Targeted therapies in pediatric oncology: A start.

Introduction

The advent of pediatric oncology in the 1940s began with the demonstration of efficacy of conventional chemotherapy, first for acute lymphoblastic leukemia 1 , 2 and, with time, to other childhood cancers. 3 , 4 , 5 , 6 Significant advancements were made over the following decades, mostly through combination chemotherapy regimens, integration of surgery and radiation therapy, and supportive care. However, these advancements reached their limits until the 1990s, when the identification of novel targeted therapies were finally brought to clinical application. Since then, the types of targeted therapies and refinements therein have continued to expand, introducing many successes but also their own limitations. In this review, I will present a concerted history of the classes of targeted therapies and their applications to pediatric malignancies, organized as “immunotherapy” and “molecular therapies.” While there are additional nonpharmacologic targeted therapies, including radiology- and radiation-oncology-based approaches, those are beyond the scope of this review. I will also discuss the challenges that remain and new directions of research to address those limitations.

Immunotherapy

Cancer research continues to elucidate the complex biology of malignancies, including those key pathways that tumors must overcome to remain viable and metastasize. One such pathway, canonized as a “Hallmark of Cancer,” 7 is evasion of the patient’s immune system. By suppressing anti-tumor immunity and hijacking the microenvironment to support tumor growth, cancers sidestep a critical function of immune system. Recognition of this process led researchers to identify therapeutics that can reactivate the immune system, with increasing complexity over time.

Monoclonal antibodies

The first attempts to repurpose the patient immune system against malignancies were monoclonal antibodies (mAbs). The simplest of these were generated using mouse hybridomas, immortalized cell clusters able to generate mouse anti-human antibodies, based on the original methodology by Kӧhler and Milstein. 8 After refinement of the technique, epitopes or proteins from malignant cells, commonly the “cluster of differentiation” or CD epitopes, would be isolated and then used to stimulate the hybridomas to produce singular mAbs. These antibodies would then be tested for binding capacity to the target epitope, for stimulation of antibody-dependent cell cytotoxicity (ADCC), and in some cases for blockade of the target from its native function. Best candidates would then be trialed in human patients. In some cases, the murine antibody as generated would be sufficient for clinical use and would not be rapidly cleared by the patient’s immune system. However, commonly, the mouse component of the antibodies would trigger immune reactions and clearance of the mAbs. 9 These antibodies were then engineered at the genetic level, using methods such as phage display genetic subcloning, 10 replacing the mouse constant heavy chains for human paralogs; these “chimeric” antibodies were often quite clinically potent, but with risk of increased inflammation and development of human anti-chimeric antibodies that neutralized or cleared the mAbs. Ongoing engineering, with further replacement of mouse constant light chains and variable chains, would generate “humanized” mAbs, with less off-target inflammation and far lower rates of neutralizing human anti-human antibodies. A useful compendium of the suffixes used in naming these antibodies can be found here, elucidating the structural components of each antibody. 11

An early successful mAb for children with cancer is rituximab. 12 Targeting CD20, rituximab was added to the chemotherapy backbones of non-Hodgkin B cell lymphomas (NHLs), which tend to express CD20 robustly. Trials progressed rapidly in adults with various lymphomas, with significant improvement in efficacy and manageable toxicity when given in combination with conventional chemotherapy, 13 , 14 with similar benefit in early phase pediatric studies. 15 , 16 , 17 This led to inclusion for frontline therapy for NHLs in pediatrics, as demonstrated in Inter-B-NHL Ritux 2010 phase 3 trial, 18 with final approval from Food and Drug Administration (FDA) in 2021. While an additional molecule, obinutuzumab, had been developed for adults with B cell leukemias and lymphomas, 19 , 20 this agent has not been advanced for pediatric studies—a recurring theme in drug development.

Another success story in pediatric cancer has been the use of anti-GD2 mAbs. GD2 is a glycosphingolipid, a fat residue that is tightly maintained across species, including mouse and human. It was found to be highly and uniformly expressed on neuroblastomas, 21 , 22 , 23 with more variable expression in other pediatric solid tumors including sarcomas. 24 , 25 The original mouse antibodies against GD2 were quite efficacious preclinically 26 , 27 but rapidly neutralized in humans. 28 From there, parallel efforts proceeded in refinement of the antibody. Dinutuximab 29 , 30 was generated as a chimeric antibody against GD2, again with good preclinical efficacy but poor responses in humans when used alone. 31 , 32 Parallel studies in melanoma demonstrated that the efficacy of the antibody was augmented through combined immune stimulation. 33 As such, sargramostim 34 and interleukin-2 35 were added to the treatment regimens, resulting in robust antitumor activity (though interleukin-2 was later removed, as it was deemed to be insignificantly beneficial and quite toxic 36 ). This culminated in the Children’s Oncology Group study ANBL0032, which was stopped prematurely due to an absolute 30% improvement in 3-year disease-free survival when used in post-consolidation therapy as compared to the historical control of isotretinoin alone. 37 Long-term follow-up revealed that some of this advantage waned with time, with relapses after 3 years; however, with a 5-year estimated absolute survival advantage of 15%–20%, 38 it remains a standard approach for neuroblastoma therapy.

In parallel, this mAb was advanced in Europe but generated instead in Chinese hamster ovary cells, which induces differential immune stimulation. This product, dinutuximab beta, 36 is used widely across Europe in an analogous approach, with similar benefits to patients.

While dinutuximab has significant survival advantages, its use is quite toxic, with very high rates of infusional pain, fever, and edema requiring significant analgesic support. 37 Researchers at Memorial Sloan Kettering Cancer Center and St Jude’s Children Cancer Research Hospital each made efforts for humanized antibodies. The former led to naxitamab 39 ; while still associated with significant pain; particularly with initial cycles of infusion, it has been considered to have less off-target inflammation. 40 , 41 It received FDA approval for use against relapsed or refractory neuroblastoma in 2020. 42 The St Jude’s antibody, identified as hu14.18K332A, also demonstrated efficacy in children with neuroblastoma, 43 though it continues along the FDA approval process. All of the stated antibodies have also been additionally evaluated for use in combination with chemotherapy, both in the frontline and relapsed settings, with generally good results 44 , 45 ; the current COG phase 3 study is evaluating dinutuximab in both the induction and post-consolidation components of therapy ( NCT06172296 ).

In contrast, dinutuximab was also used in a phase 2 study for relapsed/refractory osteosarcoma, with effectively no significant benefit for those patients. 46 Those results, as well as the significant rates of neuroblastoma relapses despite treatment, highlight the limitations of mAbs, with a consensus that the immunosuppressive tumor microenvironment (TME) remains a critical barrier to optimal use.

An initial hope against TME was the so-called immuno-oncology agents or checkpoint inhibitors. The first to clinical development targeted either PD-L1 47 or PD-1, 48 key immunosuppressive signals on tumor cells or cytotoxic T-cells, respectively, or CTLA-4, 49 another immunosuppressive target on T cells. In these cases, the antibodies block the inhibitory signaling, reactivating the patient’s immune system for antitumor activity. While these have been game-changing against many adult malignancies, they have been far less effective in pediatric oncology, with some specific exceptions. These drugs are particularly efficacious against Hodgkin lymphomas, where use of the anti-PD-1 inhibiting antibody nivolumab 50 , 51 in combination with chemotherapy induces high rates of remission and long-term disease control for patients with high-risk disease; studies with the anti-PD-1 inhibiting antibody pembrolizumab alone showed efficacy in the relapsed disease setting, 52 with combination therapies under evaluation in ongoing trials. These studies also demonstrated generally no efficacy of these agents in other pediatric solid tumors, correlating with the lack of high tumor mutational burden in most pediatric tumors. Despite the limited benefits of these specific agents, researchers recognize that immunosuppressive signaling remains important in tumorigenesis and viability. Other pathways, such as CD47/SIRPα, 53 , 54 , 55 CD70, 56 TIM3, 57 , 58 , 59 , 60 and B7-H3, 61 , 62 , 63 , 64 , 65 generally in combinations with other immuno-oncology agents and/or with standard-of-care treatment, remain areas of active study.

Antibody drug conjugates

Recognizing the limitations of mAbs, researchers considered how to repurpose the antibodies. The specificity of targeting could be generally well demonstrated, but often ADCC was insufficient for clinical benefit. Instead, toxic payloads could be conjugated to the antibodies, allowing for focused cytotoxicity. These toxic payloads often used conventional chemotherapies deemed to be too toxic for systemic administration but highly efficacious when delivery could be localized against tumor cells, either in masses or in circulation. The efficacy of these antibody drug conjugates (ADCs) has been determined to be influenced by the target antigen, the toxic payload, and the chemical conjugation that links the drug and antibody. The target antigen must be specific enough to the malignant cells but accessible and highly expressed to allow for sufficient binding. The payload must similarly be highly efficacious but without excessive systemic toxicity. Payloads have changed over time, from calicheamicins (ozogamicin) 66 to antitubulins (vedotin, 67 emtansine 68 ) to topoisomerase I inhibitors (deruxtecan 69 and govitecan 70 ), with novel nonchemotherapy payloads in development. 71 The linkers determine the number of toxic payloads that can be conjugated to each antibody, the payload that can be used, and the mechanism of release. 72 In some cases, the ADC must be internalized into the cells and the payload enzymatically released; in others, the linker may be spontaneously hydrolyzed within the tumor microenvironment, releasing the payload with less specificity but more diffuse cytotoxicity.

