1. Introduction
Over the last few decades, the treatment of hematological malignancies has gained tremendous headway, but these diseases still have high morbidity and mortality [ 1 – 3 ]. Traditionally, the treatment of hematological malignancies is administrated by chemotherapy, radiotherapy, and stem cell transplantation. In recent years, with the increased understanding of the molecular genetic basis of these malignancies, immune-targeted therapy has become a new possibility for the treatment of hematological malignancies. Novel understanding in the interaction between immune system and cancer cells of the patient holds great promise for immunotherapy development [ 4 – 6 ].
It is noted that T cell has great potential for immunotherapy of hematological malignancies. The most active T cell endogenous inhibitory pathway is the immunoglobulin superfamily such as CD28/cytotoxic T lymphocyte antigen-4 (CTLA-4): B7-1/B7-2 receptor/ligand grouping, which plays a central role in coordinating immune responses [ 7 , 8 ]. However, from the beginning of puberty after thymus degeneration, human cytomegalovirus (HCMV) persists due to the chronic activation of cytomegalovirus in humans causing repeated activation of T cells, which is considered the driving factor of human immune aging [ 9 ]. Various biological processes including immunoreaction of infection, tumor prevention, and human aging could cause telomere damage, tumor-related stress responses, and T regulatory (Treg) cells activation, which even trigger T cell senescence showing the distinctive phenotypic and functional alternation [ 9 , 10 ].
Currently, three main strategies are applied to restore the activation of senescent T cells, including replacement, restoration, and reprogramming. Removing senescent T cells from the physiological cycle to maintain the homeostasis of memory and effector T cells is the way of replacement. One method is to target senescent T cells which have selective apoptosis function. Recently, a study showed that FOXO4/p53 was interfered by an engineered peptide, which caused targeted apoptosis of the senescent fibroblasts [ 11 ]. In addition, the isolation and storage of umbilical cord blood hematopoietic stem cells have been used to rebuild the immune system for the treatment of hematological malignancies and might be promising for the dynamic equilibrium expansion of functional T cells [ 12 ]. Restoration aims to reverse the degeneration of thymus by the combination of bioengineered thymus organoids and growth-promoting factors or cytokines such as IL-21, which may restore and stabilize the thymus environment. Reprogramming is a promising treatment, which redifferentiates T-induced pluripotent stem cells (T-IPSCs) into naïve and cytotoxic T cells or dedifferentiates within their own lineage [ 13 ]. Moreover, reprogramming can extend cell lifespan and prevent telomere-dependent T cell senescence by enhancing telomerase activity and telomere length recovery, and thus potentially be used to reverse T cell senescence [ 14 ].
Adoptive cell therapy (ACT) as a method of reprogramming is used to recover the activation of senescent T cells by acquiring immune cells from patients or volunteers, performing gene editing and in vitro expansion, followed by reinjecting them into patients which is extensively applied in the treatment of T cell senescence [ 15 ]. The sufficient effector cells with antitumor recognition capabilities from patients improve the effectiveness of ACT [ 15 ]. As a type of ACT, CD-19-targeted CAR-T cell therapies have shown dramatic results for the treatment of hematological malignancies, which was approved by the US Food and Drug Administration (FDA) [ 16 ].
2. CAR-T Cell
CAR-T cell technology integrates the chimeric antigen receptor gene into the patient's T cells through genetic engineering. Specifically, T cells are extracted from patients' blood or tumor tissues, followed by applying genetically engineering and transfection in vitro to produce a certain number of CAR-T cells, which are finally reinjected into tumor patients to induce antitumor cell action. The structure of CAR is a hybrid molecule, which mainly includes three parts: extracellular domain, transmembrane domain, and intracellular domain (see Figure 1 ). The extracellular domain is a single chain variable fragment (scFv) that is responsible for surface antigen recognition based on the structure of monoclonal antibodies. The transmembrane domain mainly serves to maintain the CAR structure, and the intracellular domain is composed of the T cell receptor (TCR), which activates the signal pathways required by T cells [ 17 ]. At present, the design of CAR-T cell has mainly experienced four generations of development. The intracellular structural design of the first-generation CAR is mainly composed of CD3 ζ that is connected to a direct, independent MHC antigen recognition domain for antigen on the surface of the tumor cells, which is similar to endogenous TCR complex [ 18 ]. However, the design of the first-generation CAR-T cells do not have a costimulatory signal domain, providing T cells with full activation of the second messenger, which leads to their limited potential for expansion in vivo , poor cytotoxicity on tumor cells, and more prone to apoptosis. To make up for the shortcoming of the first-generation CAR, the researchers add a costimulatory signal domain (such as CD28 and 4-1BB) to improve the signal activation ability and the viability of T cells, which could induce an effective expansion of the modified T cells in vivo [ 18 ]. In fact, the structural design of the second-generation CAR has laid the foundation for the currently approved CAR-T cell therapy. Nevertheless, the current study shows that the role of different types of costimulatory domains in CAR signaling is specific. For example, CD28-based CAR-T cells exhibit more powerful effector cell functions and limited durability [ 19 ], but the 4-1BB tends to drive CAR-T cells to the development of central memory phenotype to improve durability [ 20 ]. Similarly, the design of the third-generation CAR-T cells combines the signal potential of two costimulatory signal domains (such as CD28 and 4-1BB) to fill the gap of the second generation [ 21 ]. The fourth-generation CAR-T cells increase the anti-tumor activity by further enhancing additional genetic modifications. It is engineered with an activation inducible element such as a nuclear factor of the activated T cell (NFAT)-responsive expression cassette to facilitate secretion of transgenic cytokines such as interleukin-12 (IL-12), interleukin-15 (IL-15), and interleukin-18 (IL-18), which are known as T cell redirected for universal cytokine-mediated killing (TRUCK) [ 22 ]. IL-12 recruits additional immune cells to fight cancer cells which are not identified by CAR-T cells [ 23 ]. Moreover, IL-12 is related to the proliferation, terminal differentiation, and exhaustion of T cells [ 24 ]. Conversely, IL-15 maintains the homeostasis of CD8 + memory T cells, enhances the antitumor activity, and reverses T cell senescence [ 24 ]. Furthermore, some researchers demonstrated that CAR-T cells expressing IL-18 exhibited continuous antitumor activity [ 25 ]. In general, these immune functional modifications exhibit great antitumor effect in fourth-generation CAR-T cells.
