechanisms that regulate the growth of cancer cells to comprehend the processes of targeted therapies. Nurses can identify the structures of MoAbs, the type of targeted therapies, and the target of the agent in the names of these agents. This knowledge can be used in symptom management and patient education that is specific to targeted therapies. In addition to the new information emergence regarding signaling mechanisms and newly identified actionable targets, more therapeutic agents will be studied and permitted for clinical uses. The order of utilizing therapeutic agents as resistance develops must be clarified to patients. Patients need to know and adhere to the regimens for maximum efficacy, when combinations of agents are utilized. In order to ensure patient safety and education, oncology nurses ought to continue to learn about each development [ 17 ]. It is challenging to provide care to patients taking oral targeted therapies owing to the shifting paradigm of monitoring cancer patients from traditional office visits during intravenous treatment to more periodic observation with oral administration. Therefore, patients have a greater level of responsibility in self-management. However, systemic therapy can be distressful for numerous patients [ 216 ].

This stress can exert negative effects on the capacity of patients to remember and understand educational content and is linked with poor health outcomes. Oncology nurses have a significant role in educating patients on the integration and management of cancer therapy as well as how to live with cancer. Indeed, nurse-led patient education can decrease stress and ameliorate patients’ level of understanding and knowledge regarding treatment [ 217 ]. In addition, patients require detailed instructions on treatment adherence, optimal dosing, the incidence of follow-up assessments and their accountability in setting up the delivery of refills to mediate safety, usage of supportive care agents, reporting and monitoring side effects, potential food and drug interactions, administration and safe handling of medications. Each oral anticancer agent might have specific administration guidelines. Moreover, foods can have substantial effects on the tolerance and bioavailability of numerous targeted therapies for the treatment of cancer. For example, first-generation EGFR inhibitors need to be administered on an empty stomach (at least 1 h before eating or 2 h after eating) and patients ought to be warned to avoid Seville oranges and grapefruit juice since they can increase the bloodstream level of targeted therapies and result in more extended, significant side effects. On the other hand, some targeted therapies need to be administered with water and food to minimize esophagitis and ameliorate bioavailability. Nurses need to have a better understanding regarding the unique administration instructions of targeted therapies so that patients can be appropriately advised [ 218 ].

Nurses should adapt both spoken and written education to the patients' language and level of health literacy [ 219 ]. Furthermore, nurses ought to involve caregivers in teaching and utilizing interpretation services for patients for whom English is a second language. The teach-back method is also useful in the case of targeted therapies which inspires patients to enthusiastically participate in the education via asking questions that can help nurses to evaluate patient understanding and learning [ 219 ]. Moreover, nurses might help with setting expectations setting, such as normalizing dose reductions or dose interruptions to manage toxicities, the timing of repeat liquid or solid biopsies to evaluate for acquired resistance mutations during the time of progression, and the continuance of drug past progression if still obtaining clinical benefit. Interestingly, the Multinational Association of Supportive Care in Cancer (MASCC) developed an effective MASCC Oral Agent Teaching Tool (MOATT) with the input of a pharmacist, nurse coordinators, and nurse experts to improve health professional, caregiver, and patient education surrounding these possible life-extending but toxic therapies. MOATT identifies that concurrent illness, culture, and age, as well as social and family support might affect education needs. Indeed, patient education is an ongoing and dynamic process and might involve the usage of authorized tools and reminder cues, brochures, and asking to provide feedback in order to ameliorate application and information retention. MOATT is now available in 12 languages and endorses that education sessions should be structured to evaluate the patient's comprehension regarding the information presented via questioning, review drug-specific instructions such as potential interactions, side effects, schedule, and doses, offer general information on remembering, disposal, handling, and storage to administer oral cancer therapies and how to report side effects, and assess understanding of patients regarding their diseases, current medications, treatment plan, and capacity to obtain and administer an oral cancer therapy [ 218 , 220 ].

Future directions

In terms of educating adult cancer patients receiving immunotherapy treatments, it is very important for these patients to learn and apply the newly learned teachings to their care. Indeed, immunotherapy and targeted therapy are quite new to nurses, caregivers, and patients. Therefore, it is crucial for nurses to understand the treatment plans, associated risks and side effects to provide care to patients on immunotherapy as well as targeted therapy and how these therapies are different from other standards of care. Moreover, a continuous collaboration is required between the nurses and caregiver/patient [ 206 ].

Conclusion

Continuous research in the field of cancer treatment has greatly increased cancer and the human immune system. A range of clinically effective immunotherapies and targeted therapies are now available in cancer treatment. The availability of these therapies has significantly increased the options of cancer treatment, particularly for chemorefractory patients. Nurses associated with the care of cancer patients can obtain benefits from an improved understanding of targeted therapies and immunotherapies, their efficacy profile, their mechanisms of action, as well as education of cancer patients. Moreover, owing to the variations in the mechanisms of action of the main groups of cancer immunotherapy and targeted therapy, as well as the heterogeneity of AEs, it is very important that nurses are familiar with the different AEs so that they can properly assess and manage those AEs and ameliorate patient outcomes. This approach will also result in an improved understanding of why certain patients develop AEs and how they can be anticipated and alleviated in cancer patients.

Funding

This research was funded by Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia (ISP22-8).

CRediT authorship contribution statement

Hamad Ghaleb Dailah: Supervision, Data curation, Conceptualization. Abdullah Abdu Hommdi: Formal analysis, Conceptualization. Mahdi Dafer Koriri: Data curation, Conceptualization. Essa Mohammed Algathlan: Writing – original draft, Data curation, Conceptualization. Syam Mohan: Writing – original draft, Supervision, Formal analysis, Conceptualization.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:The corresponding author of this manuscript is one of the associate editors If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

The authors extend their appreciation to the Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia for funding this research work through the project number ISP22-8.

References

1. Matthews H.K., Bertoli C., de Bruin R.A.M. Cell cycle control in cancer. Nat. Rev. Mol. Cell Biol. 2021;23:74–88. doi: 10.1038/s41580-021-00404-3. 2021 23:1.

2. Siegel R.L., Miller K.D., Fuchs H.E., Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72:7–33. doi: 10.3322/CAAC.21708.

3. Wilkes G. Targeted therapy: attacking cancer with molecular and immunological targeted agents. Asia Pac J Oncol Nurs. 2018;5:137. doi: 10.4103/APJON.APJON_79_17.

4. Wujcik D. Science and mechanism of action of targeted therapies in cancer treatment. Semin. Oncol. Nurs. 2014;30:139–146. doi: 10.1016/j.soncn.2014.05.002.

5. Luo Y., Sun X., Huang L., Yan J., Yu B.Y., Tian J. Artemisinin-based smart nanomedicines with self-supply of ferrous ion to enhance oxidative stress for specific and efficient cancer treatment. ACS Appl. Mater. Interfaces. 2019;11:29490–29497. doi: 10.1021/ACSAMI.9B07390/SUPPL_FILE/AM9B07390_SI_001.PDF.

6. Li D., Zhang J., Zhao X. vol. 39. 2021. pp. 675–684. (Mechanisms and Molecular Targets of Artemisinin in Cancer Treatment).

7. Abbott M., Ustoyev Y. Cancer and the immune system: the history and background of immunotherapy. Semin. Oncol. Nurs. 2019;35 doi: 10.1016/J.SONCN.2019.08.002.

8. Shahid K., Khalife M., Dabney R., Phan A.T. Immunotherapy and targeted therapy—the new roadmap in cancer treatment. Ann. Transl. Med. 2019;7 doi: 10.21037/ATM.2019.05.58. 595–595.

9. Strupeit S., Buß A., Dassen T. Effectiveness of nurse-delivered patient education interventions on quality of life in outpatients: a systematic review. Appl. Nurs. Res. 2013;26:232–238. doi: 10.1016/J.APNR.2013.08.004.

10. Baghban R., Roshangar L., Jahanban-Esfahlan R., Seidi K., Ebrahimi-Kalan A., Jaymand M., Kolahian S., Javaheri T., Zare P. Tumor microenvironment complexity and therapeutic implications at a glance. Cell Communication and Signaling 2020. 2020;18:1–19. doi: 10.1186/S12964-020-0530-4. 18:1.

11. Oh D.Y., Bang Y.J. HER2-Targeted therapies — a role beyond breast cancer. Nature Reviews Clinical Oncology 2019 17:1. 2019;17:33–48. doi: 10.1038/s41571-019-0268-3.

12. Ferguson F.M., Gray N.S. Kinase inhibitors: the road ahead. Nat. Rev. Drug Discov. 2018;17:353–377. doi: 10.1038/nrd.2018.21.

13. Tariman J.D. Changes in cancer treatment: mabs, mibs, mids, nabs, and nibs. Nurs. Clin. 2017;52:65–81. doi: 10.1016/j.cnur.2016.10.004.

14. Lee Y.T., Tan Y.J., Oon C.E. Molecular targeted therapy: treating cancer with specificity. Eur. J. Pharmacol. 2018;834:188–196. doi: 10.1016/J.EJPHAR.2018.07.034.