Perhaps the most successful of these ADCs in pediatrics has been brentuximab vedotin (BV). 67 Targeting CD40, robustly expressed on Hodgkin lymphomas and some other B cell lymphomas, BV has high clinical efficacy in monotherapy with a generally tolerable toxicity profile. 73 , 74 Later studies in adult patients replaced bleomycin, associated with relatively high rates of pulmonary toxicity, with BV as part of the chemotherapy backbone of treatment, with superior outcomes and less toxicity 75 ; these results were successfully replicated in the pediatric and adolescent/young adult (AYA) population. 76 , 77 This approach has been accepted as a standard of care for high-risk Hodgkin lymphoma and is being further evaluated in CD30+ non-Hodgkin lymphomas. New studies are comparing treatment versus chemotherapy and nivolumab, as discussed above, and also the combination of BV and nivolumab. 78

Another antibody drug conjugate, gemtuzumab ozogamicin (GO), 66 has demonstrated benefits in acute myelogenous leukemia (AML), though its course to current use was more circuitous. Initially approved for use in adult in 2007 at a dose of 9 mg/m 2 twice weekly, in combination with chemotherapy, in patients 65 years and older, 79 , 80 parallel studies in children demonstrated efficacy but with hepatic and infection toxicity. 81 , 82 , 83 It was voluntarily withdrawn by the manufacturer in 2010 due to excessive toxicity post-approval. However, clinical researchers and pharmacologists hypothesized that this dosing approach led to an excessively high-peak concentration that induced the toxicity. As such, another clinical trial was conducted in combination with cytarabine and daunorubicin at an alternate dosing schema, 3 mg/m 2 weekly for 3 weeks. In the studies in adults and children, the complete remission rate was significantly higher and toxicities were manageable, 84 , 85 , 86 leading to re-approval in adults in 2017 and in children in 2020. It is now considered part of the standard of care in this patient population. Inotuzumab ozogamicin is a similar ADC, targeting CD22 and approved for use in B cell acute lymphoblastic leukemia in combination with conventional chemotherapy. 87 Similar to GO, it has high rates of efficacy, particularly in the relapsed/refractory setting and after the use of CD19-targeting therapies (discussed below); however, it has significant hepatotoxicity, most notably increasing the risk of vaso-occlusive disease (VOD) when followed by allogeneic bone marrow transplantation. 88

In contrast, ADCs have not been as successful in most pediatric solid tumors. Fam-trastuzumab deruxtecan (TDxd) has demonstrated significant benefit in adult patients with tumors with expression of the growth receptor ERBB2, also known as HER2. 89 While initially developed for tumor with gene amplification of ERBB2 , further studies in adults have demonstrated that even trace or “ultra-low” expression of HER2 sensitizes tumors to TDxd, 90 likely due to the nature of the noncovalent linker between antibody and payload, alkaline conditions in the tumor microenvironment, and efficacy of the payload without needing internalization. With these data, a phase 2 study was conducted using TDxd for relapsed/refractory pediatric solid tumors. Despite demonstration of HER2 expression, unfortunately, there were no responses in this trial. 91 That said, ongoing preclinical and off-label application of TDxd has demonstrated the potential sensitivity of Wilms tumors and desmoplastic round cell tumors, 92 leading to repurposing of the prior phase 2 study for these tumors. 91 Additional work, including alternate targets and the role of tumor microenvironment, will be needed to demonstrate why these tumors, with comparatively low HER2 expression, are sensitive to TDxd, whereas other sarcomas were resistant. Additional ADCs continue in development through preclinical and early-phase clinical trials, including against the epidermal receptor HER3, 93 retinoid orphan receptor 1 (ROR1), 94 and GD2. 95 , 96

Bispecific antibodies

While monoclonal antibodies have served their purpose, they have had significant limitations, including reliance on ADCC, unpredictable toxicity through inflammation, and inefficient target blockade. As understanding of the structure of antibodies advanced in the 1960s, followed by alternate methods of antibody manufacture through the 1970s and 1980s, new molecules could be designed and assembled. These included variants of bispecific antibodies (BsAbs). One molecule consists of distinct variable chain regions, with each “arm” capable of binding separate epitopes, but with maintenance of the constant heavy chains. These “trifunctional” antibodies have greater specificity based on binding of multiple topographically close epitopes with maintained ADCC. 97 , 98 A second molecule maintains the antigen-binding fragments (“Fab”) that are covalently linked directly to each other without the constant heavy chains; these bispecific Fab molecules can act to transactivate two separate receptors or epitopes, including those on tumor cells and adjacent immune cells, without reliance on ADCC. 98 , 99 These molecules, including the bispecific T cell engagers (BiTEs) can induce a localized activation of antitumor immunity, but they do generally have shorter half-lives and reduced stability. Numerous additional molecular variants have been developed (well summarized in https://www.genscript.com/bispecific-antibody.html .

Perhaps the most successful of these BsAbs has been blinatumomab. 100 A BiTE, blinatumomab binds CD19, found on B cell acute lymphoblastic leukemia (B-ALL) cells, and CD3, found on otherwise healthy T cells. Infusion of the BiTE into patients with B-ALL leads to rapid recruitment of T cells and a cytotoxic immune response. Blinatumomab was demonstrated to be highly efficacious against B-ALL in adults and children, first in the relapsed/refractory setting, 101 , 102 , 103 , 104 then in consolidation in sequence with conventional chemotherapy in the frontline setting. In American and international trials, the additional blinatumomab improved overall survival by 15%–40% as compared to conventional chemotherapy alone. 105 , 106 , 107 As such, it is now recommended in the United States for use for virtually all pediatric patients with B-ALL. However, use of blinatumomab is not without challenges. The half-life of the drug is approximately 2 h; as such, it must be administered as a continuous infusion for 28 days per cycle, with supply changes every 2, 3, 4, or 7 days, with minimal interruptions. It is associated with immune toxicities, particularly in patients with residual or refractory disease, including cytokine release syndrome (CRS), immune-effector-cell-associated neurotoxicity syndrome (ICANS) and other neurotoxicities, and hypogammaglobulinemia. 101 Additional BsAbs have been developed for malignancies in adults, including lymphomas, 108 , 109 multiple myeloma, 110 , 111 and small cell lung cancer, 112 but no other agents have been developed or approved for children with cancer, despite the expression of many of these targets on pediatric malignancies. Novel modifications of these and other antibodies, including longer stability, 113 , 114 , 115 , 116 , 117 , 118 trispecificity, 119 , 120 , 121 , 122 and subcutaneous formulations, 123 , 124 , 125 , 126 will further revolutionize application of these agents in pediatric oncology.

Cancer vaccines

The premise of retraining the patient’s own immune system against malignancies has led to alternate strategies than those above. Instead of generating molecules for passive immunity, researchers have proposed methods to present tumor-specific antigens and neoantigens to the immune system through “cancer vaccines.” These vaccines have been generated in numerous ways, better reviewed here. These technologies have used dendritic cells, viral vectors, nucleic acids (including mRNA vaccines), and peptides/antigen delivery, alone, with traditional adjuvants such as oral β-glucan, or in combination with cytokines and other immune stimulants. 127 While many have entered early clinical trials, most have failed to yield significant benefits against active disease. One approach that bears mentioning is the bivalent GD2-GD3 vaccine. 128 Using exogenously produced GD2 and GD3 conjugated to keyhole limpet hemocyanin (KLH), it has been administered in clinical trials after the completion of prior consolidation therapy as a maintenance approach. Comparatively nontoxic, it has generally been administered for up to seven doses. There have been some successful responses in clinical trials, after either frontline or salvage therapy 129 , 130 ; in these trials, responders manifested early and persistent antibody titers against the targets, as would be expected. While this has been further stimulated with adjuvants, the primary limitation has been the unpredictable nature of response. Nonetheless, multiple approaches continue to be developed.

Cellular therapies

The approaches described above all rely on retargeting of the patient’s immune system generally through indirect approaches, and they require the patient to have an intact and active immune system, in particular cytotoxic T cells. However, there are multiple barriers to this approach. Cancer itself is a highly immunosuppressive disease through multiple and varied mechanisms, with paracrine and endocrine effects. 131 Immune cells are often recruited by the malignant cells into the tumor microenvironment and retrained to be protective of the cancer itself, as regulatory T cells, myeloid-derived suppressor cells, tumor-associated macrophages, and cancer-associated fibroblasts. After multiple lines of cancer therapy, including conventional chemotherapy, the patient’s bone marrow is often compromised, with low levels of circulating immune cells with generally diminished viability and function. For all these reasons, generation of trained immune cells ex vivo for adoptive immunotherapy has been an area of high interest and, in some cases, very efficacious.