3. CAR-T Cells for Hematological Malignancies
3.1. Acute Lymphoblastic Leukemia
Acute lymphoblastic leukemia (ALL) is a common hematological malignancy caused by abnormal bone marrow blasts and naïve cells with excessive proliferation. CAR-T cells are used in the treatment of ALL, especially the lethal relapsed/refractory (r/r) B-ALL [ 26 ]. CD19 is an activated transmembrane glycoprotein regulating B cells in an antigen receptor-dependent manner, which is expressed throughout the differentiation process of B cells, especially during the malignant transformation of B cells [ 27 ]. Based on this, CD19 as an ideal target for the treatment of lymphomas is attractive to researchers. Grupp et al. applied anti-CD19 antibody and T cell signaling molecule CTL019 CAR-T cells to treat 2 patients with r/r ALL. It was revealed that the level of CTL019 CAR-T cells expansion in the two patients was 1000 times than the original transplantation level by bone marrow examination. In addition, CAR-T cells were also observed to maintain high levels for at least 6 months in cerebrospinal fluid (CSF), and both patients were observed complete remission (CR) [ 28 ]. Furthermore, Maude et al. used tisagenlecleucel (formerly CTL019) to treat patients with r/r B cell ALL. 75 patients were injected with tisagenlecleucel, and the complete remission rate (CRR) within 3 months achieved 81%. All patients who responded to the treatment were evaluated by flow cytometry, and the minimal residual disease (MRD) was negative. The duration of tisagenlecleucel in the blood was observed for up to 20 months [ 29 ]. Moreover, a study reported 16 cases of r/r B-ALL patients treated with autologous T cells expressing CD19 antigen-specific 19-28Z CAR. The overall CRR achieved 88%, according to IgH deep sequencing evaluation and morphological criteria [ 30 ]. However, because leukemia cells exhibit the same antigen as normal T cells, the identification of targets for ALL cells poses challenges. Especially, CAR-T cell therapy for ALL always presents cytokine release syndrome (CRS) [ 31 ].
3.2. Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia, and patients with multiple r/r CLL have a poor prognosis [ 32 ]. It is an effective approach to treat CLL by targeting CD19 with CAR-T cells. A team of researchers at the University of Pennsylvania designed the CAR-T cell that can bind to CD3zeta (a signal-transduction component of the T cell antigen receptor) and CD137 (a costimulatory receptor in T cells). After low-dose (about 1.5 × 10 5 cells per kilogram of body weight) autologous CAR-T cells were injected into CLL patients, it was found that the number of CAR-T cells expanded 1,000 times than the initial input, and the tumor was completely relieved. In addition, the CAR was expressed continuously in the blood and bone marrow for 6 months [ 33 ]. Furthermore, this team also reported the results of the CAR-T cell therapy of 14 patients with r/r CLL. They infused CTL019 T cells at 0.14 × 10 8 − 11 × 10 8 (median 1.6 × 10 8 cells) to patients with r/r CLL and monitored the circulating CTL019 T cells for toxicity, responsiveness, expansibility, and persistence. It was indicated that the total effective rate of these treated CLL patients was 8/14 (57%), including 4 CRs and 4 partial remissions (PRs) [ 34 ]. Recently, researchers have used other therapies combined with CAR-T cell therapy for CLL patients to show a certain effect. Geyer et al. reported that CD19-targeted CAR-T cells integrated with CD28 intracellular signaling domain (19-28Z) can be a consolidation therapy for the treatment of 8 CLL patients after first-line chemotherapy of infliximab. 3 of 8 patients (38%) achieved objective response (OR), from which the clinical CR of 2 patients sustained more than 28 months. 4 patients developed self-limiting fever after infusion of CAR-T cells, while interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-2 (IL-2), and transformation growth factor- α (TGF- α ) were elevated. CAR-T cells were detected in 4 patients after infusion, and the longest duration was 48 days [ 35 ]. Further, Gauthier et al. reported 19 cases of r/r CLL patients treated with CAR-T cells and ibrutinib, discovering that the 4-week CRR was 83% and 61% of patients attained MRD by IgH sequencing negative bone marrow response. In the cases with or without ibrutinib, the 1-year PFS after CAR-T cell therapy was 38% and 50%, respectively. The simultaneous application of ibrutinib and CAR-T cell therapy was well tolerated [ 36 ]. These studies indicate that CAR-T cells are effective in the treatment of CLL.
3.3. Non-Hodgkin's Lymphoma
Non-Hodgkin's lymphoma (NHL) is also one of the most common B cell lymphomas. Recently, although chemotherapy, radiotherapy, and hematopoietic stem cell transplantation have gained significant progress in the treatment of NHL, the mortality has not declined. For patients who are resistant to standard treatment regimens, new treatment approaches are imperative. Recently, CAR-T cell therapy has received widespread attention due to its remarkable success in r/r lymphoma [ 26 ].
Diffuse large B cell lymphoma (DLBCL) is the most common subtype of NHL and has an aggressive clinical course. A study reported that CAR-T cells expressing anti-CD20 were used to treat two patients with relapsed DLBCL after autologous hematopoietic stem cell transplantation; no clinical responses and no obvious toxicities were observed [ 37 ]. Coincidentally, Kochenderfer et al. reported the application of anti-CD19 CAR-T cells in 15 patients with advanced B cell malignancies, from which, 4 of 7 chemotherapy-refractory DLBCL patients achieved CR [ 38 ]. Further, the SCHOLAR-1 study analyzed the efficacy and survival results of 636 patients with r/r DLBCL retrospectively. The objective response rate (ORR), CRR, and median overall survival (OS) of the r/r groups were 26%, 7%, and 6.3 months, respectively [ 39 ]. Moreover, Schuster et al. reported 28 lymphoma patients in adult received CTL019 CAR-T cell therapy, and 6 of 14 cases of DLBCL had CR [ 40 ]. Furthermore, Stirrups and colleagues used anti-CD19 CAR-T cells to treat patients with refractory large B cell lymphoma. They recruited 111 patients with histologically confirmed large B cell lymphoma, including DLBCL and primary mediastinal B cell lymphoma, and autologous anti-CD19 CAR-T cells were inoculated at 2 × 10 6 cells/kg body weight. Of the 101 patients included in the intention-to-treat analysis, 83 patients had OR with CR in 55 cases (54%) and PR in 28 cases (28%) [ 41 ].