15. Xie Y.H., Chen Y.X., Fang J.Y. Comprehensive review of targeted therapy for colorectal cancer. Signal Transduction and Targeted Therapy 2020 5. 2020;1(5):1–30. doi: 10.1038/s41392-020-0116-z.

16. Zhang Q., Chen G., Liu X., Qian Q. Monoclonal antibodies as therapeutic agents in oncology and antibody gene therapy. Cell Research 2007 17. 2007;17:89–99. doi: 10.1038/sj.cr.7310143. 2.

17. Wujcik D. Science and mechanism of action of targeted therapies in cancer treatment. Semin. Oncol. Nurs. 2014;30:139–146. doi: 10.1016/J.SONCN.2014.05.002.

18. Tomasini P., Egea J., Souquet-Bressand M., Greillier L., Barlesi F. Alectinib in the treatment of ALK-positive metastatic non-small cell lung cancer: clinical trial evidence and experience with a focus on brain metastases. Ther. Adv. Respir. Dis. 2019;13 doi: 10.1177/1753466619831906.

19. Shaw A.T., Gandhi L., Gadgeel S., Riely G.J., Cetnar J., West H., Camidge D.R., Socinski M.A., Chiappori A., Mekhail T., et al. Phase 2 prospective analysis of alectinib in ALK-positive, crizotinib-resistant non-small-cell lung cancer. Lancet Oncol. 2016;17:234. doi: 10.1016/S1470-2045(15)00488-X.

20. Adv J., Oncol P., Beardslee T., Lawson J. Alectinib and brigatinib: new second-generation ALK inhibitors for the treatment of non–small cell lung cancer. J Adv Pract Oncol. 2018;9:94. doi: 10.6004/jadpro.2018.9.1.8.

21. Santarpia M., Daffinà M.G., D'Aveni A., Marabello G., Liguori A., Giovannetti E., Karachaliou N., Cao M.G., Rosell R., Altavilla G. Spotlight on ceritinib in the treatment of ALK+ NSCLC: design, development and place in therapy. Drug Des. Dev. Ther. 2017;11:2047. doi: 10.2147/DDDT.S113500.

22. Kazandjian D., Blumenthal G.M., Luo L., He K., Fran I., Lemery S., Pazdur R. Benefit-risk summary of crizotinib for the treatment of patients with ROS1 alteration-positive, metastatic non-small cell lung cancer. Oncol. 2016;21:974. doi: 10.1634/THEONCOLOGIST.2016-0101.

23. Chen R., Manochakian R., James L., Azzouqa A.G., Shi H., Zhang Y., Zhao Y., Zhou K., Lou Y. Emerging therapeutic agents for advanced non-small cell lung cancer. Journal of Hematology & Oncology 2020 13:1. 2020;13:1–23. doi: 10.1186/S13045-020-00881-7.

24. Yamaoka T., Kusumoto S., Ando K., Ohba M., Ohmori T. Receptor tyrosine kinase-targeted cancer therapy. Int. J. Mol. Sci. 2018;19 doi: 10.3390/IJMS19113491.

25. Wilkes G.M. Targeted therapy: attacking cancer with molecular and immunological targeted agents. Asia Pac J Oncol Nurs. 2018;5:137–155. doi: 10.4103/apjon.apjon_79_17.

26. Fischer A., Wu S., Ho A.L., Lacouture M.E. The risk of hand-foot skin reaction to axitinib, a novel vegf inhibitor: a systematic review of literature and meta-analysis. Invest. N. Drugs. 2013;31:787–797. doi: 10.1007/S10637-013-9927-X/FIGURES/4.

27. Schmidinger M., Danesi R. Management of adverse events associated with cabozantinib therapy in renal cell carcinoma. Oncol. 2018;23:306. doi: 10.1634/THEONCOLOGIST.2017-0335.

28. Gerendash B.S., Creel P.A. Practical management of adverse events associated with cabozantinib treatment in patients with renal-cell carcinoma. OncoTargets Ther. 2017;10:5053. doi: 10.2147/OTT.S145295.

29. Elisei R., Schlumberger M.J., Müller S.P., Schöffski P., Brose M.S., Shah M.H., Licitra L., Jarzab B., Medvedev V., Kreissl M.C., et al. Cabozantinib in progressive medullary thyroid cancer. J. Clin. Oncol. 2013;31:3639. doi: 10.1200/JCO.2012.48.4659.

30. Krajewska J., Olczyk T., Jarzab B. vol. 9. 2015. pp. 69–79. (Cabozantinib for the Treatment of Progressive Metastatic Medullary Thyroid Cancer).

31. Jeong W., Doroshow J.H., Kummar S. US FDA approved oral kinase inhibitors for the treatment of malignancies. Curr. Probl. Cancer. 2013;37:110. doi: 10.1016/J.CURRPROBLCANCER.2013.06.001.

32. Hao Z., Wang P. Lenvatinib in management of solid tumors. Oncol. 2020;25 doi: 10.1634/THEONCOLOGIST.2019-0407.

33. Cabanillas M.E., Takahashi S. Managing the adverse events associated with lenvatinib therapy in radioiodine-refractory differentiated thyroid cancer. Semin. Oncol. 2019;46:57–64. doi: 10.1053/J.SEMINONCOL.2018.11.004.

34. Chen Y.Y., Yeh C.N., Cheng C.T., Chen T.W., Rau K.M., Jan Y.Y., Chen M.F. Sunitinib for Taiwanese patients with gastrointestinal stromal tumor after imatinib treatment failure or intolerance. World J. Gastroenterol. : WJG. 2011;17:2113. doi: 10.3748/WJG.V17.I16.2113.

35. Brose M.S., Nutting C.M., Jarzab B., Elisei R., Siena S., Bastholt L., De La Fouchardiere C., Pacini F., Paschke R., Shong Y.K., et al. Sorafenib in locally advanced or metastatic, radioactive iodine-refractory, differentiated thyroid cancer: a randomized, double-blind, phase 3 trial. Lancet. 2014;384:319. doi: 10.1016/S0140-6736(14)60421-9.

36. Pitoia F., Jerkovich F. Selective use of sorafenib in the treatment of thyroid cancer. Drug Des. Dev. Ther. 2016;10:1119–1131. doi: 10.2147/DDDT.S82972.

37. Rodriguez, PharmD M. Ziv-aflibercept use in metastatic colorectal cancer. J Adv Pract Oncol. 2013;4:348. doi: 10.6004/JADPRO.2013.4.5.6.

38. Tang P.A., Moore M.J. Aflibercept in the treatment of patients with metastatic colorectal cancer: latest findings and interpretations. Therap Adv Gastroenterol. 2013;6:459. doi: 10.1177/1756283X13502637.

39. Wells S.A., Robinson B.G., Gagel R.F., Dralle H., Fagin J.A., Santoro M., Baudin E., Elisei R., Jarzab B., Vasselli J.R., et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J. Clin. Oncol. 2012;30:134. doi: 10.1200/JCO.2011.35.5040.

40. Thornton K., Kim G., Maher V.E., Chattopadhyay S., Tang S., Moon Y.J., Song P., Marathe A., Balakrishnan S., Zhu H., et al. Vandetanib for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease: U.S. Food and drug administration drug approval summary. Clin. Cancer Res. 2012;18:3722–3730. doi: 10.1158/1078-0432.CCR-12-0411/85048/AM/VANDETANIB-FOR-THE-TREATMENT-OF-SYMPTOMATIC-OR.

41. Li Q., Cheng L., Shen K., Jin H., Li H., Cheng Y., Ma X. Efficacy and safety of BcL-2 inhibitor venetoclax in hematological malignancy: a systematic review and meta-analysis of clinical trials. Front. Pharmacol. 2019;10:697. doi: 10.3389/FPHAR.2019.00697/BIBTEX.

42. Bonifacio M., Stagno F., Scaffidi L., Krampera M., Di Raimondo F. Management of chronic myeloid leukemia in advanced phase. Front. Oncol. 2019;9:1132. doi: 10.3389/FONC.2019.01132/BIBTEX.

43. Talpaz M., Shah N.P., Kantarjian H., Donato N., Nicoll J., Paquette R., Cortes J., O'Brien S., Nicaise C., Bleickardt E., et al. Dasatinib in imatinib-resistant Philadelphia chromosome–positive leukemias. N. Engl. J. Med. 2006;354:2531–2541. doi: 10.1056/NEJMOA055229/SUPPL_FILE/NEJM_TALPAZ_2531SA1.PDF.

44. Keam S.J. Dasatinib: in chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. BioDrugs. 2008;22:59–69. doi: 10.2165/00063030-200822010-00007/METRICS.

45. Dianne Pulte E., Chen H., Price L.S.L., Gudi R., Li H., Okusanya O.O., Ma L., Rodriguez L., Vallejo J., Norsworthy K.J., et al. FDA approval summary: revised indication and dosing regimen for ponatinib based on the results of the OPTIC trial. Oncol. 2022;27:149. doi: 10.1093/ONCOLO/OYAB040.