T cells, particularly CD8+ cytotoxic T cells, are highly efficacious against cancer cells in the right circumstances. These cells must be able to sidestep the various immunosuppressive signaling pathways active in malignancies, most notoriously the PD-1/PD-L1 path, as well as others. They must proliferate and be present in sufficient quantities. They must remain active and avoid exhaustion, a mechanism in healthy hosts to control immune reactions and avoid toxicity but that must be suppressed to maintain cancer control. They must also be able to be targeted against tumor-specific antigens in a robust and predictable way. Endogenous T cells are activated primarily through their αβ T cell receptors (TCRs) that bind antigens presented as peptides through major histocompatibility complex (MHC) presentation on antigen-presenting cells. This process of peptide processing and presentation, while very sensitive at low quantities of antigen (as low as one peptide per T cell for activation), has historically been very hard to reliably reproduce due to the complexity of the biology therein.

For these reasons, researchers examined alternative ways to train T cells against cancer antigens. They identified that membrane-bound B cell antibodies have the capacity to bind surface antigens on cells of interest without the need for MHC presentation. They then genetically engineered the production of proteins that consist of membrane antibodies fused to the transmembrane and cytoplasmic domains of TCRs required for T cell activation. These so-called “chimeric antigen receptors,” or CARs, 132 , 133 could be transduced into autologous patient T cells collected by leukapheresis to generate CAR-T cells, which could then be transfused back into patients after a course of lymphodepleting chemotherapy, to target the malignant cells of interest.

While CAR-T cells were first designed preclinically and in early phase trials in the 1980s and 1990s, 134 , 135 , 136 , 137 , 138 optimization was needed to the transmembrane and cytoplasmic domains of the TCR to maintain T cell viability and optimize T cell expansion in vivo . This process was first successfully applied clinically at the University of Pennsylvania and Children’s Hospital of Philadelphia. Researchers generated second-generation CAR-T cells that target CD19, found on B-ALL, from the autologous T cells of patients with multiply relapsed B-ALL, creating tisagenlecleucel. Three adult patients were treated in a phase 1 trial with prompt responses. 139 In the first pediatric patient to receive this CAR-T cell in the phase 1 trial, there was prompt antileukemic activity noted as well, promptly followed by what would eventually be termed cytokine release syndrome (CRS), an overwhelming showering of interleukins and cytokines that induced a shock-like phenomenon. 140 Of these, it was noted that interleukin-6 (IL-6) was particularly highly expressed and released. Tocilizumab, an anti-IL6 mAb, was administered, alongside other immunosuppressants, which suppressed the CRS sufficiently while maintaining CAR-T cell viability. With that administration, the patient entered a complete remission with complete marrow recovery. While initially meant to be a bridge to allogeneic bone marrow transplant, that patient was able to maintain a complete remission, even to this day 13 years later. Early phase trials allowed for approval of tisagenlecleucel in the United States, Europe, and Japan at third line or later, specifically for patients 1–22 years of age. 141 Published long-term data show a median 3-year overall survival as not reached and a 3-year relapse-free survival of 52%, 142 which is still quite impressive in the patients with multiply relapsed B-ALL. This work has led to the creation of six other CAR-T cell therapies for lymphomas 143 , 144 , 145 , 146 and multiple myeloma. 147 , 148 Later trials elucidated other risks of CAR-T cells, including immune-effector-cell-associated neurotoxicity syndrome (ICANS), an acute transient neurotoxicity, as well as the rare development of a chronic Parkinsonian-like sequela; these have been more commonly seen in adult patients comparatively. 149 Only tisagenlecleucel has been submitted for and received pediatric approval.

While CAR-T cells have proven to be game-changing against hematologic malignancies, they have not been as successful against solid tumors. One of the earliest efforts in this way was to again target GD2 in neuroblastomas and osteosarcomas. Early trials using first-generation CAR-T cells showed comparatively low efficacy against active disease 137 , 138 , 150 (0%–35% complete responses) though there was evidence of prolongation of disease control in patients with radiologic evidence of disease at the time of treatment (after prior salvage therapy for relapsed/refractory neuroblastoma). Those first CAR-T cells were faulted due to the lack of costimulatory domains with the CAR, resulting in poor T cell viability and early exhaustion. Since then, multiple generations of CAR-T cells against many targets including GD2, 151 , 152 , 153 B7-H3, 63 , 154 NKG2D, 60 EGFR, 155 GPC2, 156 , 157 , 158 and GPC3( NCT04377932 ) have been developed for early-phase clinical trials against pediatric solid tumors. Most of these have not shown the types of durable responses seen against B-ALL with perhaps one exception: researchers in Italy have demonstrated efficacy of their anti-GD2 CAR-T against neuroblastoma with an overall response rate of 66% in all comers and 77% in patients with “low” disease burden, with 5-year overall survival of 42% and 63%, respectively. 159 Even in this study, response was challenging to predict and primarily correlated with number of prior lines of therapy (earlier responded better), disease burden (less responded better), and timing of leukapheresis (collection at diagnosis responded better). The tumor microenvironment is widely hypothesized to contribute significantly to treatment resistance, but identification of critical targets remains an ongoing process.

There are clear limitations to CAR-T cells. First, the target antigen must be expressed on the surface of malignant cells robustly. Second, T cells can be limited by viability and exhaustion, a complex process of progressively decreased T cell activity over time. 160 , 161 Third, these cells are only active against cells with the target antigen, and downregulation of that antigen can lead to treatment resistance. 162 Additionally, most CAR-T cells have been generated from αβ T cells, which requires bespoke autologous cell production for each patient and has risks of graft-versus-host disease (GVHD). 163 Researchers are pursuing alternative options therein to sidestep these limitations, as well as reconsideration of manipulation of the actual T cell receptors for greater targeting of intracellular or low-quantity antigen. 164

Natural killer (NK) cells are a subset of lymphocytes, distinct from T and B cells, which are part of the innate immune system. Unlike T cells, which require antigen presentation through MHC, NK cells can recognize cells for targeting through a complex set of activating and inhibitory mechanisms. 165 , 166 They are routinely activated in the setting of inflammation and can be directly cytotoxic, promote antibody-dependent cell-mediated cytotoxicity (ADCC), and can cooperate with cytotoxic T cells. 166 It is theorized that a major role of these cells is clearance of senescent cells and cells early in the oncogenic process. 167 Despite this clearance function, the inhibitory cascades GVHD and can be optimized, through KIR-KIR-ligand mismatching, for best antitumor efficacy. 168 These traits have led researchers to explore NK cells as an augment to current therapies. One limitation to NK cells is the relatively low numbers in patients, 169 even more so in children with cancers who have received prior therapies. 170 Unlike with CAR-T cells, collection of NK cells from these children is generally challenging, and, even when cells are collected, they are usually poorly functioning. Researchers have developed methods to expand cells ex vivo , using combinations of co-culture and cytokine stimulation. Using anonymous MHC-characterized NK cells from healthy donors, researchers have generated banks of “off the shelf” allogeneic NK cells for clinical application. 171 , 172 In pediatrics, researchers have trialed NK cells for a number of malignancies, including AML, ALL, and neuroblastoma. Usually administered after completion of cytotoxic conventional chemotherapy and/or myeloablative chemotherapy, these cells can be administered alone or in combination with targeted mAbs or other immune stimulants. To date, such administration has been demonstrated to be safe and tolerated, with some studies reporting infrequent and transient CRS. 173 , 174 , 175 , 176 , 177 However, efficacy has been limited, with multiple hypothesized mechanisms, reviewed here. 178 One approach for greater efficacy is the generation of engineered and/or cytokine-stimulated NK cells, with loss of inhibitory signaling receptors and/or with the expression of CARs to augment specificity. 179 , 180 , 181 , 182 , 183 These methods are still in preclinical development but may offer paths forward.

Another approach to improve upon CAR-T cells has been the use of γδ T cells. These lymphocytes, less numerous than their αβ counterparts, have greater innate immunity, can be efficacious against a variety of antigens, and are not reliant on MHC presentation of antigens. These cells are also not alloreactive and can thus also be acquired from allogeneic donors for use. Research with these cells has been comparatively more limited, 184 , 185 , 186 , 187 , 188 , 189 but they are expected to be safe and tolerable. As with NK cells, current research seeks to identify ways to augment tumor specificity and activity, including the engineering of cells with CAR expression.