In addition, mantle cell lymphoma (MCL) accounts for 7% in all NHL [ 42 ]. CAR-T cell therapy is an effective approach for the treatment of MCL, and it is possible to make MCL a curable disease. Till et al. conducted a preclinical trial in 4 patients with relapsed indolent B cell and MCL, evaluating the effect of the third-generation CD20-specific CAR-T cells with CD28 and 4-1BB costimulatory domains. According to the result, this therapy was well tolerated, although transient infusion symptoms were tested in 1 patient. No progress was continuous in 2 patients at 12 and 24 months, but an objective PR occurred in another patient, and the disease relapsed 12 months after injection [ 43 ].
Additionally, some researchers also applied CAR-T cells for the treatment of other subtypes of NHL. Schuster et al. applied CTL019 in a Phase IIa study of 14 follicular lymphoma (FL) patients, suggesting that they had disease progression within 2 years after treatment with 2 or more treatment lines [ 40 ]. In addition, Neelapu et al. treated refractory and aggressive B cell NHL patients with KTE-C19 consisting of a single-chain antibody called FMC-63 in the extracellular region, which recognize CD19 on the surface of tumor cells. After treatment, it was found that 62 patients have a total effective rate of 79% and a complete effective rate of 52% [ 44 ]. Besides, Chen et al. reported a case of r/r acute B cell lymphoblastic lymphoma (B-LBL) with Li-Fraumeni syndrome (LFS), receiving anti-CD19 and anti-CD22 CAR-T cell “cocktail” treatment. The morphology and multiparameter flow cytometry showed that the tumor was completely relieved, and the MRD was negative [ 45 ]. It was worth noting that Burkitt lymphoma (BL) was also one of the most common subtypes of NHL in children, and 5%-10% of patients with a poor prognosis still relapsed after intensive chemotherapy. Recently, Du et al. treated an eight-year-old boy with CAR-T cells targeted to the antigens CD19, CD22, and CD20 sequentially. The results showed that the child had no obvious response to anti-CD19 CAR-T cell therapy and showed progressive disease (PD). After CAR-T cell therapy guided by CD22, the child experienced PR but unfortunately relapsed quickly. Finally, after receiving anti-CD20 CAR-T cell therapy, the child achieved CR [ 46 ].
In addition, CD23 and orphan tyrosine kinase receptor (ROR1) have also become potential targets for the treatment of B cell lymphomas, and CAR-T cell therapy has shown great promise in the advancement of the r/r NHL therapy [ 26 ].
3.4. Hodgkin's Lymphoma
Hodgkin's lymphoma (HL) is a hematological malignancy originating from B cells and overexpresses CD30 which is a potential therapeutic target [ 26 ]. According to a Phase I study, 7 patients with r/r HL were treated with anti-CD30 CAR-T cells, 1 case achieved CR for more than 2.5 years, 1 case sustained CR for almost 2 years, and 3 cases had transient stable disease (SD). It was a remarkable fact that the anti-CD30 CAR-T cell therapy had no toxicity in this study [ 47 ]. Furthermore, Wang et al. performed anti-CD30 CAR-T cell therapy on 11 patients with r/r HL, infusing 1.5 × 10 7 CAR-T cells per kg of weight. It was indicated that 9 cases (82%) responded to treatment, 1 case (9%) maintained continuous CR, 1 case (46%) achieved PR, and 3 cases (27%) were stable. Tolerable infusion-related fever syndrome was occurred in all patients. One patient (9%) had self-limited arthralgia, myalgia, and swelling of both knees for 5 days after 2 weeks of infusion [ 48 ]. These results confirm that CD30 has great potential in the treatment of HL.
3.5. Multiple Myeloma
Multiple myeloma (MM) is a refractory malignancy of bone marrow origin, which is caused by a malignant mutation of plasma cells forming in the final stage of B cell development [ 49 ]. CD19 is hardly expressed on the surface of MM cells, and the killing effect of anti-CD19 CAR-T cells on MM cells is weak, which even damages some healthy tissues [ 50 ]. Therefore, searching for specific targets expressed on MM cells but not on healthy tissue cells is a potentially effective method for the treatment of MM. Hosen et al. found a specific therapeutic target (active conformation of integrin) for the treatment of MM. By screening more than 10,000 anti-MM monoclonal antibodies, they identified MMG49 as the MM monoclonal antibody recognizing the integrin β 7 molecule specifically. It was therefore evident that the transduced MMG49-derived CAR-T cells played an anti-MM role without damaging normal hematopoietic cells [ 51 ]. Furthermore, B cell maturation antigen (BCMA, CD269) is another identified target molecule for the treatment of MM. Xu et al. reported a female patient with r/r MM after infusion of anti-BCMA CAR-T cells achieved CR. However, patients with a disease-free survival of 7.6 months developed grade 1 CRS which was mainly manifested as fever and nausea and eventually led to the relapse of MM [ 52 ]. Similarly, CD138 (also known as syndecan 1) is highly expressed on the surface of both normal and malignant plasma cells, which has been identified as an attractive target for a long time. Sun et al. found that T cells from healthy donors and patients with MM could eliminate MM cell lines and primary myeloma cells in vitro and in vivo when transduced with CD138-specific chimeric antigen receptors. Through preclinical analysis, no off-target tumor cytotoxicity occurred in normal epithelial or endothelial cells [ 53 ]. Further, they used SLAMF7 as the target to prepare CAR from anti-SLAMF7 antibody huLuc63 (elotuzumab), indicating that these CAR-T cells had a rapid lysis effect against MM cell lines and primary MM cells in vitro [ 54 ]. All in all, CAR-T cell therapy for MM has become a promising strategy.