46. Cortes J.E., Apperley J.F., Deangelo D.J., Deininger M.W., Kota V.K., Rousselot P., Gambacorti-Passerini C. Management of adverse events associated with bosutinib treatment of chronic-phase chronic myeloid leukemia: expert panel review. J. Hematol. Oncol. 2018;11 doi: 10.1186/S13045-018-0685-2.

47. Daud A., Tsai K. Management of treatment-related adverse events with agents targeting the MAPK pathway in patients with metastatic melanoma. Oncol. 2017;22:823–833. doi: 10.1634/THEONCOLOGIST.2016-0456/-/DC1.

48. Patel H., Yacoub N., Mishra R., White A., Yuan L., Alanazi S., Garrett J.T. Current advances in the treatment of BRAF-mutant melanoma. Cancers. 2020;12:482. doi: 10.3390/CANCERS12020482. 2020, Vol. 12, Page 482.

49. Schmitt A.M., Dumas L., Larkin J. vol. 22. 2022. pp. 17–25. (Atezolizumab, Cobimetinib, and Vemurafenib as First-Line Treatment for Unresectable Metastatic BRAF V600 Mutated Melanoma).

50. Gutzmer R., Stroyakovskiy D., Gogas H., Robert C., Lewis K., Protsenko S., Pereira R.P., Eigentler T., Rutkowski P., Demidov L., et al. Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAFV600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020;395:1835–1844. doi: 10.1016/S0140-6736(20)30934-X.

51. Kreitman R.J., Moreau P., Ravandi F., Hutchings M., Gazzah A., Michallet A.S., Wainberg Z.A., Stein A., Dietrich S., de Jonge M.J.A., et al. Dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation–positive hairy cell leukemia. Blood. 2023 doi: 10.1182/BLOOD.2021013658/486621/DABRAFENIB-PLUS-TRAMETINIB-IN-PATIENTS-WITH.

52. Cabanillas M.E., Ryder M., Jimenez C. Targeted therapy for advanced thyroid cancer: kinase inhibitors and beyond. Endocr. Rev. 2019;40:1573–1604. doi: 10.1210/ER.2019-00007.

53. Ruan G.J., Hazim A., Abeykoon J.P., Scheckel C., Vassallo R., Ryu J.H., Tobin W.O., Koster M.J., Bennani N.N., Rech K.L., et al. Low-dose vemurafenib monotherapy in brafv600e-mutated erdheim-chester disease. Leuk. Lymphoma. 2020;61:2733. doi: 10.1080/10428194.2020.1783447.

54. Ghia P., Dlugosz-Danecka M., Scarfò L., Jurczak W. vol. 62. 2021. pp. 1066–1076. (Acalabrutinib: A Highly Selective, Potent Bruton Tyrosine Kinase Inhibitor for the Treatment of Chronic Lymphocytic Leukemia).

55. Abbas H.A., Wierda W.G. Acalabrutinib. A selective bruton tyrosine kinase inhibitor for the treatment of B-cell malignancies. Front. Oncol. 2021;11:1620. doi: 10.3389/FONC.2021.668162/BIBTEX.

56. Wang K., Xu Q., Zhong H. The bruton's tyrosine kinase inhibitor ibrutinib impairs the vascular development of zebrafish larvae. Front. Pharmacol. 2021;11:2361. doi: 10.3389/FPHAR.2020.625498/BIBTEX.

57. Davids M.S., Brown J.R. Ibrutinib. A first in class covalent inhibitor of bruton's tyrosine kinase. Future Oncol. 2014;10:957. doi: 10.2217/FON.14.51.

58. Göçer M., Kurtoğlu E. Safety and efficacy analysis of ibrutinib in 32 patients with CLL and various B-cell lymphomas: real-world Data from a single-center study in Turkey. Blood Res. 2020;55:206. doi: 10.5045/BR.2020.2020158.

59. Neven P., Rugo H.S., Tolaney S.M., Iwata H., Toi M., Goetz M.P., Kaufman P.A., Lu Y., Haddad N., Hurt K.C., et al. Abemaciclib plus fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in premenopausal women: subgroup analysis from the MONARCH 2 trial. Breast Cancer Res. 2021;23:1–10. doi: 10.1186/S13058-021-01463-2/TABLES/3.

60. Tolaney S.M., Beeram M., Beck J.T., Conlin A., Dees E.C., Puhalla S.L., Rexer B.N., Burris H.A., Jhaveri K., Helsten T., et al. Abemaciclib in combination with endocrine therapy for patients with hormone receptor-positive, HER2-negative metastatic breast cancer: a phase 1b study. Front. Oncol. 2022:11. doi: 10.3389/FONC.2021.810023/FULL.

61. Shah A.N., Metzger O., Bartlett C.H., Liu Y., Huang X., Cristofanilli M. Hormone receptor–positive/human epidermal growth receptor 2–negative metastatic breast cancer in young women: emerging Data in the era of molecularly targeted agents. Oncol. 2020;25 doi: 10.1634/THEONCOLOGIST.2019-0729.

62. Rascon K., Flajc G., De Angelis C., Liu X., Trivedi M.V., Ekinci E. vol. 53. 2018. (Ribociclib in HR+/HER2− Advanced or Metastatic Breast Cancer Patients). 501–509.

63. Parati M.C., Pedersini R., Perego G., Reduzzi R., Savio T., Cabiddu M., Borgonovo K., Ghilardi M., Luciani A., Petrelli F. Ribociclib in the treatment of hormone-receptor positive/HER2-negative advanced and early breast cancer: overview of clinical Data and patients selection. Breast Cancer. 2022;14:101. doi: 10.2147/BCTT.S341857.

64. Kim E.S., Scott L.J. Palbociclib: a review in HR-positive, HER2-negative, advanced or metastatic breast cancer. Targeted Oncol. 2017;12:373–383. doi: 10.1007/S11523-017-0492-7/TABLES/1.

65. Harvey R.D., Adams V.R., Beardslee T., Medina P. Afatinib for the treatment of EGFR mutation-positive NSCLC: a review of clinical findings. J. Oncol. Pharm. Pract. 2020;26:1461. doi: 10.1177/1078155220931926.

66. Yang J.C.H., Schuler M., Popat S., Miura S., Heeke S., Park K., Märten A., Kim E.S. Afatinib for the treatment of NSCLC harboring uncommon EGFR mutations: a database of 693 cases. J. Thorac. Oncol. 2020;15:803–815. doi: 10.1016/j.jtho.2019.12.126.

67. Harrison P.T., Vyse S., Huang P.H. Rare epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer. Semin. Cancer Biol. 2020;61:167. doi: 10.1016/J.SEMCANCER.2019.09.015.

68. Zhang T., Wan B., Zhao Y., Li C., Liu H., Lv T., Zhan P., Song Y. Treatment of uncommon EGFR mutations in non-small cell lung cancer: new evidence and treatment. Transl. Lung Cancer Res. 2019;8:302. doi: 10.21037/TLCR.2019.04.12.

69. Singh H., Walker A.J., Amiri-Kordestani L., Cheng J., Tang S., Balcazar P., Barnett-Ringgold K., Palmby T.R., Cao X., Zheng N., et al. U.S. Food and drug administration approval: neratinib for the extended adjuvant treatment of early-stage HER2-positive breast cancer. Clin. Cancer Res. 2018;24:3486–3491. doi: 10.1158/1078-0432.CCR-17-3628/73806/AM/U-S-FOOD-AND-DRUG-ADMINISTRATION-APPROVAL.

70. Opdam F.L., Guchelaar H.-J., Beijnen J.H., Schellens J.H.M. Lapatinib for advanced or metastatic breast cancer. Oncol. 2012;17:536. doi: 10.1634/THEONCOLOGIST.2011-0461.

71. Blackwell K.L., Pegram M.D., Tan-Chiu E., Schwartzberg L.S., Arbushites M.C., Maltzman J.D., Forster J.K., Rubin S.D., Stein S.H., Burstein H.J. Single-agent lapatinib for HER2-overexpressing advanced or metastatic breast cancer that progressed on first- or second-line trastuzumab-containing regimens. Ann. Oncol. 2009;20:1026–1031. doi: 10.1093/annonc/mdn759.

72. Nakashima K., Kimura M., Akamatsu H., Daga H., Imai H., Taira T., Ko R., Hisamatsu Y., Nishino K., Sugimoto T., et al. Osimertinib for patients with EGFR T790M mutation-positive non–small-cell lung cancer and a poor performance status. Jpn. J. Clin. Oncol. 2019;49:671–675. doi: 10.1093/JJCO/HYZ041.

73. Provencio M., Terrasa J., Garrido P., Campelo R.G., Aparisi F., Diz P., Aguiar D., García-Giron C., Hidalgo J., Aguado C., et al. Osimertinib in advanced EGFR-t790m mutation-positive non-small cell lung cancer patients treated within the special use medication program in Spain: OSIREX-Spanish lung cancer group. BMC Cancer. 2021;21:1–12. doi: 10.1186/S12885-021-07922-5/TABLES/4.