While not explicitly a “cell” therapy, oncolytic viruses have represented another approach to retargeting the immune system against pediatric cancers. Scientists have utilized the innate functions of common viruses, including herpes simplex virus (HSV) and adenovirus, among others, to infect cells, enter a replication and cytotoxic cycle that leads to cytolysis, and release “progeny virions” that can continue the process. 190 This infection process also induces the release of tumor-specific antigens and neoantigens, priming and reactivating the host immune system against malignant cells. 191 , 192 Engineering of these viruses has led to improved targeting of specific malignancies for greater toxicity and resilience, administered through various routes including intratumoral, intrathecal, intraventricular, and intravenous delivery. While only one oncolytic virotherapy has received FDA approval, for adults with melanoma, these therapies remain a fervent area of research, particularly for their potential use against central nervous system (CNS) tumors. 193 , 194 , 195 , 196 , 197 , 198

Viral vectors have been utilized for other diseases, most notably for delivery of gene therapies, including the treatments for muscular dystrophy 199 , 200 and sickle cell disease. 201 , 202 Similarly, researchers have made use of a number of viral vectors to induce endogenous antibody production within patient cells, termed “viro-antibody therapy.” In the past, these approaches generated both conventional antibodies and bispecific antibodies against immune-oncology targets (e.g., PD-L1 and CTLA4) 203 , 204 , 205 , 206 or tumor targets (e.g., EGFR, FAP, HER2, VEGF, and FOLR2). 207 , 208 , 209 , 210 , 211 , 212 , 213 While preclinical studies showed some potential, none attained FDA approval. In a recent approach, T cells are infected with adenovirus-associated virus (AAV) for gene transfer. These T cells are then transfused into patients and stably secrete T cell engagers, TransJoin molecules, that can persistently recruit native T cells against their target antigens on malignant cells. 214 This method is in early clinical trials but shows the promise of cell therapies in novel ways.

Molecular targeted therapies

There are numerous precision oncology approaches that do not strictly utilize the immune system. These approaches have numerous subtypes and are variably described with such nondescript labels as “small molecules,” “targeted agents,” or “biomarker-driven therapies.” None of these labels satisfactorily encompass all of these agents, due to their often multipotent effects. Nonetheless, this section will review those agents that are more classically considered “drugs” and their potential applications.

Kinase inhibitors

It has long been recognized that aberrant signal transduction is a key pathway in oncogenesis. This can result from various processes, including genetic translocations resulting in constitutively active kinases, amplification events resulting in excessive expression, or mutations in inhibitory pathways that allow for uncontrolled oncogenic signaling. The resultant kinases can be prime targets in many cases for direct inhibition through use of small molecules.

In adult and pediatric malignancies alike, the first successful inhibitor was a receptor tyrosine kinase (RTK) inhibitor, imatinib. It was designed to bind the ATP-binding pocket of the BCR-ABL fusion protein 215 , 216 that drives malignancy in chronic myelogenous leukemia (CML) as well as some B-ALL (so-called Ph+ ALL). The hypothesis behind the drug was that, by targeting specifically a fusion protein only expressed and active on the clonal malignant cells, the use of conventional chemotherapy and the toxicities therein could be avoided. Early studies were dramatic in their efficacy, quickly turning CML from a disease that could only be cured by bone marrow transplantation into a chronic disease managed with an oral pill. 217 , 218 , 219 For Ph+ALL, use of imatinib improved event-free survival from <40% in children to 60%, 220 , 221 , 222 with ongoing improvements based on treatment approach and with next-generation BCR-ABL inhibitors. 223 , 224 , 225 , 226 Since those initial drugs, a total of six BCR-ABL targeting TKIs have been developed, 227 , 228 , 229 , 230 including asciminib, which does not bind the ATP-binding pocket and thus can sidestep resistance mechanisms. Of these six, only three are approved for use in children, imatinib, dasatinib, and nilotinib. In some patients with CML who attain a deep molecular response, discontinuation of treatment is possible, though pretreatment identification of those patients is ongoing; nonetheless, select patients are “cured” with oral tyrosine kinase inhibitors (TKIs). 231 , 232

However, it quickly became obvious that these “targeted” agents were not as specific as billed. A major reason for this is the high homology between RTKs. While imatinib primarily binds BCR-ABL (and wild-type ABL), it can also bind KIT, PDGFRA, and PDGFRB, either in alternate fusions or as the wild-type protein. 233 , 234 This likely accounts for much of the on-target, off-tumor effect seen with imatinib, including edema, cytopenias, growth delays, and cardiotoxicity. While these toxicities are comparatively milder than conventional chemotherapy and certainly than BMT, they are challenging to predict and still require significant monitoring. 235

After the BCR-ABL RTKis, the pharmaceutical industry promptly expanded development of new agents for malignancies in adults. As many adult cancers rely on point mutations in driver oncogenes that were commonly RTKs, this was a reliable approach. However, because of the focus on mutated RTKs, most of these agents were not readily translatable to pediatric cancers (e.g., EGFRi). There were some exceptions, such as larotrectinib, 236 entrectinib, 237 and repotrectinib 238 for NTRK-translocated tumors, lorlatinib 239 for ALK-mutated or amplified neuroblastoma, crizotinib 240 for ALK-translocated anaplastic large cell lymphoma, and selpercatinib 241 , 242 and pralsetinib 243 for RET-mutated tumors. These tumors are all very infrequent even within pediatric oncology but do offer high efficacy, including tumoricidal effects, in cancers that were otherwise commonly refractory to chemotherapy.

Multitargeted TKIs gained interest in pediatric oncology over the last decade. Instead of focusing on a single-driver mutation, these drugs take advantage of nonspecificity to inhibit multiple oncogenic pathways. These usually include angiogenic pathways, such as AXL and VEGFR2, and proliferative signaling of wild-type RTKs such as RET and MET. Preclinical studies also suggest these agents can modulate the tumor microenvironment, as demonstrated clinically in renal and hepatic tumors in adults where combinations with anti-PD-1 antibodies shows a synergistic effect. Three drugs, cabozantinib, 244 , 245 , 246 pazopanib, 247 , 248 and regorafenib, 249 , 250 have shown activity against pediatric solid tumors, including sarcomas and neuroblastoma, and have proceeded to phase 2 and 3 clinical trials. However, in single-agent use, these drugs are generally cytostatic and inefficient in inducing tumor shrinkage; as such, combination approaches are being considered, discussed further below.

In addition to RTKs, intracellular kinases have examined as targets. BRAF is an intracellular serine/threonine kinase that is commonly altered in select pediatric tumors, including melanomas and low-grade gliomas (LGGs). BRAF can gain either point mutations, such as V600E, or gene translocations, resulting in fusion events. It is important to differentiate these events; type 1 RAF inhibitors, such as dabrafenib and encorafenib, can block point mutations but can actually induce tumor growth when used in the setting of a fusion event. 251 For low-grade gliomas, clinical researchers have made use of BRAF inhibitors, either alone or in combination with MEK inhibitors (inhibitors of the dual-specificity kinase downstream of BRAF in the signaling cascade), with good efficacy in disease control (>80%) and significant response (>50%, though most of those are partial). 252 , 253 Combination use in particular has been associated with lower rates of treatment resistance, and monotherapy of MEK inhibitors also has activity. 254 , 255 More recently, so-called “pan-RAF” inhibitors that can block signaling for both types of BRAF alterations also showed excellent outcomes in clinical trials, with FDA approval of tovorafenib 256 , 257 and ongoing studies for additional agents. In children with these BRAF-altered LGGs, treatment with an oral agent can often delay or obviate the need for radiation therapy and the associated neurocognitive effects, showing good outcomes. One benefit of tovorafenib and similar pan-RAF inhibitors is the lack of need of dual BRAF/MEK inhibition, preserving MEK inhibitors for later lines of therapy if needed.

MEK inhibitors have also been evaluated for other diseases in children, notably in neurofibromatosis type 1 (NF1). Downstream of the pathogenic mutation in the NF1 gene, MEK acts as a critical node in the development of plexiform neurofibromas (PNs), noncancerous growths that can have significant mass effect and morbidity. Two MEK inhibitors, selumetinib 258 , 259 and mirdametinib, 260 now have approval for treatment of NF1-associated PNs not amenable to complete resection, with excellent outcomes and positive impact on patient-reported outcomes.

FLT3 is an intracellular kinase that is commonly found to be amplified in AML either through internal tandem duplication or mutated in the tyrosine kinase domain. Subsequent constitutive activity is a clear disease driver with particularly poor outcomes. However, as this same alteration is commonly found in AML in adults, inhibitors have been developed for clinical use. Gilteritinib is a second-generation FLT3 inhibitor that demonstrated efficacy in combination with chemotherapy in phase 2 studies 261 , 262 for relapsed/refractory AML and is currently being evaluated in an open phase 3 study. Another FLT3 inhibitor, quizartinib, was shown to be safe and tolerated in a phase 1/2 study 263 and remains under study. FLT3 has been shown to be active, though usually not mutated, in pediatric solid tumors as well, so there may be applications of these inhibitors in other malignancies.

Other intracellular kinases remain areas of active interest, though with limited success. The aurora kinases AURKA and AURKB are serine/threonine kinases that function in different phases of mitosis, and AURKA was later found to have functions in stabilization of MYC and MYCN, key transcription factors in multiple solid tumors that have not been successfully directly targeted. Preclinical work demonstrated the efficacy of inhibition of AURKA and AURKB with direct tumoricidal effects. 264 , 265 , 266 , 267 One AURKA inhibitor, alisertib, was evaluated in phase 1 and phase 2 trials in the COG; however, at the recommended phase 2 dose, no significant efficacy was demonstrated in single-agent use. 268 , 269 Alisertib was then deprioritized by its manufacturer, prohibiting additional studies, though preclinical studies showed synergistic combinations could improve efficacy at reduced dosing, 270 , 271 , 272 , 273 , 274 avoiding dose-limiting toxicity.