3.6. Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is a hematological malignancy with high relapse rate in adults and children [ 55 , 56 ]. In this regard, some studies have shown that the application of CAR-T cells to treat AML has achieved significant effects. A research team showed an anti-CD123 CAR-T cell therapy for the treatment of AML [ 55 ]. According to the initial in vitro study, anti-CD123 CAR-expressing cytokine-induced killer T cells demonstrated great antitumor activity [ 55 ]. Moreover, a method for preparing allogeneic CAR-T cells by targeting CD33/Siglec-3 antigen from healthy donors has been developed [ 57 ]. Anti-CD33 CAR-T cells reduced AML tumors effectively in mouse model trials [ 57 ]. Furthermore, FMS-like tyrosine kinase 3 (FLT3) was discovered as a novel target for CAR-T cell therapy in AML [ 58 ]. FLT3-inhibitor crenolanib and FLT3 CAR-T cells demonstrated synergistic antileukemia effects in mouse trials [ 58 ]. In addition, John et al. demonstrated that leukocyte immuno-globulin-like receptor-B4 (LILRB4) was highly expressed on the surface of AML cells [ 56 ]. They constructed anti-LILRB4 CAR-T cells successfully, which had a specific recognition effect on AML cells [ 56 ]. Although the above CAR-T cell therapy targets for AML have not been used in clinical trials, they provide hope for the further development of treatment for AML.
4. Disadvantages of CAR Treatment
4.1. Cytokine Release Syndrome
CRS is a systemic immune stress inflammation, which is caused by the rapid proliferation and release of cytokines after the introduction of CAR-T cells into the patient. It is one of the most common adverse events in CAR-T cell therapy. It usually exhibits symptoms such as hypotension, fever, neurological changes, and hypoxia [ 59 ]. According to the above experimental results, anti-CD19 CAR-T cells are effective in treating hematological malignancies, but they also produce a large number of cytokines, resulting in CRS in most patients after treatment. At present, many researchers have designed new CAR-T cell therapy programs for CRS. A research team determined the diagnostic criteria for severe cytokine release syndrome (SCRS) through clinical analysis of 21 days after T cell infusion and systemic analysis of serum cytokine levels, with the aim of better identifying patient subgroups which may require corticosteroids or IL-6 receptor blockers for therapeutic intervention to suppress CRS. In addition, they also found that serum C-reactive protein (CRP) could be applied as a reliable standard to evaluate the severity of CRS, paving a way for patient management in centers currently considering CAR-T cell therapy [ 30 ]. Tocilizumab is a humanized anti-IL-6 receptor (IL-6R) monoclonal antibody approved by the FDA for the treatment of SCRS. A study has shown that CRS subsides rapidly after taking tocilizumab and will not adversely affect CAR-T cell therapy [ 60 ]. Caimi et al. found that the application of prophylactic tocilizumab (PT) before injecting anti-CD19 CAR-T cells with CD3zeta/4-1BB costimulatory domain could reduce the incidence of SCRS [ 61 ]. Moreover, Jiang et al. found that CRS caused by CAR-T cell therapy would further lead to disseminated intravascular coagulation (DIC) and proposed the application of immunosuppressive agents and corticosteroids for early and appropriate interventions for CRS-related coagulation disorders, which could be used to control the side effects of CAR-T treatment [ 62 ].
4.2. Neurotoxicity
Neurotoxicity is the second most severe adverse event of CAR-T cell therapy. Typical manifestations of neurotoxicity include mild headache, language disorder, visual hallucination, seizure, severe encephalopathy, and even death [ 63 ]. Neurotoxicity is related to CRS, which can occur alone or with CRS after CAR-T cell therapy, but the mechanism leading to neurotoxicity is not yet clear. Based on data from patients and animal models, Gust et al. reported that damage to the blood-brain barrier (BBB) in patients is related to high levels of cytokines and endothelial activation in the blood and cerebrospinal fluid. Patients with neurotoxicity were often treated by corticosteroids, IL-6 targeted therapy, and supportive care, but their effectiveness needed to be proved [ 64 ]. Further, they also provided evidence of severe neurotoxicity showing endothelial activation in 133 patients with refractory B cell malignancies treated with anti-CD19 CAR-T cells, including capillary leak, diffuse intravascular coagulation, and increased BBB permeability [ 65 ]. A study showed that after CAR-T cell therapy of patients with r/r DLBCL, the level of IL-15 and granulocyte-macrophage colony-stimulating factor (GM-CSF) was increased, which was associated with severe neurotoxicity [ 66 ]. Sterner et al. showed that neutralizing GM-CSF could prevent CRS and reduced neurotoxicity significantly, and this method reduced neuroinflammation and BBB damage by 75% and enhanced antitumor activity [ 67 ]. Recently, Harden et al. analyzed 12 plasma samples of adult patients with varying degrees of neurotoxicity after CAR-T cell therapy, suggesting that the levels of apolipoprotein A1 (ApoA1) and angiogenin changed over time, which might indicate the risk of neurotoxicity. This correlation offers great promise in the clinical treatment of neurotoxicity research and development, but it needs to be verified by quantifying the absolute concentration of ApoA1 and angiogenin in the blood of a larger patient population [ 68 ].
4.3. On-Target/off-Tumor Toxicity
In addition to tumor tissues, biomolecular markers of hematological malignancies are also expressed in some normal tissues, especially lymphoid tissues. Although CAR-T cells have relative specificity, each scheme may cause different degrees of tissue damage called on-target/off-tumor toxicity [ 69 ]. Comprehensive treatment based on the combined control system of switchable dual receptor CAR-T cells and immune checkpoint blockade has become a new paradigm for CAR-T cell therapy [ 70 ]. Wendell Lim's laboratory has developed a system that requires two antigens to fully activate CAR-T cells, called synNotch, consisting of an engineered antigen recognition domain, an artificial transcription factor (ATF), and a Notch core. Among it, the ATF is activated under antigen stimulation to induce CAR expression specifically. Intermediate signal molecules are not required in this system which works in an orthogonal manner. However, whether the ATF is immunogenic remains to be studied [ 71 – 73 ]. Moreover, Fedorov et al. designed an inhibitory CAR (iCAR) therapy that could coexpress and recognize antigens expressed in nontumor tissues. iCAR is connected to the intracellular domain of T cell checkpoint protein by an antigen recognition domain, named cytotoxic T lymphocyte associated protein 4 (CTLA-4) or programmed cell death protein 1 (PD-1). Although cells expressing iCAR targets have activated CAR antigens, they will not activate T cells to avoid damage to normal tissues [ 74 ]. These methods not only ensure the antitumor activity of CAR-T cells but also prevent off-tumor toxicity.