74. Szudy-Szczyrek A., Bachanek-Mitura O., Gromek T., Chromik K., Mital A., Szczyrek M., Krupski W., Szumiło J., Kanduła Z., Helbig G., et al. Real-world efficacy of midostaurin in aggressive systemic mastocytosis. J. Clin. Med. 2021;10:1–13. doi: 10.3390/JCM10051109.

75. Kayser S., Levis M.J., Schlenk R.F. vol. 10. 2017. pp. 1177–1189. (Midostaurin Treatment in FLT3-Mutated Acute Myeloid Leukemia and Systemic Mastocytosis).

76. Jain S., Song R., Xie J. Sonidegib: mechanism of action, pharmacology, and clinical utility for advanced basal cell carcinomas. OncoTargets Ther. 2017;10:1645. doi: 10.2147/OTT.S130910.

77. Ben Ishai M., Tiosano A., Fenig E., Ben Simon G., Yassur I. Outcomes of vismodegib for periocular locally advanced basal cell carcinoma from an open-label trial. JAMA Ophthalmol. 2020;138:749–755. doi: 10.1001/JAMAOPHTHALMOL.2020.1539.

78. Sekulic A., Migden M.R., Oro A.E., Dirix L., Lewis K.D., Hainsworth J.D., Solomon J.A., Yoo S., Arron S.T., Friedlander P.A., et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N. Engl. J. Med. 2012;366:2171. doi: 10.1056/NEJMOA1113713.

79. Bertrand N., Guerreschi P., Basset-Seguin N., Saiag P., Dupuy A., Dalac-Rat S., Dziwniel V., Depoortère C., Duhamel A., Mortier L. Vismodegib in neoadjuvant treatment of locally advanced basal cell carcinoma: first results of a multicenter, open-label, phase 2 trial (VISMONEO study): neoadjuvant vismodegib in locally advanced basal cell carcinoma. EClinicalMedicine. 2021;35 doi: 10.1016/j.eclinm.2021.100844.

80. Sawas A., Ma H., Shustov A., Hsu P., Bhat G., Acosta M., Horwitz S.M., O'Connor O.A. Belinostat induces high overall response rate (ORR) in patients with relapsed or refractory angioimmunoblastic T-cell lymphoma (AITL) Blood. 2019;134 doi: 10.1182/BLOOD-2019-127155. 4050–4050.

81. O'Connor O.A., Horwitz S., Masszi T., Van Hoof A., Brown P., Doorduijn J., Hess G., Jurczak W., Knoblauch P., Chawla S., et al. Belinostat in patients with relapsed or refractory peripheral T-cell lymphoma: results of the pivotal phase II BELIEF (CLN-19) study. J. Clin. Oncol. 2015;33:2492. doi: 10.1200/JCO.2014.59.2782.

82. Duvic M., Bates S.E., Piekarz R., Eisch R., Kim Y.H., Lerner A., Robak T., Samtsov A., Becker J.C., McCulloch W., et al. Responses to romidepsin in patients with cutaneous T-cell lymphoma and prior treatment with systemic chemotherapy. Leuk. Lymphoma. 2018;59:880–887. doi: 10.1080/10428194.2017.1361022/SUPPL_FILE/ILAL_A_1361022_SM6144.RTF.

83. Grant C., Rahman F., Piekarz R., Peer C., Frye R., Robey R.W., Gardner E.R., Figg W.D., Bates S.E. Romidepsin: a new therapy for cutaneous T-cell lymphoma and a potential therapy for solid tumors. Expert Rev. Anticancer Ther. 2010;10:997. doi: 10.1586/ERA.10.88.

84. Pan D., Mouhieddine T.H., Upadhyay R., Casasanta N., Lee A., Zubizarreta N., Moshier E., Richter J. Outcomes with panobinostat in heavily pretreated multiple myeloma patients. Blood. 2022;140:12483–12484. doi: 10.1182/BLOOD-2022-159806.

85. Moore D. Panobinostat (farydak): a novel option for the treatment of relapsed or relapsed and refractory multiple myeloma. Pharmacy and Therapeutics. 2016;41:296.

86. Duvic M., Vu J. Update on the treatment of cutaneous T-cell lymphoma (CTCL): focus on vorinostat. Biologics. 2007;1:377.

87. Stein E.M., DiNardo C.D., Pollyea D.A., Fathi A.T., Roboz G.J., Altman J.K., Stone R.M., Deangelo D.J., Levine R.L., Flinn I.W., et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130:722. doi: 10.1182/BLOOD-2017-04-779405.

88. de Botton S., Montesinos P., Schuh A.C., Papayannidis C., Vyas P., Wei A.H., Ommen H., Semochkin S., Kim H.J., Larson R.A., et al. Enasidenib vs conventional care in older patients with late-stage mutant-IDH2 relapsed/refractory AML: a randomized phase 3 trial. Blood. 2023;141:156–167. doi: 10.1182/BLOOD.2021014901.

89. Hudes G., Carducci M., Tomczak P., Dutcher J., Figlin R., Kapoor A., Staroslawska E., Sosman J., McDermott D., Bodrogi I., et al. vol. 356. 2007. pp. 2271–2281. (Temsirolimus, Interferon Alfa, or Both for Advanced Renal-Cell Carcinoma).

90. Dutcher J.P., De Souza P., McDermott D., Figlin R.A., Berkenblit A., Thiele A., Krygowski M., Strahs A., Feingold J., Hudes G. Effect of temsirolimus versus interferon-α on outcome of patients with advanced renal cell carcinoma of different tumor histologies. Med. Oncol. 2009;26:202–209. doi: 10.1007/S12032-009-9177-0/FIGURES/1.

91. Shen X.-B., Li G.-L., Zheng Y.-B., Chen Z.-H., Cao W.-M., Wang X.-J., Shao X.-Y. Combined everolimus and endocrine therapy in advanced HR-positive, HER2-negative Chinese breast cancer patients: a retrospective study. Ann. Transl. Med. 2021;9 doi: 10.21037/ATM-21-3840. 1334–1334.

92. Antolin A.A., Ameratunga M., Banerji U., Clarke P.A., Workman P., Al-Lazikani B. The kinase polypharmacology landscape of clinical PARP inhibitors. Scientific Reports 2020 10:1. 2020;(10):1–14. doi: 10.1038/s41598-020-59074-4.

93. Arora S., Balasubramaniam S., Zhang H., Berman T., Narayan P., Suzman D., Bloomquist E., Tang S., Gong Y., Sridhara R., et al. FDA approval summary: olaparib monotherapy or in combination with bevacizumab for the maintenance treatment of patients with advanced ovarian cancer. Oncol. 2021;26:e164. doi: 10.1002/ONCO.13551.

94. Scott L.J. Niraparib. First global approval. Drugs. 2017;77:1029–1034. doi: 10.1007/S40265-017-0752-Y/METRICS.

95. Kerliu L., Myruski S., Bhatti A., Soni P., Petrosius P., Pervanas H.C., Horton E.R. vol. 54. 2020. pp. 1010–1015. (Niraparib for the Treatment of Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer).

96. Dal Molin G.Z., Omatsu K., Sood A.K., Coleman R.L. Rucaparib in ovarian cancer: an update on safety, efficacy and place in therapy. Ther Adv Med Oncol. 2018;10 doi: 10.1177/1758835918778483.

97. Coleman R.L., Oza A.M., Lorusso D., Aghajanian C., Oaknin A., Dean A., Colombo N., Weberpals J.I., Clamp A., Scambia G., et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390:1949. doi: 10.1016/S0140-6736(17)32440-6.

98. Magagnoli M., Carlo-Stella C., Santoro A. 2020. Copanlisib for the Treatment of Adults with Relapsed Follicular Lymphoma; pp. 813–823.

99. Chauhan A.F., Cheson B.D. Copanlisib in the treatment of relapsed follicular lymphoma: utility and experience from the clinic. Cancer Manag. Res. 2021;13:677. doi: 10.2147/CMAR.S201024.

100. Bird S.T., Tian F., Flowers N., Przepiorka D., Wang R., Jung T.H., Kessler Z., Woods C., Kim B., Miller B.W., et al. Idelalisib for treatment of relapsed follicular lymphoma and chronic lymphocytic leukemia: a comparison of treatment outcomes in clinical trial participants vs medicare beneficiaries. JAMA Oncol. 2020;6:248. doi: 10.1001/JAMAONCOL.2019.3994.

101. Andorsky D., Chan R.J., Clark J., Ruzicka B., Robert N.J., Awan F.T. Treatment patterns and outcomes of patients with relapsed or refractory follicular lymphoma treated with idelalisib in a community oncology setting. Blood. 2019;134 doi: 10.1182/BLOOD-2019-124013. 2810–2810.