Cyclin-dependent kinases (CDKs) have also been pursued as therapeutic targets both for their biological roles and the development of inhibitors for use in malignancies in adults. The CDK4/6 inhibitors ribociclib, palbociclib, and abemaciclib have all been studied in preclinical 275 , 276 , 277 , 278 , 279 and early phase trials 280 , 281 , 282 , 283 , 284 ; while single-agent use has shown prolonged disease control in some patients with brain tumors, Ewing sarcoma and neuroblastoma, few objective responses were appreciated. Current studies are investigating potential combination therapy approaches, including chemotherapy, radiation therapy, or mTOR inhibitors. Other CDKs, including CDK7 285 , 286 and CDK9, 287 are also of interest, but studies in these areas are preliminary.

As you can see, there are numerous diverse kinase inhibitors, and their applications are varied. It is worth noting that there are additional challenges in their application to pediatrics. In many cases, the pharmacokinetics of the drugs are very different in prepubescent children in contrast to adolescents and young adults. An interesting example of this is the use of lorlatinib in neuroblastoma; at the recommended adult-equivalent dose, there was limited activity against neuroblastoma, alone or with chemotherapy. However, higher dosing was tolerated in young children and then demonstrated objective responses, leading to the current recommended phase 3 dose under study in frontline disease. 239 In contrast, the toxicity profiles in children can be quite different from those seen in adults and can also be hard to predict. For example, with cabozantinib, toxicities can include thyroid suppression, appetite suppression, palmar-plantar erythrodysesthesia (PPE), diarrhea, weight loss, poor wound healing, and hair color changes; however, it is virtually impossible to predict which patients will suffer from any specific toxicity or any at all. 245 While many toxicities of conventional chemotherapy are not present with these agents, including severe cytopenias and mucositis, much care must be taken to be proactive with management of toxicities, including early use of supportive care (e.g., loperamide for diarrhea, olanzapine for nausea and loss of appetite, 288 and topical agents for PPE).

Other protein inhibitors

Beyond kinase inhibitors, there are a host of other protein inhibitors that have varied though generally narrow uses in pediatric cancers. One of the oldest class of drugs is L-asparaginase. Studies in the 1960s showed that ALL cells are particularly reliant on exogenous asparagine for viability, and the bacterial enzyme L-asparaginase induces cell death in lymphoblasts, 289 , 290 , 291 with approval of the first drug, derived from Escherichia coli , in 1978. Since then, additional versions have been developed to address different concerns. Up to 20% of patients will manifest hypersensitivity reactions to the E. coli -derived L-asparaginase, so alternative enzymes were derived from Erwinia chrysanthemi , 292 which have nonoverlapping hypersensitivity profiles. Unmodified L-asparaginases also have relatively short half-lives and must be administered either intravenously or via intramuscular injection, generally every 48 h. Manufacturers created pegylated versions with progressively longer duration of activity, requiring infusion as infrequently as monthly. 293 , 294 , 295 , 296 , 297 In clinical trials, L-asparaginase improved disease-free survival from 10% to 30% compared to control arms, showing the importance of this agent. 298 , 299 , 300 However, there are numerous toxicities associated with asparaginase, including hypersensitivity to the pegylation, silent drug immune inactivation, thrombophilia, coagulopathy, hypertriglyceridemia, pancytopenia, and pancreatitis. Current efforts to maintain efficacy but reduce toxicity will include routine use of asparaginase activity quantitation and dosimetry to optimize individualized patient dose. Outside of ALL, L-asparaginase is being investigated for use against AML 301 as well.

The proteasome inhibitor bortezomib has been examined in a number of hematologic malignancies in children with limited success except in one case: T cell lymphoblastic lymphomas (T-Lly). Later-phase clinical trials aimed to compare the addition of either bortezomib or the nucleoside analog nelarabine to conventional chemotherapy for either T-Lly or T-ALL. 302 , 303 Conventionally these diseases had been considered to be equivalent, similar to how B-Lly and B-ALL are treated with similar protocols. However, trials demonstrated that T-Lly responded to bortezomib but not nelarabine, but T-ALL responded to nelarabine and not bortezomib. While researchers further elucidate the molecular underpinnings of this difference, bortezomib has become standard of care for T-Lly.

Processes to inhibit the lysine methyltransferase KMT2A (previously known as MLL) have long been sought out for both B-ALL, where the t(4;11) translocation in infants is associated with abysmal disease outcomes, 304 and for AML, particularly therapy-related secondary AML, also with poor survival. 305 In these tumors, KMT2A is perturbed through the translocation event and relies on key partners for altered epigenetic signaling. One of these partner proteins, menin, works as a scaffold for the larger epigenetic machinery that drives leukemogenesis. Menin inhibitors are now coming to market, with revumenib being the first agent to achieve FDA approval in relapsed/refractory KMT2A-altered AML, 306 in combination with chemotherapy. Current studies are evaluating this drug in the frontline setting for AML and infant ALL as well as for AML with NPM1 mutations.

Anti-apoptotic pathways have always been of high interest across pediatric tumors as a critical nexus for chemotherapy resistance. Mitochondrial processes are critical to pro- and anti-apoptosis, with the latter driven by BCL2 family members including BCL2, BCL2L1 (AKA Bcl-X(L)), and MCL1, which act at the mitochondrial membrane to prevent TP53 activation and the release of reactive oxidative species. 307 Inhibitors to BCL2 and MCL1, venetoclax and navitoclax, respectively, were developed for clinical use, including in pediatric malignancies. The former has had good success in hematologic malignancies; having received approval in multiple adult hematologic cancers, 308 , 309 , 310 , 311 , 312 it is currently being studied in relapsed AML 313 ( NCT05183035 ) and phase 2 studies with combination therapies for ALL 314 ( NCT06863259 and NCT06561074 ). Navitoclax, in contrast, failed to demonstrate benefit against solid tumors, likely due to the high homology of the BCL2 family members and reflexive upregulation of MCL1 BCL2 and BCL2L1 in response to BCL2 inhibition. 315 New agents are in preclinical development for combined inhibition of all BCL2 family members.

Telomere maintenance mechanisms (TMMs) have been implicated as a predictive biomarker of therapeutic resistance and a major cause of disease relapse across multiple pediatric malignancies, including leukemias, sarcomas, and neuroblastoma. 316 , 317 , 318 , 319 , 320 , 321 The approach to pharmacologic disruption of these pathways continues to evolve. The most obvious approach, direct inhibition of telomerase, led to the development of imetelstat, a modified oligonucleotide that disrupts the enzymatic function. 322 Initially studied in a host of malignancies in adults in children, it was advanced in pediatrics for extracranial solid tumors, 323 brain tumors, 324 and leukemias. 325 While found to be safe and tolerable, it had very limited efficacy in bone sarcomas and no objective responses in brain tumors. It has found a second life with recent approval in low-risk myelodysplastic syndrome (MDS) in adults, 326 leading to a combination clinical trial with chemotherapy in children with AML, MDS, or juvenile myelomonocytic leukemia ( NCT06247787 ). Another way to target maintenance has been through its interacting proteins. ATM and ATR are DNA damage response serine/threonine kinases, which, through mechanisms that are still being elucidated, help to recruit telomerase to telomeres. 327 , 328 , 329 It had been previously appreciated that ATM and ATR inhibitors had efficacy against numerous tumor types in preclinical testing, including neuroblastoma, 330 , 331 , 332 sarcomas, 333 , 334 and high-grade glioma. 335 , 336 , 337 Regrettably, because of limited efficacy against adult cancers, many of these drugs have been deprioritized by their manufacturer, though one, AZD1390, remains under evaluation in high-grade glioma with radiation in children. 338

Few pediatric tumors harbor driver oncogenic point mutations; instead, larger chromosomal changes and epigenetic changes often drive disease biology. Efforts to identify efficacious epigenetic modifiers have been ongoing but challenging. Tazemetostat, an EZH2 inhibitor that is intended to reactive expression of tumor suppressors, was expected to have broader activity, as EZH2 has been implicated in numerous solid tumors including brain tumors, 339 , 340 neuroblastomas, 341 sarcomas, 342 and INI1-deficient tumors. 343 However, it is currently only approved for adolescents and young adults with epithelioid sarcomas, 344 as well as for adults with follicular lymphomas. 345 This is likely due to the broad activity of EZH2 as part of the polycomb repressive complex 2 (PRC2), a critical regulator of normal biology throughout the body; as a result, cancer-specific targeting is highly challenging. Another limitation of epigenetic modifiers is the long time to effect, with treatment often requiring weeks of administration before a change in epigenetic profiles but prompt reversion to the baseline signature with discontinuation of the drug. This has limited other epigenetic modifiers, including bromodomain and extra-terminal motif (BET) protein inhibitors, which alter the recognition of histone acetylation by transcriptional machinery. While BET inhibitors have strong efficacy in preclinical models of disease, including numerous pediatric solid tumors, virtually all agents have failed in single-agent clinical trials. 346 , 347 , 348 New approaches to epigenetic modification, including the use of protein degraders such as proteolysis-targeting chimeras (PROTACs) 349 may eventually improve efficacy while limiting toxicity.