4.4. Relapse with CAR-T Cell Therapy
Although most patients after receiving CAR-T cell therapy would achieve high CR, relapse of hematological malignancies may occur [ 75 ]. One cause of relapse is the loss of antigen after CAR-T cell therapy, which is also called target-negative relapse [ 75 ]. Additionally, a study has shown that changes in the CAR-T cell microenvironment may induce antigen-positive relapse [ 28 ]. Searching novel targets and allogeneic hematopoietic stem cell transplantation (allo-HSCT) are the main strategies for the treatment of relapse [ 26 ].
5. Future Direction
In recent decades, CAR-T cell offers tremendous progress in the treatment of hematological malignancies, but there are still many challenges. The problems mainly include how to improve the effectiveness and durability of CAR-T cells in patients and how to alleviate the adverse events after treatment [ 69 ]. A novel bispecific CAR targets two tumor-specific markers, leading to better therapeutic efficacy [ 69 ]. A study reported that a functional CAR called TanCAR was designed to mediate bispecific activation of T cells [ 76 ]. It was suggested that TanCAR induced T cells reactivity against two different antigens and produced synergistic enhancement of T cell activation [ 76 ]. In terms of achieving the durability of CAR-T cell therapy, there have been reports of using oncolytic viruses with chemokine genes to recruit CAR-T cells for the treatment of solid tumors. Oncolytic viruses have the ability to prolong their duration and directly attack tumor cells [ 77 , 78 ], which might have great potential to treat hematological malignancies. Moreover, the development of universal CAR-T cell therapy for the treatment of hematological malignancies can avoid the problem that patients' autologous T cells are difficult to obtain and reduce the cost of treatment. We hypothesize that the application of CRISPR technology to edit allogeneic genes provides potential for the development of universal CAR-T cell therapy.
For the adverse events generated after CAR-T cell therapy, the main therapeutic drugs include tocilizumab and corticosteroids, which have been mentioned specific cases in the above. Furthermore, Laborda et al. summarized an approach to activate predesigned cell triggers allowing CAR-T cells to be eliminated in case of adverse events in patients [ 79 ]. For example, some researchers designed epitope markers expressed by the CAR vector in the form of cistrons and approved that monoclonal antibodies could then eliminate the labeled cells [ 79 ]. This strategy has been used to reverse the anti-CD19 CAR-T cell-mediated B cell aplasia in mice, which has shown great promise of the elimination for patients' CAR-T cells after a period of remission [ 80 ]. Another method called “suicide gene system” is also worthy of attention [ 81 ]. Chemically induced caspase 9 (iCas9) dimerization is one of the most prominent suicide genes in T cell based immunotherapy, which has shown extraordinary efficiency in clinical trials of patients [ 82 ]. In general, these therapies might avoid the adverse events caused by CAR-T cells for secondary drug treatment, which also show a new perspective for future direction.
6. Conclusion
CAR-T cells have shown great potential in the treatment of hematological malignancies such as ALL, CLL, NHL, HL, MM, and AML. According to different types of hematological malignancies, it is the basic idea of this therapy to screen out specific targets on the surface of the respective tumor cells and construct CAR-T cells in vitro to be imported into patients. CAR-T cells have been applied in clinical treatment for a long time and have gained headway in the field of hematological malignancies. However, there are still many disadvantages, such as CRS, neurotoxicity, off-tumor toxicity, and relapse. The development of new CAR-T cell therapies to compensate for or alleviate these deficiencies is the great responsibility of the researchers.
Acknowledgments
This study was financially supported by the National Natural Science Foundation of China (No. 81970186) and the Beijing Advanced Innovation Center Research Foundation (No. 10287).
Conflicts of Interest
The authors declare that there is no conflict of interest regarding the publication of this paper.
1 Smith M. T. Zhang L. Wang Y. Increased translocations and aneusomy in chromosomes 8 and 21 among workers exposed to benzene Cancer Research 1998 58 10 2176 2181 9605763
2 Demirel A. Tabak F. Ar M. C. Secondary infections in febrile neutropenia in hematological malignancies: more than another febrile neutropenic episode Turkish Journal of Hematology 2015 32 3 243 250 10.4274/tjh.2013.0422 2-s2.0-84938509702 25913035 PMC4563200
3 Cornely O. A. Bohme A. Buchheidt D. Prophylaxis of invasive fungal infections in patients with hematological malignancies and solid tumors Annals of Hematology 2003 82 S186 S200 10.1007/s00277-003-0773-3 2-s2.0-0142125774 13680164
4 Roex G. Feys T. Beguin Y. Chimeric antigen receptor-T-cell therapy for B-cell hematological malignancies: an update of the pivotal clinical trial data Pharmaceutics 2020 12 2 10.3390/pharmaceutics12020194 32102267 PMC7076393
5 Candeias S. M. Gaipl U. S. The immune system in cancer prevention, development and therapy Anti-Cancer Agents in Medicinal Chemistry 2016 16 7 101 107 10.2174/1871520615666150824153523 26299661
6 Dhodapkar M. V. Dhodapkar K. M. Immune modulation in hematologic malignancies Seminars in Oncology 2015 42 4 617 625 10.1053/j.seminoncol.2015.05.009 2-s2.0-84940387185 26320065 PMC4555986