102. Raedler L. Velcade (bortezomib) receives 2 new FDA indications: for retreatment of patients with multiple myeloma and for first-line treatment of patients with mantle-cell lymphoma. Am Health Drug Benefits. 2015;8:135.

103. Robak P., Robak T. Bortezomib for the treatment of hematologic malignancies: 15 Years later. Drugs R. 2019;19:73–92. doi: 10.1007/S40268-019-0269-9/TABLES/6.

104. Facon T., Venner C.P., Bahlis N.J., Offner F., White D.J., Karlin L., Benboubker L., Rigaudeau S., Rodon P., Voog E., et al. Oral ixazomib, lenalidomide, and dexamethasone for transplant-ineligible patients with newly diagnosed multiple myeloma. Blood. 2021;137:3616. doi: 10.1182/BLOOD.2020008787.

105. Moreau P., Masszi T., Grzasko N., Bahlis N.J., Hansson M., Pour L., Sandhu I., Ganly P., Baker B.W., Jackson S.R., et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N. Engl. J. Med. 2016;374:1621–1634. doi: 10.1056/NEJMOA1516282/SUPPL_FILE/NEJMOA1516282_DISCLOSURES.PDF.

106. Raedler L.A. Kyprolis (carfilzomib) received new indications as combination therapy for use in relapsed and/or refractory multiple myeloma. Am Health Drug Benefits. 2016;9:93.

107. Usmani S.Z., Quach H., Mateos M.V., Landgren O., Leleu X., Siegel D., Weisel K., Gavriatopoulou M., Oriol A., Rabin N., et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): updated outcomes from a randomised, multicentre, open-label, phase 3 study. Lancet Oncol. 2022;23:65–76. doi: 10.1016/S1470-2045(21)00579-9.

108. Slaney C.Y., Kershaw M.H., Darcy P.K. Trafficking of T Cells into tumors. Cancer Res. 2014;74:7168–7174. doi: 10.1158/0008-5472.CAN-14-2458/660511/P/TRAFFICKING-OF-T-CELLS-INTO-TUMORSTRAFFICKING-OF-T.

109. Hughes P.E., Caenepeel S., Wu L.C. Targeted therapy and checkpoint immunotherapy combinations for the treatment of cancer. Trends Immunol. 2016;37:462–476. doi: 10.1016/J.IT.2016.04.010.

110. Gasparri M.L., Ruscito I., Taghavi K., Farooqi A.A., Papadia A., Focaccetti C., Barnaba V., Panici P.B., Mueller M.D. The immunobiology of cancer: from tumor escape to cancer immunoediting towards immunotherapy in gynecologic oncology. Mol. Oncol.: Underlying Mechanisms and Translational Advancements. 2017:193–204. doi: 10.1007/978-3-319-53082-6_9.

111. Chen D.S., Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1–10. doi: 10.1016/J.IMMUNI.2013.07.012.

112. Muller W.A. Localized signals that regulate transendothelial migration. Curr. Opin. Immunol. 2016;38:24–29. doi: 10.1016/J.COI.2015.10.006.

113. Garcia C.A., El-Ali A., Rath T.J., Contis L.C., Gorantla V., Drappatz J., Davar D. Neurologic immune-related adverse events associated with adjuvant ipilimumab: report of two cases. J Immunother Cancer. 2018;6:1–6. doi: 10.1186/S40425-018-0393-Z/TABLES/2.

114. Twomey J.D., Zhang B. Cancer immunotherapy update: FDA-approved checkpoint inhibitors and companion diagnostics. AAPS J. 2021;23:1–11. doi: 10.1208/S12248-021-00574-0/FIGURES/2.

115. Wang M., Ma X., Guo L., Xia F. Safety and efficacy profile of pembrolizumab in solid cancer: pooled reanalysis based on randomized controlled trials. Drug Des. Dev. Ther. 2017;11:2851. doi: 10.2147/DDDT.S146286.

116. Chang E., Pelosof L., Lemery S., Gong Y., Goldberg K.B., Farrell A.T., Keegan P., Veeraraghavan J., Wei G., Blumenthal G.M., et al. Systematic review of PD‐1/PD‐L1 inhibitors in oncology: from personalized medicine to public health. Oncol. 2021;26 doi: 10.1002/ONCO.13887.

117. Almutairi A.R., McBride A., Slack M., Erstad B.L., Abraham I. Potential immune-related adverse events associated with monotherapy and combination therapy of ipilimumab, nivolumab, and pembrolizumab for advanced melanoma: a systematic review and meta-analysis. Front. Oncol. 2020;10 doi: 10.3389/FONC.2020.00091/BIBTEX.

118. Rotte A. Combination of CTLA-4 and PD-1 blockers for treatment of cancer. J. Exp. Clin. Cancer Res. 2019;38:1–12. doi: 10.1186/S13046-019-1259-Z. 2019 38:1.

119. Postow M.A., Sidlow R., Hellmann M.D. Immune-related adverse events associated with immune checkpoint blockade. N. Engl. J. Med. 2018;378:158–168. doi: 10.1056/NEJMRA1703481/SUPPL_FILE/NEJMRA1703481_DISCLOSURES.PDF.

120. Socinski M.A., Jotte R.M., Cappuzzo F., Nishio M., Mok T.S.K., Reck M., Finley G.G., Kaul M.D., Yu W., Paranthaman N., et al. Association of immune-related adverse events with efficacy of atezolizumab in patients with non–small cell lung cancer: pooled analyses of the phase 3 IMpower130, IMpower132, and IMpower150 randomized clinical trials. JAMA Oncol. 2023;9:527. doi: 10.1001/JAMAONCOL.2022.7711.

121. Montenegro G.B., Serzan M., Belouali A., Sackstein P., Chen K., Rao S., Veytsman I., Madhavan S., Liu S., Kim C. Immune-related adverse events with durvalumab consolidation in a real-world cohort of patients with non–small cell lung cancer (NSCLC) J. Thorac. Oncol. 2021;16:S366. doi: 10.1016/j.jtho.2021.01.587.

122. Ugolini H., Bryan J., Hennessy M., Kaufman H.L., D'Angelo S.P. vol. 23. 2019. pp. E1–E9. (Avelumab Immunotherapy: Management of Adverse Events Associated with New Treatment for Merkel Cell Carcinoma). Number 1/February 2019.

123. Hernández-López A., Téllez-González M.A., Mondragón-Terán P., Meneses-Acosta A. Chimeric antigen receptor-T cells: a pharmaceutical scope. Front. Pharmacol. 2021:12. doi: 10.3389/FPHAR.2021.720692.

124. Sharma P., Kanapuru B., George B., Lin X., Xu Z., Bryan W.W., Pazdur R., Theoret M.R. FDA approval summary: idecabtagene vicleucel for relapsed or refractory multiple myeloma. Clin. Cancer Res. 2022;28:1759. doi: 10.1158/1078-0432.CCR-21-3803.

125. Xiong F., Wang Q., Wu G. hua, Liu W. zheng, Wang B., Chen Y. Jun direct and indirect effects of IFN-Α2b in malignancy treatment: not only an archer but also an arrow. Biomark. Res. 2022:10. doi: 10.1186/S40364-022-00415-Y.

126. Ningrum R.A. Human interferon alpha-2b: a therapeutic protein for cancer treatment. Scientifica (Cairo) 2014. 2014:1–8. doi: 10.1155/2014/970315.

127. Alva A., Daniels G.A., Wong M.K.K., Kaufman H.L., Morse M.A., McDermott D.F., Clark J.I., Agarwala S.S., Miletello G., Logan T.F., et al. Contemporary experience with high-dose interleukin-2 therapy and impact on survival in patients with metastatic melanoma and metastatic renal cell carcinoma. Cancer Immunol. Immunother. 2016;65:1533. doi: 10.1007/S00262-016-1910-X.

128. Buchbinder E.I., Dutcher J.P., Daniels G.A., Curti B.D., Patel S.P., Holtan S.G., Miletello G.P., Fishman M.N., Gonzalez R., Clark J.I., et al. Therapy with high-dose interleukin-2 (HD IL-2) in metastatic melanoma and renal cell carcinoma following PD1 or PDL1 inhibition. J Immunother Cancer. 2019;7:1–7. doi: 10.1186/S40425-019-0522-3/FIGURES/2.

129. Wargowski E., Johnson L.E., Eickhoff J.C., Delmastro L., Staab M.J., Liu G., McNeel D.G. Prime-boost vaccination targeting prostatic acid phosphatase (PAP) in patients with metastatic castration-resistant prostate cancer (MCRPC) using sipuleucel-T and a DNA vaccine. J Immunother Cancer. 2018;6:1–12. doi: 10.1186/S40425-018-0333-Y/FIGURES/6.

130. Pol J., Kroemer G., Galluzzi L. First oncolytic virus approved for melanoma immunotherapy. OncoImmunology. 2016;5 doi: 10.1080/2162402X.2015.1115641.