A recently approved drug for pediatric cancers has been the hypoxia inducible factor 2a (HIF2A) inhibitor belzutifan. 350 As its name suggests, HIF2A is constitutively expressed but activated, through dimerization with HIF1B, under conditions of hypoxia or pseudohypoxia to induce broad transcriptional changes that promote neovascularization, antiapoptosis, proliferation, and metastasis. In Von Hippel Lindau (VHL) syndrome, VHL has a loss-of-function mutation resulting in persistent activation of HIF2A and growth of various tumors and cancers. 351 Belzutifan directly binds HIF2A and prevents dimerization. It is currently approved for use in children, adolescents, and adults with VHL syndrome and associated tumors, including hemangioblastomas, pheochromocytomas, and paragangliomas, 352 with multiple ongoing studies in additional indications. More broadly, hypoxic conditions have been described in the tumor microenvironments of virtually all pediatric malignancies 353 , 354 , 355 , 356 , 357 , 358 , 359 and has been associated with antiapoptosis, viability, and cancer “stemness.” As a result, HIF2A inhibitors may have a role in combination with current antineoplastic therapies.

The most recently approved drug for pediatric cancers is dordaviprone. It is a first-in-class imipridone with complex cellular effects. It was first identified through a small-molecule screen to identify inducers of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). 360 Further characterization demonstrated that it also inhibits the D 2 dopamine receptor 361 and induces activity of the mitochondrial caseinolytic protease P. 362 H3K27M-mutant diffuse midline gliomas, among other tumors, were found to be sensitive to the effects of dordaviprone and studied in a number of single-arm early-phase trials, 363 , 364 , 365 showing a cumulative overall response rate of 22% and median duration of response of 10.3 months when used after frontline radiation therapy. It received accelerated approval for use in DIPG after progression after radiation therapy, and ongoing approval is contingent on the ongoing phase 3 trial. 366 This drug does highlight the potential of novel classes of drugs for use against pediatric cancers, as well as the diverse effects that such agents may have against tumors, supporting ongoing research even after regulatory approval.

Anti-metabolic agents and differentiation agents

Many pediatric cancers are theorized to result from a premature halt of normal differentiation and development. While this theory is best demonstrated in embryonal malignancies, e.g., neuroblastoma, Wilms tumor, medulloblastoma, etc., features of this process have been identified across the range of malignancy in children. Studies from the 1940s considered lack of differentiation could be due, part, to vitamin deficiencies. 367 , 368 , 369 , 370 Furthermore, researchers hypothesized that so-called differentiation drugs could induce these malignant cells to subsequently undergo terminal differentiation, becoming permanently benign neoplastic cells or undergoing apoptosis in response to cellular instability. The retinoids, vitamin A derivatives, were examined as early as the 1970s across many malignancies. 371 , 372 , 373 , 374 , 375 These studies demonstrated that retinoids have diverse effects in cells, many of which are induced by binding of retinoic acid receptors 376 , 377 with differential effects on cell transcription and responses to various stimuli in the cell. Despite great initial interest, most formulations of retinoic acid, including all- trans retinoic acid (ATRA) and 13- cis retinoic acid, also known as isotretinoin, failed to have clinical impact in most cancers, 378 , 379 , 380 , 381 with two notable exceptions in children. ATRA was demonstrated to be active against acute promyelocytic leukemia (APL), a rare AML variant seen in adults and children and defined by the t(15;17) translocation involving the RARA gene locus. ATRA, in combination with arsenic trioxide (which had long been used in various ways in traditional Chinese medicine), led to dramatic and prompt remission in patients with standard-risk APL 382 , 383 , 384 , 385 and improved outcomes with chemotherapy in high-risk disease, 386 , 387 , 388 leading to FDA approval and use as standard of care for this disease in 2000. While sparing many of the long-term complications of chemotherapy, ATRA is notorious for induction of ATRA differentiation syndrome in these patients, 389 with massive cytokine release, acute respiratory distress, disseminated intravascular coagulation, and shock; however, if managed in a timely fashion, this can be managed with mortality of <5%. This does appear to be a phenomenon associated with APL alone.

Isotretinoin was similarly shown preclinically to have great efficacy against neuroblastoma. 390 , 391 Translation of isotretinoin to clinical use was best demonstrated in the Children’s Cancer Group trial A3973, where patients with high-risk disease treated with high-dose chemotherapy, radiation therapy, and autologous stem cell rescue followed by isotretinoin maintenance after induction chemotherapy had superior event-free survival compared to patients treated with conventional chemotherapy and radiation alone. 392 Isotretinoin has remained a part of standard therapy in the United States as a result, with some evidence of induction of GD2 expression sensitizing cancer cells to dinutuximab. It is interesting that the studies of isotretinoin in Europe failed to show significant benefit, though the dosing approach was different than that used in the United States. 393 A later study from the UK demonstrated variable pharmacokinetics of isotretinoin based on age, body weight, and the need to extract medication from capsules for young children unable to swallow the capsules, 394 a consideration that may merit re-examination. Currently, isotretinoin is being considered for use in patients with bilateral Wilms tumor or otherwise predisposed to Wilms tumor, though this approach needs validation in a prospective clinical trial.

These studies showed that the retinoids also had effects on tumor energetics and metabolomics. It has been recognized that cancers often utilize alternative energy pathways, including the Warburg effect 395 and the ornithine decarboxylase cycle 396 , 397 (ODC), to remain viable independently of oxidative phosphorylation. Inhibition of these pathways seemed to potentiate the effects of the retinoids, and vice versa. 398 , 399 , 400 , 401 , 402 Difluoromethylornithine (DFMO), also known as eflornithine, is an inhibitor of ODC used against the parasites that cause trypanosomiasis. 403 Researchers showed it was efficacious against the human homolog ODC1, 404 , 405 and it was studied in combination with isotretinoin as early as the 1980s preclinically with good results. 402 , 406 , 407 , 408 , 409 However, there was concern that the high dosing of DFMO necessary for ODC1 inhibition in humans was associated with ototoxicity and risk of cytopenias, leading to decreased interest. In the 2000s, researchers renewed interest in DFMO against neuroblastoma specifically, thought to be sensitized to its effects because of MYCN amplification and MYC overexpression, either of which upregulates ODC1 expression. 410 , 411 , 412 , 413 , 414 One set of clinical researchers built off this work to use DFMO as a maintenance agent after post-consolidation therapy for neuroblastoma, with a chronic low-dose (500 mg/m 2 twice daily) approach. In their clinical trial, there seemed to be a benefit of use of DFMO in patients with high-risk neuroblastoma who attained a complete response at the end of consolidation therapy, as compared to an external control propensity-score-matched cohort. 415 The study design and the treatment dose were controversial, as this dose had been considered to be ineffective against ODC1 preclinically 416 , 417 ; nonetheless, DFMO was approved for use after frontline therapy in 2023. In parallel, researchers have trialed higher-dose DFMO (2500 mg/m 2 twice daily) in combination with other agents, including chemoimmunotherapy, for neuroblastoma and medulloblastoma ( NCT03794349 ); toxicity was significantly higher, requiring pulse treatment, and early studies have failed to show clinical efficacy as compared to prospective randomized control cohorts. 418 It is also being examined against other tumors, including sarcomas. 419 , 420 More research is needed to elucidate if other pathways are being impacted by DFMO, which may identify rational drug combinations, as well as optimal timing of therapy.