7 Montoro J. Pinana J. L. Sanz J. Guerreiro M. T lymphocytes as therapeutic arsenal for patients with hematological malignancies Current Opinion in Oncology 2018 30 6 1 434 10.1097/CCO.0000000000000481 2-s2.0-85054757313 30124521
8 Peggs K. S. Quezada S. A. Allison J. P. Cell intrinsic mechanisms of T-cell inhibition and application to cancer therapy Immunological Reviews 2008 224 1 141 165 10.1111/j.1600-065X.2008.00649.x 2-s2.0-45149111788 18759925
9 Solana R. Tarazona R. Aiello A. E. CMV and immunosenescence: from basics to clinics Immunity & Ageing 2012 9 1 10.1186/1742-4933-9-23 2-s2.0-84868252990 23114110 PMC3585851
10 van Deursen J. M. The role of senescent cells in ageing Nature 2014 509 7501 439 446 10.1038/nature13193 2-s2.0-84901288438 24848057 PMC4214092
11 Baar M. P. Brandt R. M. C. Putavet D. A. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging Cell 2017 169 1 132 147.e16 10.1016/j.cell.2017.02.031 2-s2.0-85016052515 28340339 PMC5556182
12 Rizk M. Aziz J. Shorr R. Allan D. S. Cell-based therapy using umbilical cord blood for novel indications in regenerative therapy and immune modulation: an updated systematic scoping review of the literature Biology of Blood and Marrow Transplantation 2017 23 10 1607 1613 10.1016/j.bbmt.2017.05.032 2-s2.0-85025432321 28602892
13 Karagiannis P. Iriguchi S. Kaneko S. Reprogramming away from the exhausted T cell state Seminars in Immunology 2016 28 1 35 44 10.1016/j.smim.2015.10.007 2-s2.0-84949008277 26589493
14 Allsopp R. Telomere length and iPSC re-programming: survival of the longest Cell Research 2012 22 4 614 615 10.1038/cr.2012.6 2-s2.0-84859421119 22212477 PMC3317569
15 June C. H. Sadelain M. Chimeric antigen receptor therapy The New England Journal of Medicine 2018 379 1 64 73 10.1056/NEJMra1706169 2-s2.0-85049646425 29972754 PMC7433347
16 Han X. Wang Y. Wei J. Han W. Multi-antigen-targeted chimeric antigen receptor T cells for cancer therapy Journal of hematology & oncology 2019 12 1 10.1186/s13045-019-0813-7 31783889 PMC6884912
17 Zhang C. Liu J. Zhong J. F. Zhang X. Engineering CAR-T cells Biomarker research 2017 5 1 10.1186/s40364-017-0102-y PMC5482931 28652918
18 van der Stegen S. J. Hamieh M. Sadelain M. The pharmacology of second-generation chimeric antigen receptors Nature Reviews. Drug Discovery 2015 14 7 499 509 10.1038/nrd4597 2-s2.0-84934268032 26129802 PMC6410718
19 Weinkove R. George P. Dasyam N. McLellan A. D. Selecting costimulatory domains for chimeric antigen receptors: functional and clinical considerations Clinical & translational immunology 2019 8 5, article e1049 10.1002/cti2.1049 2-s2.0-85065989389 31110702 PMC6511336
20 Long A. H. Haso W. M. Shern J. F. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors Nature Medicine 2015 21 6 581 590 10.1038/nm.3838 2-s2.0-84930765209 25939063 PMC4458184
21 Brentjens R. J. Curran K. J. Novel cellular therapies for leukemia: CAR-modified T cells targeted to the CD19 antigen Hematology 2012 2012 1 143 151 10.1182/asheducation.V2012.1.143.3798224 23233573 PMC5536093
22 Ajina A. Maher J. Strategies to address chimeric antigen receptor tonic signaling Molecular Cancer Therapeutics 2018 17 9 1795 1815 10.1158/1535-7163.MCT-17-1097 2-s2.0-85053125995 30181329 PMC6130819
23 Chmielewski M. Abken H. TRUCKs: the fourth generation of CARs Expert Opinion on Biological Therapy 2015 15 8 1145 1154 10.1517/14712598.2015.1046430 2-s2.0-84936934796 25985798
24 Hurton L. V. Singh H. Najjar A. M. Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells Proceedings of the National Academy of Sciences of the United States of America 2016 113 48 E7788 E7797 10.1073/pnas.1610544113 2-s2.0-84999293269 27849617 PMC5137758
25 Hu B. Ren J. Luo Y. Augmentation of antitumor immunity by human and mouse CAR T cells secreting IL-18 Cell Reports 2017 20 13 3025 3033 10.1016/j.celrep.2017.09.002 2-s2.0-85029864617 28954221 PMC6002762
26 Yang X. Wang G. X. Zhou J. F. CAR T cell therapy for hematological malignancies Current Medical Science 2019 39 6 874 882 10.1007/s11596-019-2118-z 31845217
27 Zheng X. H. Zhang X. Y. Dong Q. Q. Chen F. Yang S. B. Li W. B. Efficacy and safety of chimeric antigen receptor-T cells in the treatment of B cell lymphoma Chinese Medical Journal 2020 133 1 74 85 10.1097/CM9.0000000000000568 31923107 PMC7028209
28 Grupp S. A. Kalos M. Barrett D. Chimeric antigen receptor–modified T cells for acute lymphoid leukemia New England Journal of Medicine 2013 368 16 1509 1518 10.1056/NEJMoa1215134 2-s2.0-84876325876 23527958 PMC4058440
29 Maude S. L. Laetsch T. W. Buechner J. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia New England Journal of Medicine 2018 378 5 439 448 10.1056/NEJMoa1709866 2-s2.0-85041428116 29385370 PMC5996391
30 Brentjens R. Davila M. Riviere I. 766. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia Molecular Therapy 2014 22 S295 S296 10.1126/scitranslmed.3008226 PMC4684949 24553386
31 Atrash S. Bano K. Harrison B. Abdallah A. O. CAR-T treatment for hematological malignancies Journal of Investigative Medicine 2020 68 5 956 964 10.1136/jim-2020-001290 32200355
32 Brown J. R. The treatment of relapsed refractory chronic lymphocytic leukemia Hematology. American Society of Hematology. Education Program 2011 2011 1 110 118 10.1182/asheducation-2011.1.110 2-s2.0-84859410688 22160021
33 Porter D. L. Levine B. L. Kalos M. Bagg A. June C. H. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia The New England Journal of Medicine 2011 365 8 725 733 10.1056/NEJMoa1103849 2-s2.0-80051720194 21830940 PMC3387277