131. Baysal H., De Pauw I., Zaryouh H., Peeters M., Vermorken J.B., Lardon F., De Waele J., Wouters A. The right partner in crime: unlocking the potential of the anti-EGFR antibody cetuximab via combination with natural killer cell chartering immunotherapeutic strategies. Front. Immunol. 2021;12:3627. doi: 10.3389/FIMMU.2021.737311/BIBTEX.

132. Jacobs S.A. 90Yttrium ibritumomab tiuxetan in the treatment of non-hodgkin’s lymphoma: current status and future prospects. Biologics. 2007;1:215.

133. Warner J.L., Arnason J.E. Alemtuzumab use in relapsed and refractory chronic lymphocytic leukemia: a history and discussion of future rational use. Ther Adv Hematol. 2012;3:375. doi: 10.1177/2040620712458949.

134. Nami B., Maadi H., Wang Z. Mechanisms underlying the action and synergism of trastuzumab and pertuzumab in targeting HER2-positive breast cancer. Cancers. 2018;10 doi: 10.3390/CANCERS10100342.

135. Bradley R., Braybrooke J., Gray R., Hills R., Liu Z., Peto R., Davies L., Dodwell D., McGale P., Pan H., et al. Trastuzumab for early-stage, HER2-positive breast cancer: a meta-analysis of 13 864 women in seven randomised trials. Lancet Oncol. 2021;22:1139–1150. doi: 10.1016/S1470-2045(21)00288-6.

136. Savoia P., Astrua C., Fava P. Ipilimumab (Anti-Ctla-4 mab) in the treatment of metastatic melanoma: effectiveness and toxicity management. Hum. Vaccines Immunother. 2016;12:1092. doi: 10.1080/21645515.2015.1129478.

137. Li Q.H., Wang Y.Z., Tu J., Liu C.W., Yuan Y.J., Lin R., He W.L., Cai S.R., He Y.L., Ye J.N. Anti-EGFR therapy in metastatic colorectal cancer: mechanisms and potential regimens of drug resistance. Gastroenterol Rep (Oxf) 2020;8:179–191. doi: 10.1093/GASTRO/GOAA026.

138. Oza A.M., Dubois F., Hegg R., Hernández C.A., Finocchiaro G., Ghiringhelli F., Zamagni C., Nick S., Irahara N., Perretti T., et al. A long‐term extension study of bevacizumab in patients with solid tumors. Oncol. 2021;26:e2254. doi: 10.1002/ONCO.13971.

139. Cvetković R.S., Perry C.M. Spotlight on rituximab in non-hodgkin lymphoma and chronic lymphocytic leukemia. BioDrugs. 2006;20:253–257. doi: 10.2165/00063030-200620040-00006/METRICS.

140. Sandhu S., Mulligan S.P. Ofatumumab and its role as immunotherapy in chronic lymphocytic leukemia. Haematologica. 2015;100:411. doi: 10.3324/HAEMATOL.2015.124107.

141. Andemariam B., Leonard J.P., Rm S.B. Radioimmunotherapy with tositumomab and iodine-131 tositumomab for non-hodgkin’s lymphoma. Biologics. 2007;1:113.

142. Kottschade L.A. The future of immunotherapy in the treatment of cancer. Semin. Oncol. Nurs. 2019;35 doi: 10.1016/j.soncn.2019.08.013.

143. Markovic S.N., Suman V.J., Ingle J.N., Kaur J.S., Pitot H.C., Loprinzi C.L., Rao R.D., Creagan E.T., Pittelkow M.R., Allred J.B., et al. Peptide vaccination of patients with metastatic melanoma: improved clinical outcome in patients demonstrating effective immunization. Am. J. Clin. Oncol. 2006;29 doi: 10.1097/01.coc.0000217877.78473.a4.

144. Andtbacka R.H.I., Kaufman H.L., Collichio F., Amatruda T., Senzer N., Chesney J., Delman K.A., Spitler L.E., Puzanov I., Agarwala S.S., et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J. Clin. Oncol. 2015;33:2780–2788. doi: 10.1200/jco.2014.58.3377.

145. Andtbacka R.H.I., Collichio F., Harrington K.J., Middleton M.R., Downey G., Ӧhrling K., Kaufman H.L. Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III–iv melanoma. J Immunother Cancer. 2019;7:145. doi: 10.1186/s40425-019-0623-z.

146. Karabajakian A., Reverdy T., Gau M., Fayette J. vol. 14. 2017. pp. 603–609. (Nivolumab in Recurrent/Metastatic Head and Neck Cancers).

147. Cohen E.E.W., Soulières D., Le Tourneau C., Dinis J., Licitra L., Ahn M.J., Soria A., Machiels J.P., Mach N., Mehra R., et al. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet. 2019;393:156–167. doi: 10.1016/S0140-6736(18)31999-8.

148. Shah M.A., Kojima T., Hochhauser D., Enzinger P., Raimbourg J., Hollebecque A., Lordick F., Kim S.B., Tajika M., Kim H.T., et al. Efficacy and safety of pembrolizumab for heavily pretreated patients with advanced, metastatic adenocarcinoma or squamous cell carcinoma of the esophagus: the phase 2 KEYNOTE-180 study. JAMA Oncol. 2019;5:546. doi: 10.1001/JAMAONCOL.2018.5441.

149. Janjigian Y.Y., Kawazoe A., Yañez P., Li N., Lonardi S., Kolesnik O., Barajas O., Bai Y., Shen L., Tang Y., et al. The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature. 2021;600:727–730. doi: 10.1038/s41586-021-04161-3.

150. Hodi F.S., O'Day S.J., McDermott D.F., Weber R.W., Sosman J.A., Haanen J.B., Gonzalez R., Robert C., Schadendorf D., Hassel J.C., et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 2010;363:711–723. doi: 10.1056/NEJMoa1003466.

151. Brahmer J., Reckamp K.L., Baas P., Crinò L., Eberhardt W.E.E., Poddubskaya E., Antonia S., Pluzanski A., Vokes E.E., Holgado E., et al. Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer. N. Engl. J. Med. 2015;373:123–135. doi: 10.1056/NEJMoa1504627.

152. Brahmer J.R., Tykodi S.S., Chow L.Q.M., Hwu W.-J., Topalian S.L., Hwu P., Drake C.G., Camacho L.H., Kauh J., Odunsi K., et al. Safety and activity of anti–PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 2012;366:2455–2465. doi: 10.1056/NEJMoa1200694.

153. Luke J.J., Ott P.A. PD-1 pathway inhibitors: the next generation of immunotherapy for advanced melanoma. Oncotarget. 2015;6(6) doi: 10.18632/oncotarget.2980.

154. Ott P.A., Hodi F.S., Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin. Cancer Res. 2013;19:5300–5309. doi: 10.1158/1078-0432.CCR-13-0143.

155. Postow M.A., Callahan M.K., Wolchok J.D. Immune checkpoint blockade in cancer therapy. J. Clin. Oncol. 2015;33:1974–1982. doi: 10.1200/JCO.2014.59.4358.

156. Robert C., Ribas A., Wolchok J.D., Hodi F.S., Hamid O., Kefford R., Weber J.S., Joshua A.M., Hwu W.-J., Gangadhar T.C., et al. Anti-Programmed-Death-Receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014;384:1109–1117. doi: 10.1016/S0140-6736(14)60958-2.

157. Robert C., Schachter J., Long G.V., Arance A., Grob J.J., Mortier L., Daud A., Carlino M.S., McNeil C., Lotem M., et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 2015;372:2521–2532. doi: 10.1056/NEJMoa1503093.

158. Robert C., Long G.V., Brady B., Dutriaux C., Maio M., Mortier L., Hassel J.C., Rutkowski P., McNeil C., Kalinka-Warzocha E., et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 2014;372:320–330. doi: 10.1056/NEJMoa1412082.

159. Larkin J., Chiarion-Sileni V., Gonzalez R., Grob J.J., Cowey C.L., Lao C.D., Schadendorf D., Dummer R., Smylie M., Rutkowski P., et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 2015;373:23–34. doi: 10.1056/NEJMoa1504030.

160. Postow M.A., Chesney J., Pavlick A.C., Robert C., Grossmann K., McDermott D., Linette G.P., Meyer N., Giguere J.K., Agarwala S.S., et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N. Engl. J. Med. 2015;372:2006–2017. doi: 10.1056/NEJMoa1414428.

161. Rizvi N.A., Hellmann M.D., Brahmer J.R., Juergens R.A., Borghaei H., Gettinger S., Chow L.Q., Gerber D.E., Laurie S.A., Goldman J.W., et al. Nivolumab in combination with platinum‐based doublet chemotherapy for first-line treatment of advanced non–small-cell lung cancer. J. Clin. Oncol. 2016;34:2969–2979. doi: 10.1200/JCO.2016.66.9861.

162. Wolchok J.D., Chiarion-Sileni V., Gonzalez R., Rutkowski P., Grob J.-J., Cowey C.L., Lao C.D., Wagstaff J., Schadendorf D., Ferrucci P.F., et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 2017;377:1345–1356. doi: 10.1056/NEJMoa1709684.