Barriers and future directions

There are currently 98 distinct FDA approvals for antineoplastic medications against pediatric cancers, with 78 of those approval since 1994, summarized in Tables 1 and 2 . In contrast, 573 agents were approved for malignancies in adults between January 2000 and October 2022. There are some pragmatic reasons for this disparity. Pediatric cancers uncommonly are dependent on a targetable hotspot driver mutation; as such, development of single-agent therapies is unlikely, requiring novel study designs including combination therapies. Pediatric cancers represent less than 1% of all cancers in the United States, making it challenging from a business model to invest in pediatric cancer research and limiting enrollments on conventionally designed clinical trials. There are dozens of distinct pediatric malignancies, further complicating the application of novel agents to any single disease type. Young children often also need alternative drug formulations of oral agents, such as sprinkles, mini-pills, or liquid formulations, slowing drug development. That said, surmountable disparities continue to occur, including delays to first-in-pediatric studies even when there is a clear application, such as the development of lorlatinib, rituximab, and ATRA as noted above. Table 1 FDA-approved immunotherapeutics for pediatric malignancies Therapeutic name Type of therapeutic Target Disease indication References Dinutuximab chimeric mAb GD2 high-risk neuroblastoma having achieved at least a partial response to first-line multimodality therapy, with sargramostim, IL-2, and isotretinoin Yu et al. 37 ; Yu et al. 38 Avelumab fully human mAb PD-L1 advanced Merkel cell carcinoma, ≥12 y/o D'Angelo et al. 427 ; D'Angelo et al. 428 Pembrolizumab (IV/SC) humanized mAb PD-1 MSI-H, TMB-H, or dMMR solid tumors, ≥12 y/o; adjuvant use stage IIB, IIC, III melanoma, ≥12 y/o; advanced Merkel cell carcinoma, ≥12 y/o; refractory classical Hodgkin lymphoma after 2+ lines of therapy Geoerger et al. 52 ; Kuruvilla et al. 429 ; Marabelle et al. 430 ; Le et al. 431 Naxitamab humanized mAb GD2 relapsed/refractory neuroblastoma ≥1 year/o, with sargramostim Mora et al. 42 Rituximab chimeric mAb CD20 diffuse large B-cell lymphoma, Burkitt lymphoma, Burkitt-like lymphoma, or mature B-cell acute leukemia, with chemotherapy, ≥6 m/o Minard-Colin et al. 18 Nivolumab and relatlimab fully human mAbs PD-1/LAG3 advanced melanoma, ≥12 y/o Long et al. 432 Nivolumab fully human mAb PD-1 adjuvant use stage IIB, IIC, III melanoma, ≥12 y/o Kirkwood et al. 433 Nivolumab and Ipilimumab fully human mAbs PD-1/CTLA-4 MSI-H, dMMR CRC, ≥12 y/o; advanced melanoma, ≥12 y/o Andre et al. 434 ; Larkin et al. 435 Atezolizumab humanized mAb PD-L1 advanced Alveolar soft parts sarcoma, ≥2 y/o Chen et al. 436 Gemtuzumab ozogamicin antibody-drug conjugate CD33 CD33+ AML, ≥1 m/o OR relapsed/refractory AML, ≥2 y/o Pollard et al. 85 ; Gamis et al. 86 Brentuximab vedotin antibody-drug conjugate CD30 HR classical Hodgkin lymphoma, with AVE-PC chemotherapy, ≥2 y/o Locatelli et al. 76 ; Castellino et al. 77 Inotuzumab ozogamicin antibody-drug conjugate CD22 relapsed/refractory CD22+ B-ALL, MSI-H, dMMR CRC, ≥1 year/o Pennesi et al. 87 ; O'Brien et al. 437 Blinatumomab bispecific T cell engager CD19-CD3 CD19+ Ph- B-ALL in consolidation of frontline therapy or in relapsed therapy Hogan et al. 101 ; Locatelli et al. 102 ; Brown et al. 103 ; Dombret et al. 104 ; Gupta et al. 105 ; Litzow et al. 106 ; van der Sluis et al. 107 Tisagenlecleucel CAR-T cell CD19 B-ALL, refractory or in second or later relapse, up to 25 y/o Laetsch et al. 142 Table 2 Molecular-targeted therapies Therapeutic name Type of therapeutic Primary target Disease indication References Imatinib tyrosine kinase inhibitor BCR-ABL Ph+ B-ALL, with chemotherapy; Ph+ CML in chronic phase Talpaz et al. 217 ; Druker et al. 218 ; Kantarjian et al. 219 ; Manabe et al. 220 ; Biondi et al. 221 ; Schultz et al. 222 Dasatinib tyrosine kinase inhibitor BCR-ABL Ph+ B-ALL with chemotherapy, ≥1 year/o; Ph+ CML in chronic phase, ≥1 year/o Hunger et al. 223 ; Shen et al. 224 ; Slayton et al. 226 Nilotinib tyrosine kinase inhibitor BCR-ABL Ph+ B-ALL with chemotherapy, ≥1 year/o; Ph+ CML in chronic or accelerated phase after at least 1 prior line of therapy, ≥1 year/o Hijiya et al. 225 ; Chalandon et al. 228 Larotrectinib tyrosine kinase inhibitor NTRK1/2/3 advanced solid tumor with NTRK gene fusion Hong et al. 236 Pralsetinib tyrosine kinase inhibitor RET RET-mutant medullary thyroid cancer or RET-fusion-positive radioactive iodine-refractory thyroid cancer Hamidi et al. 243 Crizotinib tyrosine kinase inhibitor ALK, MET, ROS1 advanced ALK-positive inflammatory myofibroblastic tumor, ≥1 year/o; relapsed/refractory ALK-positive ALCL Brugieres et al. 240 ; Balis et al. 438 Cabozantinib tyrosine kinase inhibitor multitargeted advanced neuroendocrine tumors, ≥12 y/o; Differentiated thyroid cancer after prior VEGF targeting therapy and radioactive-iodine refractory/ineligible, ≥12 y/o Chan et al. 439 ; Capdevila et al. 440 Dabrafenib + Trametinib serine/threonine kinase inhibitor BRAF V600E (Class 1) relapsed/refractory solid tumors with BRAF V600E mutation, ≥1 year/o; pediatric low-grade glioma with BRAF V600E mutation, ≥1 year/o Barbato et al. 441 ; Whitlock et al. 442 Bosutinib tyrosine kinase inhibitor BCR-ABL Ph+ CML in chronic phase, ≥1 year/o Brivio et al. 229 Entrectinib tyrosine kinase inhibitor NTRK1/2/3, ROS1, ALK advanced solid tumor with NTRK gene fusion Desai et al. 237 Tovorafenib serine/threonine kinase inhibitor BRAF (Class 2) relapsed/refractory pediatric low-grade glioma with BRAF alteration, ≥6 m/o van Tilburg et al. 256 ; Kilburn et al. 257 Selpercatinib tyrosine kinase inhibitor RET advanced solid tumor with RET gene fusion, ≥2 y/o; medullary thyroid cancer with RET mutation, ≥2 y/o Chiu et al. 241 ; Bradford et al. 242 Repotrectinib tyrosine kinase inhibitor NTRK1/2/3, ROS1 advanced solid tumor with NTRK gene fusion Yang and Laetsch 238 Mirdametinib dual-specificity kinase inhibitor MEK unresectable plexiform neurofibroma in patient with NF1, ≥2 y/o Moertel et al. 260 Selumetinib dual-specificity kinase inhibitor MEK symptomatic inoperable plexiform neurofibroma in patients with NF1, ≥1 year/o Chen et al. 258 ; Gross et al. 259 Everolimus Cis -trans prolyl isomerase inhibitor mTORC1 complex (via FKBP1A) unresectable subependymal giant cell astrocytoma in patients with TSC, ≥1 year/o French et al. 443 Tazemetostat methyltransferase inhibitor EZH2 advanced epithelioid sarcoma Gounder et al. 344 Vorasidenib decarboxylase inhibitor IDH1/2 grade 2 astrocytoma or oligodendroglioma with IDH1 or IDH2 mutation following surgery Mellinghoff et al. 444 Revumenib menin inhibitor Menin/KMT2A relapsed/refractory acute leukemia with KMT2A or NPM1 translocation, ≥1 year/o Issa et al. 306 ; Arellano et al. 445 Belzutifan transcription factor inhibitor HIF2A advanced pheochromocytoma or paraganglioma, ≥12 y/o Jimenez et al. 446 Dordaviprone pluripotent effects D2 dopamine receptor, CLpP diffuse midline glioma with H3K27M mutation, progressive after radiation therapy Chi et al. 363 ; Duchatel et al. 364 ; Gardner et al. 365 Asparaginase bacterial enzyme asparagine ALL with chemotherapy Ortega et al. 447 Pegaspargase bacterial enzyme asparagine ALL, first-line, or hypersensitivity to asparaginase, with chemotherapy Avramis et al. 296 ; Vrooman et al. 298 Asparaginase Erwinia chrisanthemi bacterial enzyme asparagine ALL in patients with hypersensitivity to E. coli -derived asparaginase, with chemotherapy Vrooman et al. 448 ; Vrooman et al. 449 Calaspargase bacterial enzyme asparagine ALL with chemotherapy, 1 m/o-21 y/o Angiolillo et al. 297 Asparaginase Erwinia chrysanthemi (recombinant) bacterial enzyme asparagine ALL or lymphoblastic lymphoma in patients with hypersensitivity to E. coli-derived asparaginase, ≥1 m/o Maese et al. 450 Tretinoin differentiation agent PML-RARA APL, refractory to, relapsed from, or contraindicated to anthracycline chemotherapy Bapna et al. 382 ; Tallman et al. 383 ; Zheng et al. 384 ; Kutny et al. 385 ; Kutny et al. 386 ; Zhang et al. 387 ; Kutny et al. 388 Isotretinoin differentiation agent RARA high-risk neuroblastoma, with dinutuximab Matthay et al. 392 Eflornithine differentiation agent ODC1 high-risk neuroblastoma, after multimodal therapy including anti-GD2 immunotherapy with at least partial response Oesterheld et al. 415