34 Porter D. L. Hwang W. T. Frey N. V. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia Science Translational Medicine 2015 7 303, article 303ra139 10.1126/scitranslmed.aac5415 2-s2.0-84940881287 26333935 PMC5909068
35 Geyer M. B. Rivière I. Sénéchal B. Autologous CD19-targeted CAR T cells in patients with residual CLL following initial purine analog-based therapy Molecular Therapy 2018 26 8 1896 1905 10.1016/j.ymthe.2018.05.018 2-s2.0-85048545983 29910179 PMC6094824
36 Gauthier J. Hirayama A. V. Purushe J. Feasibility and efficacy of CD19-targeted CAR T cells with concurrent ibrutinib for CLL after ibrutinib failure Blood 2020 135 19 1650 1660 10.1182/blood.2019002936 32076701 PMC7205814
37 Jensen M. C. Popplewell L. Cooper L. J. Antitransgene rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans Biology of Blood and Marrow Transplantation 2010 16 9 1245 1256 10.1016/j.bbmt.2010.03.014 2-s2.0-77955510549 20304086 PMC3383803
38 Kochenderfer J. N. Dudley M. E. Kassim S. H. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor Journal of Clinical Oncology 2015 33 6 540 549 10.1200/JCO.2014.56.2025 2-s2.0-84923118622 25154820 PMC4322257
39 Crump M. Neelapu S. Farooq U. Outcomes in refractory aggressive diffuse large B cell lymphoma (DLBCL): results from the international SCHOLAR-1 study Clinical Lymphoma Myeloma & Leukemia 2017 16 p. S101 10.1182/blood-2017-03-769620 PMC5649550 28774879
40 Schuster S. J. Svoboda J. Chong E. A. Chimeric antigen receptor T cells in refractory B-cell lymphomas The New England Journal of Medicine 2017 377 26 2545 2554 10.1056/NEJMoa1708566 2-s2.0-85040171486 29226764 PMC5788566
41 Stirrups R. CAR T-cell therapy in refractory large B-cell lymphoma The Lancet Oncology 2018 19 1 10.1016/S1470-2045(17)30928-2 29249304
42 Morton L. M. Wang S. S. Devesa S. S. Hartge P. Weisenburger D. D. Linet M. S. Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001 Blood 2006 107 1 265 276 10.1182/blood-2005-06-2508 2-s2.0-30144443996 16150940 PMC1895348
43 Till B. G. Jensen M. C. Wang J. CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: pilot clinical trial results Blood 2012 119 17 3940 3950 10.1182/blood-2011-10-387969 2-s2.0-84860333968 22308288 PMC3350361
44 Neelapu S. S. An interim analysis of the ZUMA-1 study of KTE-C19 in refractory, aggressive non-Hodgkin lymphoma Clinical Advances in Hematology & Oncology : H&O 2017 15 2 117 120 28398281
45 Chen L. Xu B. Long X. CAR T-cell therapy for a relapsed/refractory acute B-cell lymphoblastic lymphoma patient in the context of Li-Fraumeni syndrome Journal for Immunotherapy of Cancer 2019 8 1, article e000364 10.1136/jitc-2019-000364 PMC7213909 32345625
46 Du J. Zhang Y. Sequential anti-CD19, 22, and 20 autologous chimeric antigen receptor T-cell (CAR-T) treatments of a child with relapsed refractory Burkitt lymphoma: a case report and literature review Journal of Cancer Research and Clinical Oncology 2020 146 6 1575 1582 10.1007/s00432-020-03198-7 32222815 PMC11804458
47 Ramos C. A. Ballard B. Zhang H. Clinical and immunological responses after CD30-specific chimeric antigen receptor-redirected lymphocytes The Journal of Clinical Investigation 2017 127 9 3462 3471 10.1172/JCI94306 2-s2.0-85028909387 28805662 PMC5669573
48 Wang C. M. Wu Z. Q. Wang Y. Autologous T cells expressing CD30 chimeric antigen receptors for relapsed or refractory Hodgkin lymphoma: an open-label phase I trial Clinical Cancer Research 2017 23 5 1156 1166 10.1158/1078-0432.CCR-16-1365 2-s2.0-85014625466 27582488
49 International Myeloma Working Group Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the international myeloma working group British Journal of Haematology 2003 121 5 749 757 10.1046/j.1365-2141.2003.04355.x 2-s2.0-0038509089 12780789
50 Atanackovic D. Radhakrishnan S. V. Bhardwaj N. Luetkens T. Chimeric antigen receptor (CAR) therapy for multiple myeloma British Journal of Haematology 2016 172 5 685 698 10.1111/bjh.13889 2-s2.0-84958899793 26791002
51 Hosen N. Matsunaga Y. Hasegawa K. The activated conformation of integrin β 7 is a novel multiple myeloma-specific target for CAR T cell therapy Nature Medicine 2017 23 12 1436 1443 10.1038/nm.4431 2-s2.0-85039047406 29106400
52 Xu J. Wang Q. Xu H. Anti-BCMA CAR-T cells for treatment of plasma cell dyscrasia: case report on POEMS syndrome and multiple myeloma Journal of Hematology & Oncology 2018 11 1 p. 128 10.1186/s13045-018-0672-7 2-s2.0-85055183509 30348186 PMC6198365
53 Sun C. Mahendravada A. Ballard B. Safety and efficacy of targeting CD138 with a chimeric antigen receptor for the treatment of multiple myeloma Oncotarget 2019 10 24 2369 2383 10.18632/oncotarget.26792 2-s2.0-85064857584 31040928 PMC6481321
54 Gogishvili T. Danhof S. Prommersberger S. SLAMF7-CAR T cells eliminate myeloma and confer selective fratricide of SLAMF7+ normal lymphocytes Blood 2017 130 26 2838 2847 10.1182/blood-2017-04-778423 2-s2.0-85039772833 29089311
55 Tettamanti S. Biondi A. Biagi E. Bonnet D. CD123 AML targeting by chimeric antigen receptors: a novel magic bullet for AML therapeutics? Oncoimmunology 2014 3 5, article e28835 10.4161/onci.28835 2-s2.0-84904052509 25083319 PMC4106165
56 John S. Chen H. Deng M. A novel anti-LILRB4 CAR-T cell for the treatment of monocytic AML Molecular Therapy 2018 26 10 2487 2495 10.1016/j.ymthe.2018.08.001 2-s2.0-85051719854 30131301 PMC6171100
57 McEwan B. Padalia Z. Porras A. Allogeneic CRISPR/Cas9 gene-edited CAR-T cells targeting CD33 show potent preclinical activity against AML cells Cancer Research 2019 79 13 p. 1428