163. Hammers H.J., Plimack E.R., Infante J.R., Rini B.I., McDermott D.F., Lewis L.D., Voss M.H., Sharma P., Pal S.K., Razak A.R.A., et al. Safety and efficacy of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: the CheckMate 016 study. J. Clin. Oncol. 2017;35:3851–3858. doi: 10.1200/JCO.2016.72.1985.

164. Eggermont A.M.M., Chiarion-Sileni V., Grob J.-J., Dummer R., Wolchok J.D., Schmidt H., Hamid O., Robert C., Ascierto P.A., Richards J.M., et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (eortc 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015;16:522–530. doi: 10.1016/S1470-2045(15)70122-1.

165. Weber J., Mandala M., Del Vecchio M., Gogas H.J., Arance A.M., Cowey C.L., Dalle S., Schenker M., Chiarion-Sileni V., Marquez-Rodas I., et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N. Engl. J. Med. 2017;377:1824–1835. doi: 10.1056/NEJMoa1709030.

166. Eggermont A.M.M., Robert C., Suciu S. Adjuvant pembrolizumab in resected stage III melanoma. N. Engl. J. Med. 2018;379:593–595. doi: 10.1056/nejmc1807505.

167. Ascierto P.A., Bono P., Bhatia S., Melero I., Nyakas M.S., Svane I.-M., Larkin J., Gomez-Roca C., Schadendorf D., Dummer R., et al. Combination with Nivolumab in Pts with Melanoma Who Progressed during Prior Anti–PD-1/pd-L1 Therapy (Mel Prior IO) in All-Comer and Biomarker-Enrich. Annals of Oncology; 2017. Efficacy of BMS-986016, a monoclonal antibody that targets lymphocyte activation gene-3 (LAG-3) pp. v611–v612. 28.

168. Choi J., Lee S.Y. Clinical characteristics and treatment of immune-related adverse events of immune checkpoint inhibitors. Immune Netw. 2020:20. doi: 10.4110/IN.2020.20.E9.

169. Vanneman M., Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat. Rev. Cancer. 2012;12:237–251. doi: 10.1038/nrc3237.

170. McDermott D., Lebbé C., Hodi F.S., Maio M., Weber J.S., Wolchok J.D., Thompson J.A., Balch C.M. Durable benefit and the potential for long-term survival with immunotherapy in advanced melanoma. Cancer Treat Rev. 2014;40:1056–1064. doi: 10.1016/j.ctrv.2014.06.012.

171. Cooper Z.A., Juneja V.R., Sage P.T., Frederick D.T., Piris A., Mitra D., Lo J.A., Hodi F.S., Freeman G.J., Bosenberg M.W., et al. Response to BRAF inhibition in melanoma is enhanced when combined with immune checkpoint blockade. Cancer Immunol. Res. 2014;2:643. doi: 10.1158/2326-6066.CIR-13-0215.

172. Wargo J.A., Reuben A., Cooper Z.A., Oh K.S., Sullivan R.J. Immune effects of chemotherapy, radiation, and targeted therapy and opportunities for combination with immunotherapy. Semin. Oncol. 2015;42:601. doi: 10.1053/J.SEMINONCOL.2015.05.007.

173. Vo D.D., Prins R.M., Begley J.L., Donahue T.R., Morris L.F., Bruhn K.W., de la Rocha P., Yang M.-Y., Mok S., Garban H.J., et al. Enhanced antitumor activity induced by adoptive T-cell transfer and adjunctive use of the histone deacetylase inhibitor LAQ824. Cancer Res. 2009;69:8693–8699. doi: 10.1158/0008-5472.CAN-09-1456.

174. Christiansen A.J., West A., Banks K.-M., Haynes N.M., Teng M.W., Smyth M.J., Johnstone R.W. Eradication of solid tumors using histone deacetylase inhibitors combined with immune-stimulating antibodies. Proc. Natl. Acad. Sci. USA. 2011;108:4141–4146. doi: 10.1073/pnas.1011037108.

175. Brogdon J.L., Xu Y., Szabo S.J., An S., Buxton F., Cohen D., Huang Q. Histone deacetylase activities are required for innate immune cell control of Th1 but not Th2 effector cell function. Blood. 2007;109:1123–1130. doi: 10.1182/BLOOD-2006-04-019711.

176. Reilly C.M., Mishra N., Miller J.M., Joshi D., Ruiz P., Richon V.M., Marks P.A., Gilkeson G.S. Modulation of renal disease in MRL/lpr mice by suberoylanilide hydroxamic acid. J. Immunol. 2004;173:4171–4178. doi: 10.4049/JIMMUNOL.173.6.4171.

177. Johnson J., Pahuja A., Graham M., Hering B., Hancock W.W., Bansal-Pakala P. Effects of histone deacetylase inhibitor SAHA on effector and FOXP3+Regulatory T cells in rhesus macaques. Transplant. Proc. 2008;40:459–461. doi: 10.1016/J.TRANSPROCEED.2008.01.039.

178. Tao R., De Zoeten E.F., Özkaynak E., Chen C., Wang L., Porrett P.M., Li B., Turka L.A., Olson E.N., Greene M.I., et al. Deacetylase inhibition promotes the generation and function of regulatory T cells. Nature Medicine 2007 13:11. 2007;(13):1299–1307. doi: 10.1038/nm1652.

179. Kato Y., Yoshimura K., Shin T., Verheul H., Hammers H., Sanni T.B., Salumbides B.C., Van Erp K., Schulick R., Pili R. Synergistic in vivo antitumor effect of the histone deacetylase inhibitor MS-275 in combination with interleukin 2 in a murine model of renal cell carcinoma. Clin. Cancer Res. 2007;13:4538–4546. doi: 10.1158/1078-0432.CCR-07-0014.

180. Ribas A., Wolchok J.D. Combining cancer immunotherapy and targeted therapy. Curr. Opin. Immunol. 2013;25:291–296. doi: 10.1016/J.COI.2013.02.011.

181. Heidorn S.J., Milagre C., Whittaker S., Nourry A., Niculescu-Duvas I., Dhomen N., Hussain J., Reis-Filho J.S., Springer C.J., Pritchard C., et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. 2010;140:209–221. doi: 10.1016/J.CELL.2009.12.040.

182. Poulikakos P.I., Zhang C., Bollag G., Shokat K.M., Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 2010 464:7287. 2010;464:427–430. doi: 10.1038/nature08902.

183. Halaban R., Zhang W., Bacchiocchi A., Cheng E., Parisi F., Ariyan S., Krauthammer M., McCusker J.P., Kluger Y., Sznol M. PLX4032, a selective BRAFV600E kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAFWT melanoma cells. Pigment Cell Melanoma Res. 2010;23:190–200. doi: 10.1111/J.1755-148X.2010.00685.X.

184. Su F., Viros A., Milagre C., Trunzer K., Bollag G., Spleiss O., Reis-Filho J.S., Kong X., Koya R.C., Flaherty K.T., et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N. Engl. J. Med. 2012;366:207–215. doi: 10.1056/NEJMOA1105358/SUPPL_FILE/NEJMOA1105358_DISCLOSURES.PDF.

185. Callahan M.K., Rampal R., Harding J.J., Klimek V.M., Chung Y.R., Merghoub T., Wolchok J.D., Solit D.B., Rosen N., Abdel-Wahab O., et al. Progression of RAS-mutant leukemia during RAF inhibitor treatment. N. Engl. J. Med. 2012;367:2316–2321. doi: 10.1056/NEJMOA1208958/SUPPL_FILE/NEJMOA1208958_DISCLOSURES.PDF.

186. Oberholzer P.A., Kee D., Dziunycz P., Sucker A., Kamsukom N., Jones R., Roden C., Chalk C.J., Ardlie K., Palescandolo E., et al. RAS mutations are associated with the development of cutaneous squamous cell tumors in patients treated with RAF inhibitors. J. Clin. Oncol. 2012;30:316. doi: 10.1200/JCO.2011.36.7680.

187. Koya R.C., Mok S., Otte N., Blacketor K.J., Comin-Anduix B., Tumeh P.C., Minasyan A., Graham N.A., Graeber T.G., Chodon T., et al. BRAF inhibitor vemurafenib improves the antitumor activity of adoptive cell immunotherapy. Cancer Res. 2012;72:3928–3937. doi: 10.1158/0008-5472.CAN-11-2837.

188. Li Q., Rao R.R., Araki K., Pollizzi K., Odunsi K., Powell J.D., Shrikant P.A. A central role for MTOR kinase in homeostatic proliferation induced CD8+ T cell memory and tumor immunity. Immunity. 2011;34:541–553. doi: 10.1016/j.immuni.2011.04.006.

189. Rao R.R., Li Q., Odunsi K., Shrikant P.A. The MTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet and eomesodermin. Immunity. 2010;32:67–78. doi: 10.1016/j.immuni.2009.10.010.