Pharmaceutical companies, academia, advocacy groups, and regulatory groups are coming together to tackle these challenges, as noted in ongoing clinical trials listed in Table 3 . Legislative changes have required companies to consider pediatric applications of any new drug, in the United States within 60 days of the End-Of-Phase 2 study report to the FDA, and waivers for any agents must be specifically justified. There are also incentives for pediatric drug development, in the form of priority review vouchers for companies who attain a first-in-pediatrics approval for their drug and 6-month extension of patent and market exclusivity for any existing drug used in pediatric trials (regardless of final approval). 421 , 422 Initiatives such as the ACCELERATE Platform, 423 Innovative Therapies for Children and adolescents with Cancer (ITCC), 424 and the Pediatric Early Phase Clinical Trials Network (PEP-CTN) 425 have strengthened partnerships between academia and pharma to expedite and prioritize applications of agents in pediatric cancers. Advocacy groups—too numerous to list here without risk of excluding key partners—have demonstrated the importance of concerted focus on new targeted therapies for children with cancer, positively influencing stakeholders and providing critical funding. Table 3 Targeted agents pending regulatory approval or label extension Therapeutic name Therapeutic class Target Relevant disease(s) Pertinent clinical trial(s) Dinutuximab mAb GD2 neuroblastoma NCT07261241 , NCT06995872 , NCT06450041 , NCT06172296 Naxitamab mAb GD2 neuroblastoma NCT06528496 , NCT06438614 , NCT05489887 Dinutuximab beta mAb GD2 pediatric solid tumors NCT06485947 , NCT06839703 , NCT05558280 , NCT04221035 Hu14.18 mAb GD2 neuroblastoma NCT01857934 Nivolumab mAb PD-L1 pediatric solid tumors NCT06712875 , NCT06639607 , NCT05675410 , NCT05352828 , NCT05255601 , NCT04759586 , NCT04546399 , NCT03907488 Daratumumab mAb CD38 T-ALL and T cell lymphoma NCT07072585 Cobolimab and dostarlimab mAb TIM3/PD-1 pediatric solid tumors NCT06521567 Trastuzumab deruxtecan ADC HER2 pediatric solid tumors NCT04616560 Patritumab deruxtecan ADC HER3 pediatric solid tumors NCT06941272 Zilovertamab Vedotin ADC ROR1 pediatric solid tumors NCT06395103 AZD4512 ADC CD22 B-ALL NCT07109219 Brentuximab Vedotin ADC CD30 Hodgkin lymphoma NCT05675410 , NCT03907488 Brentuximab Vedotin and Nivolumab ADC and mAb CD30 and PD-L1 early-stage Hodgkin lymphoma NCT03712202 Inotuzumab ozogamicin ADC CD22 B-ALL and B lymphoblastic lymphoma NCT03959085 , NCT03913559 , NCT02981628 Blinatumomab and (dasatinib or imatinib) BsAb and TKI CD19 and BCR-ABL Ph+ B-ALL NCT06124157 Blinatumomab and venetoclax BsAb and BCL2 inhibitor CD19 and BCL2 infant ALL NCT06317662 Blinatumomab and nivolumab BsAb and mAb CD19 and PD-L1 relapsed B-ALL NCT04546399 Subcutaneous blinatumomab BsAb CD19 relapsed/refractory or MRD-positive B-ALL NCT07134088 Bivalent vaccine cancer vaccine GD2 and GD3 neuroblastoma NCT06057948 , NCT04936529 Combination vaccine approach dendritic cell vaccine, adoptive T cell therapy, mAb Tumor antigens and PD-L1 medulloblastoma NCT06514898 RNA lipid particle cancer vaccine Tumor neoantigens high-grade glioma, osteosarcoma NCT05660408 , NCT04573140 PEP-CMV cancer vaccine CMV antigen high-grade glioma, DIPG, medulloblastoma NCT05096481 Various CAR-T Cell GD2 neuroblastoma, brain tumors NCT03373097 , NCT05298995 , NCT04539366 , NCT04196413 , NCT04099797 , NCT03721068 PHOX2B PC-CAR-T CAR-T Cell PHOX2B neuroblastoma NCT07007117 Autologous B&-H3 CAR-T CAR-T cell B7-H3 solid tumors NCT06500819 VNX-101 viro-antibody therapy CD19 hematologic malignancies NCT06533579 Asciminib TKI BCR-ABL CML NCT04925479 Larotrectinib TKI NTRK1/2/3 high-grade glioma NCT04655404 Entrectinib TKI NTRK1/2/3; ROS1 CNS tumors; solid tumors NCT06528691 , NCT05770544 Repotrectinib TKI NTRK1/2/3, ALK, ROS1 solid tumors NCT04094610 , NCT05004116 Lorlatinib TKI ALK, ROS1 neuroblastoma, high-grade glioma NCT03126916 , NCT06333899 Regorafenib TKI Multitargeted Ewing sarcoma, osteosarcoma NCT06820957 , NCT04803877 Cabozantinib, with or without chemotherapy TKI Multitargeted osteosarcoma, solid tumors NCT06341712 , NCT06156410 , NCT05691478 , NCT05135975 Tovorafenib serine/threonine kinase inhibitor Altered BRAF protein gliomas, Langerhans cell histiocytosis, craniopharyngioma NCT07206849 , NCT06381570 , NCT05828069 , NCT05566795 , NCT05465174 , NCT04775485 Dabrafenib and trametinib kinase inhibitors BRAF V600E/MEK solid tumors NCT05868629 Trametinib and chemotherapy kinase inhibitor MEK hematologic malignancies NCT05658640 Binimetinib kinase inhibitor MEK pediatric adamantinomatous craniopharyngioma NCT05286788 Selumetinib kinase inhibitor MEK low-grade glioma NCT04576117 , NCT04166409 , NCT03871257 Mirdametinib kinase inhibitor MEK low-grade glioma, histiocytic disorders NCT04923126 , NCT06153173 Avutometinib RAF/MEK clamp MEK solid tumors NCT06104488 Gilteritinib kinase inhibitor FLT3 AML NCT04293562 Quizartinib and chemotherapy kinase inhibitor FLT3 AML NCT06262438 , NCT03793478 Palbociclib and chemotherapy cyclin inhibitor CDK4/6 acute lymphoblastic leukemia, solid tumors NCT04996160 , NCT03792256 , NCT03709680 Ribociclib and Everolimus cyclin inhibitor/mTOR inhibitor CDK4/6; mTORC1 high-grade gliomas NCT05843253 Abemaciclib and chemotherapy cyclin inhibitor CDK4/6 high-grade glioma, Ewing sarcoma NCT06413706 , NCT05440786 Olutasidenib and chemotherapy IDH1 inhibitor IDH1 high-grade gliomas NCT06161974 Vorasidenib and chemotherapy IDH inhibitor IDH1/2 IDH-mutant gliomas NCT06478212 Revumenib and chemotherapy menin inhibitor menin acute leukemias NCT06177067 , NCT05761171 Ziftomenib and chemotherapy menin inhibitor menin acute leukemias NCT06448013 , NCT06376162 Venetoclax with various combinations BCL2 inhibitor BCL2 acute leukemias NCT07175415 , NCT07133997 , NCT06863259 , NCT06561074 , NCT06317662 , NCT06177067 , NCT05751044 , NCT05745714 , NCT05183035

New approaches must build on these pragmatic advancements to further treatment for childhood malignancies. New treatment modalities, including PROTACs, immunomodulators such as celebron-E3 ligase modulators, trispecific antibodies, and multispecific cell therapies, can be used to target previously “undruggable” targets, including transcription factors such as MYCN. Combination therapies must be identified to take advantage of synthetic lethality, to augment therapeutic targeting (such as the dual approach of the immunoglobulin G1 [IgG1]-derived BsAb amivantamab, targeting and blocking EGFR and MET, and the TKI Lazertinib, inhibiting EGFR, in non-small-cell lung cancer 426 ) and to use synergy to use reduced doses of drugs, minimize toxicity, and maintain or even surpass efficacy, as has been shown to be possible in preclinical models. Single-agent trials, while important to define drug toxicity profiles in patients, should be limited to only what is necessary, particularly in cases where combination therapies must be used for tumor reduction (such as with TKIs in tumors without driver mutations). Novel trial designs must also be developed, including variations on n = 1 studies, Bayesian approaches, and greater use of pharmacokinetic and pharmacodynamic biomarkers to indicate efficacious drug dose, not just maximally tolerated dose. Finally, legislative and administrative approaches must be updated to incentivize development of therapeutics for pediatric patients in a more robust way while also strengthening the penalties of failure to do so, given the numerous agents described within this review that have potential roles for childhood cancers but have never undergone clinical trials. These are just the tip of the spear that will drive the new era of targeted therapeutic approaches against pediatric cancers.

Acknowledgments

N.S. has an ongoing investigator-initiated trial with 10.13039/100010544 Exelixis ( NCT05135975 ); he receives no direct compensation from that trial, but the company does provide all funding support of the trial. He has no other acknowledgments or disclosures.

Author contributions

N.S. performed all planning, research, and writing of the manuscript.

Declaration of interests

N.S. has an investigator-initiated trial funded by Exelixis, Inc. ( NCT05135975 ) but receives no direct financial compensation. He has no other financial conflicts of interest or conflicts of effort.

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