58 Prommersberger S. Jetani H. Danhof S. Novel targets and technologies for CAR-T cells in multiple myeloma and acute myeloid leukemia, Current Research in Translational Medicine 2018 66 2 37 38 10.1016/j.retram.2018.03.006 2-s2.0-85045285981 29655962
59 Riches J. C. Gribben J. G. Understanding the immunodeficiency in chronic lymphocytic Leukemia Hematology/Oncology Clinics of North America 2013 27 2 207 235 10.1016/j.hoc.2013.01.003 2-s2.0-84875787670 23561470
60 Neelapu S. S. Locke F. L. Bartlett N. L. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma The New England Journal of Medicine 2017 377 26 2531 2544 10.1056/NEJMoa1707447 2-s2.0-85040170618 29226797 PMC5882485
61 Caimi P. F. Ahmed N. Rojas P. Prophylactic tocilizumab before CD3/4-1bb anti-CD19 car-T cell infusion decreases incidence of severe crs without increased risk of neurotoxicity Cytotherapy 2020 22 5 S16 S17 10.1016/j.jcyt.2020.03.483
62 Jiang H. Liu L. Guo T. Improving the safety of CAR-T cell therapy by controlling CRS-related coagulopathy Annals of Hematology 2019 98 7 1721 1732 10.1007/s00277-019-03685-z 2-s2.0-85065330778 31055613
63 Neelapu S. S. Tummala S. Kebriaei P. Chimeric antigen receptor T-cell therapy - assessment and management of toxicities Nature Reviews. Clinical Oncology 2018 15 1 47 62 10.1038/nrclinonc.2017.148 2-s2.0-85038265543 28925994 PMC6733403
64 Gust J. Taraseviciute A. Turtle C. J. Neurotoxicity associated with CD19-targeted CAR-T cell therapies CNS Drugs 2018 32 12 1091 1101 10.1007/s40263-018-0582-9 2-s2.0-85055968065 30387077 PMC7295115
65 Gust J. Hay K. A. Hanafi L. A. Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells Cancer Discovery 2017 7 12 1404 1419 10.1158/2159-8290.CD-17-0698 2-s2.0-85037359093 29025771 PMC5718945
66 Ahmed O. CAR-T–cell neurotoxicity: hope is on the horizon Blood 2019 133 20 2114 2116 10.1182/blood-2019-03-900985 2-s2.0-85066853750 31097533
67 Sterner R. M. Sakemura R. Cox M. J. GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts Blood 2019 133 7 697 709 10.1182/blood-2018-10-881722 2-s2.0-85058641028 30463995 PMC6376281
68 Harden A. Puebla-Osorio N. Najjar A. Modifiers of endothelial permeability in the setting of CAR-t therapy related immune cell associated neurotoxicity syndrome Biology of Blood and Marrow Transplantation 2020 26 3 p. S258 10.1016/j.bbmt.2019.12.452
69 Zhao Z. Chen Y. Francisco N. M. Zhang Y. Wu M. The application of CAR-T cell therapy in hematological malignancies: advantages and challenges Acta Pharmaceutica Sinica. B 2018 8 4 539 551 10.1016/j.apsb.2018.03.001 2-s2.0-85045003617 30109179 PMC6090008
70 Zhang E. Xu H. A new insight in chimeric antigen receptor-engineered T cells for cancer immunotherapy Journal of Hematology & Oncology 2017 10 1 p. 1 10.1186/s13045-016-0379-6 2-s2.0-85007529846 28049484 PMC5210295
71 Roybal K. T. Williams J. Z. Morsut L. Engineering T cells with customized therapeutic response programs using synthetic notch receptors Cell 2016 167 2 419 432.e16 10.1016/j.cell.2016.09.011 2-s2.0-84990855364 27693353 PMC5072533
72 Roybal K. T. Rupp L. J. Morsut L. Precision tumor recognition by T cells with combinatorial antigen-sensing circuits Cell 2016 164 4 770 779 10.1016/j.cell.2016.01.011 2-s2.0-84958214384 26830879 PMC4752902
73 Morsut L. Roybal K. T. Xiong X. Engineering customized cell sensing and response behaviors using synthetic notch receptors Cell 2016 164 4 780 791 10.1016/j.cell.2016.01.012 2-s2.0-84958230998 26830878 PMC4752866
74 Fedorov V. D. Themeli M. Sadelain M. PD-1- and CTLA-4-based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses Science Translational Medicine 2013 5 215 p. 172 10.1126/scitranslmed.3006597 PMC4238416 24337479
75 Wei G. Ding L. Wang J. Hu Y. Huang H. Advances of CD19-directed chimeric antigen receptor-modified T cells in refractory/relapsed acute lymphoblastic leukemia Experimental Hematology & Oncology 2017 6 1 1 7 28413717 10.1186/s40164-017-0070-9 PMC5391552
76 Grada Z. Hegde M. Byrd T. TanCAR: a novel bispecific chimeric antigen receptor for cancer immunotherapy Molecular Therapy-Nucleic Acids 2013 2 7, article e105 10.1038/mtna.2013.32 PMC3731887 23839099
77 Nishio N. Diaconu I. Liu H. Armed oncolytic virus enhances immune functions of chimeric antigen receptor-modified T cells in solid tumors Cancer Research 2014 74 18 5195 5205 10.1158/0008-5472.CAN-14-0697 2-s2.0-84907546628 25060519 PMC4167556
78 Shaw A. R. Porter C. E. Watanabe N. Adenovirotherapy delivering cytokine and checkpoint inhibitor augments CAR T cells against metastatic head and neck cancer Molecular Therapy 2017 25 11 2440 2451 10.1016/j.ymthe.2017.09.010 2-s2.0-85030467955 28974431 PMC5675597
79 Laborda E. Young T. S. Strategies to control CAR-T cell therapy: perspective on next-generation CARs Cell and Gene Therapy Insights 2018 4 4 275 285 10.18609/cgti.2018.028
80 Paszkiewicz P. J. Fräßle S. P. Srivastava S. Targeted antibody-mediated depletion of murine CD19 CAR T cells permanently reverses B cell aplasia The Journal of Clinical Investigation 2016 126 11 4262 4272 10.1172/JCI84813 2-s2.0-84994560141 27760047 PMC5096899
81 Jones B. S. Lamb L. S. Goldman F. Di Stasi A. Improving the safety of cell therapy products by suicide gene transfer Frontiers in Pharmacology 2014 5 p. 254 10.3389/fphar.2014.00254 PMC4245885 25505885
82 Zhou X. Dotti G. Krance R. A. Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation Blood 2015 125 26 4103 4113 10.1182/blood-2015-02-628354 2-s2.0-84933529009 25977584 PMC4481597