190. Araki K., Turner A.P., Shaffer V.O., Gangappa S., Keller S.A., Bachmann M.F., Larsen C.P., Ahmed R. MTOR regulates memory CD8 T-cell differentiation. Nature. 2009;460:108–112. doi: 10.1038/nature08155.

191. Srivastava, R.K.; Utley, A.; Shrikant, P.A. Rapamycin. https://doi.org/10.4161/onci.20663 2012, 1, 1189–1190, doi:10.4161/ONCI.20663.

192. Parsa A.T., Waldron J.S., Panner A., Crane C.A., Parney I.F., Barry J.J., Cachola K.E., Murray J.C., Tihan T., Jensen M.C., et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat. Med. 2006;13:84–88. doi: 10.1038/nm1517. 2006 13:1.

193. Marshall N.A., Galvin K.C., Corcoran A.-M.B., Boon L., Higgs R., Mills K.H.G. Immunotherapy with PI3K inhibitor and toll-like receptor agonist induces IFN-Γ+IL-17+ polyfunctional T cells that mediate rejection of murine tumors. Cancer Res. 2012;72:581–591. doi: 10.1158/0008-5472.CAN-11-0307.

194. Borg C., Terme M., Taïeb J., Ménard C., Flament C., Robert C., Maruyama K., Wakasugi H., Angevin E., Thielemans K., et al. Novel mode of action of C-kit tyrosine kinase inhibitors leading to NK cell–dependent antitumor effects. J. Clin. Invest. 2004;114:379–388. doi: 10.1172/JCI21102.

195. Taieb J., Chaput N., Ménard C., Apetoh L., Ullrich E., Bonmort M., Péquignot M., Casares N., Terme M., Flament C., et al. A novel dendritic cell subset involved in tumor immunosurveillance. Nature Medicine 2006 12:2. 2006;12:214–219. doi: 10.1038/nm1356.

196. Balachandran V.P., Cavnar M.J., Zeng S., Bamboat Z.M., Ocuin L.M., Obaid H., Sorenson E.C., Popow R., Ariyan C., Rossi F., et al. Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido. Nat. Med. 2011;17:1094–1100. doi: 10.1038/nm.2438.

197. Yang Y., Liu C., Peng W., Lizée G., Overwijk W.W., Liu Y., Woodman S.E., Hwu P. Antitumor T-cell responses contribute to the effects of dasatinib on c-KIT mutant murine mastocytoma and are potentiated by anti-OX40. Blood. 2012;120:4533–4543. doi: 10.1182/BLOOD-2012-02-407163.

198. Bae J., Mitsiades C., Tai Y.-T., Bertheau R., Shammas M., Batchu R.B., Li C., Catley L., Prabhala R., Anderson K.C., et al. Phenotypic and functional effects of heat shock protein 90 inhibition on dendritic cell. J. Immunol. 2007;178:7730–7737. doi: 10.4049/JIMMUNOL.178.12.7730.

199. Yun T.J., Harning E.K., Giza K., Rabah D., Li P., Arndt J.W., Luchetti D., Biamonte M.A., Shi J., Lundgren K., et al. EC144, a synthetic inhibitor of heat shock protein 90, blocks innate and adaptive immune responses in models of inflammation and autoimmunity. J. Immunol. 2011;186:563–575. doi: 10.4049/JIMMUNOL.1000222.

200. Wang Y., Wang X.Y., Subjeck J.R., Shrikant P.A., Kim H.L. Temsirolimus, an MTOR inhibitor, enhances anti-tumour effects of heat shock protein cancer vaccines. Br. J. Cancer. 2011;104:643. doi: 10.1038/BJC.2011.15.

201. Feng X., Yan J., Wang Y., Zierath J.R., Nordenskjöld M., Henter J.I., Fadeel B., Zheng C. The proteasome inhibitor bortezomib disrupts tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression and natural killer (NK) cell killing of TRAIL receptor-positive multiple myeloma cells. Mol. Immunol. 2010;47:2388–2396. doi: 10.1016/J.MOLIMM.2010.05.003.

202. Wang X., Ottosson A., Ji C., Feng X., Nordenskjöld M., Henter J.I., Fadeel B., Zheng C. Proteasome inhibition induces apoptosis in primary human natural killer cells and suppresses NKp46-mediated cytotoxicity. Haematologica. 2009;94:470. doi: 10.3324/HAEMATOL.13783.

203. Rossi L.E., Avila D.E., Spallanzani R.G., Ziblat A., Fuertes M.B., Lapyckyj L., Croci D.O., Rabinovich G.A., Domaica C.I., Zwirner N.W. Histone deacetylase inhibitors impair NK cell viability and effector functions through inhibition of activation and receptor expression. J. Leukoc. Biol. 2012;91:321–331. doi: 10.1189/JLB.0711339.

204. Dranoff G. Experimental mouse tumour models: what can Be learnt about human cancer immunology? Nat. Rev. Immunol. 2011;12:61–66. doi: 10.1038/nri3129. 2011 12:1.

205. Kocak E., Lute K., Chang X., May K.F., Exten K.R., Zhang H., Abdessalam S.F., Lehman A.M., Jarjoura D., Zheng P., et al. Combination therapy with anti–CTL antigen-4 and anti-4-1BB antibodies enhances cancer immunity and reduces autoimmunity. Cancer Res. 2006;66:7276–7284. doi: 10.1158/0008-5472.CAN-05-2128.

206. Lasa-Blandon M., Stasi K., Hehir A., Fischer-Cartlidge E. Patient education issues and strategies associated with immunotherapy. Semin. Oncol. Nurs. 2019;35 doi: 10.1016/J.SONCN.2019.08.012.

207. Puzanov I., Diab A., Abdallah K., Bingham C.O., Brogdon C., Dadu R., Hamad L., Kim S., Lacouture M.E., LeBoeuf N.R., et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the society for immunotherapy of cancer (SITC) toxicity management working group. J Immunother Cancer. 2017;5 doi: 10.1186/S40425-017-0300-Z.

208. Fereidouni Z., Sabet Sarvestani R., Hariri G., Kuhpaye S.A., Amirkhani M., Najafi Kalyani M. Moving into action: the master key to patient education. J. Nurs. Res. 2019;27:1. doi: 10.1097/JNR.0000000000000280.

209. Tariq S.M., Haider S.A., Hasan M., Tahir A., Khan M., Rehan A., Kamal A. Chimeric antigen receptor T-cell therapy: a beacon of hope in the fight against cancer. Cureus. 2018;10 doi: 10.7759/CUREUS.3486.

210. Ledezma B., Heng A. Real-world impact of education: treating patients with ipilimumab in a community practice setting. Cancer Manag. Res. 2013;6:5–14. doi: 10.2147/CMAR.S52543.

211. McGettigan S., Rubin K.M. vol. 21. 2017. pp. 42–51. (PD-1 Inhibitor Therapy: Consensus Statement from the Faculty of the Melanoma Nursing Initiative on Managing Adverse Events). Number 4/August 2017.

212. Fitzgerald C. Approaches to patient education in managing adverse events of ipilimumab. Cancer Nurs. Pract. 2017;16:20–24. doi: 10.7748/CNP.2017.E1391.

213. Cannon C. Telehealth. Mobile applications, and wearable devices are expanding cancer care beyond walls. Semin. Oncol. Nurs. 2018;34:118–125. doi: 10.1016/J.SONCN.2018.03.002.

214. Tonsaker T., Bartlett G., Trpkov C. Health information on the internet: gold mine or minefield? Can. Fam. Physician. 2014;60:407.

215. Laugesen J., Hassanein K., Yuan Y. The impact of internet health information on patient compliance: a research model and an empirical study. J. Med. Internet Res. 2015;17:e143. doi: 10.2196/JMIR.4333.

216. Cordova M.J., Riba M.B., Spiegel D. Post-traumatic stress disorder and cancer. Lancet Psychiatr. 2017;4:330–338. doi: 10.1016/S2215-0366(17)30014-7.

217. Apor E., Connell N.T., Faricy-Anderson K., Barth P., Youssef R., Fenton M.A., Sikov W.M., Thomas A., Rosati K., Schumacher A., et al. Prechemotherapy Education: Reducing Patient Anxiety Through Nurse-Led Teaching Sessions. 2018;22:76–82. doi: 10.1188/18.CJON.76-82. Number 1/February. 1200.

218. Targeted Therapies in Lung Cancer: Management Strategies for Nurses and Practitioners. 2019. Springer nature, ©; Switzerland, A.G. Nursing considerations for patients treated with targeted therapies; pp. 105–120.

219. Wittenberg E., Ferrell B., Kanter E., Buller H. Health literacy: exploring nursing challenges to providing support and understanding. 2018;22:53–61. doi: 10.1188/18.CJON.53-61. Number 1/February.

220. Rittenberg C.N. Meeting educational needs and enhancing adherence of patients receiving oral cancer agents through use of the MASCC oral agent teaching Tool©. Eur Oncol Haematol. 2012;8:97–100. doi: 10.17925/EOH.2012.08.02.97.