Why Pediatric CAR ‐T Therapies Still Lag Behind: Insights from Six Treatments Centrally Approved in Europe

Significant advances have been made in chimeric antigen receptor (CAR) T-cell therapy within the field of pediatric oncology in recent years. Yet, of the six currently approved CAR-T therapies in oncology in the EU, only one is authorized for use in pediatric patients. With more than 40 CAR-T products targeting pediatric populations currently in clinical development, there is a need for a better understanding of the dynamism and current limitations associated with the development of CAR-T therapies in childhood malignancies. CAR T-cell therapies have shown considerable potential in oncology in recent years.1 Yet pediatric indications remain limited: Of the six currently approved CAR-T therapies at EU level following positive opinion by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency's (EMA), only one—tisagenlecleucel (Kymriah®)—is authorized for use in pediatric patients with B-cell acute lymphoblastic leukemia (ALL) as of 2024.2 Nevertheless, according to the World Health Organization (WHO), 46 CAR-T products targeting pediatric populations are currently in phase I or II clinical trials.3 This context highlights both the dynamism and current limitations associated with CAR-T therapies in childhood malignancies.4-7 In light of the rapidly evolving CAR-T landscape, characterized by the emergence of new products and indications, it is essential to update regulatory analyses and clinical strategies regularly, ensuring alignment with the latest scientific and technological advances. Equally important, the rapid progress underscores the ethical imperative to involve patient families in clinical decision-making and to ensure research protocols are sensitive to the unique needs of pediatric patients.6 Within the European regulatory framework, pediatric development is structured through defined procedural pathways. Applicants are required to either submit a product-specific waiver, which exempts them from generating pediatric data for a given specific condition and pediatric subset, or submit a PIP, generally established per condition, outlining the studies intended to support pediatric development. An agreed PIP may subsequently be changed through a Modification of PIP. Waivers and deferrals may be granted at either the initial PIP stage or during its modification. The objective of this study was to examine how regulatory decisions reflected in Pediatric Investigation Plans (PIPs) have shaped the development of CAR-T therapies for children, using a systematic review of European Medicines Agency (EMA) records to identify key trends and limitations. We conducted a systematic review of pediatric procedures registered in the IRIS system, the secure online platform managing regulatory procedures with the EMA. Product-specific waiver and both initial and modification PIPs for all currently marketed CAR-T cell therapies were identified between 2014 and 2024. The analysis focused primarily on waivers, with some emphasis on the scope and content of pediatric development obligations. Deferrals in PIP were briefly described to provide some information on study implementation. Waivers were considered irrespective of whether they were granted as standalone decisions or within an agreed PIP. Each document was independently screened, and the rationale for full or partial pediatric study waivers was extracted, categorized as technical, population-based, or implementation-based reasons, according to information available in opinion documents. Where available, modifications and justifications for amendments were cross-checked to ensure longitudinal consistency in regulatory decision-making. For PIPs with a partial waiver in their latest amendments, marketing authorization decisions were reviewed to determine whether the accepted pediatric studies had resulted in an indication extension or remained pending at the time of the review. Limitations of this approach include the incomplete coverage of pediatric procedures records and the absence of post-acceptance regulatory updates, which may limit the completeness of the analysis and preclude longitudinal assessment of study outcomes. A total of 10 pediatric procedures were reviewed for the six currently approved CAR-T cell products in the EU. All procedures were granted a partial waiver for patients < 6 kg due to manufacturing-related constraints (Figure 1). Three full waivers—one for MM and two for MCL—were also granted prior to any PIP submission, based on the rarity of these diseases in the pediatric population. Among the seven PIPs, three were granted a full waiver based on study-related reasons, two have led to marketing authorization with a pediatric indication, and the remaining two are still under evaluation. Overall, the regulatory follow-up of CAR-T PIPs revealed a median of three modifications per PIP (range 0–4), reflecting their progressive adaptation over time. In PIP modifications, eight study timeline extensions were linked to slow recruitment and three to safety-related considerations. The median time between regulatory submission and corresponding EMA decision was 143 days (115–331). The interval between the decision and planned completion date of the pediatric procedures was 1,355 days (−172 to 2,888), the negative minimum reflecting the temporary suspension of the concerned study due to safety considerations. The weight limitation systematically applied across PIPs was primarily attributed to technical and safety challenges inherent to cell collection and manufacturing (Table 1). Specifically, the apheresis procedure used for leukocyte extraction requires peripheral venous access and a substantial blood volume. These factors pose considerable technical obstacles and increase risks—such as hypovolemia—in small children. Additionally, applicants cited the side effects of anticoagulant use, such as hypocalcaemia, muscle cramps, and cardiac arrhythmia. Together with the complexity of vascular access, these risks underpin the near-universal weight-based waiver. Technical rationales predominated for ALL (n = 3) and B-cell non-Hodgkin lymphoma (B-NHL, n = 5). For multiple myeloma (MM, n = 2) and mantle cell lymphoma (MCL, n = 2), waivers were granted based on epidemiological data, reflecting the very low incidence of these diseases in pediatric populations. Similar arguments applied to ALL (n = 1) and B-NHL (n = 2), further supported by the exceptionally low likelihood that a child weighing less than 6 kg would develop these conditions and subsequently relapse.4 Moreover, because children under 2 years of age have underdeveloped immune systems, their risk of infection is heightened during procedures that require lymphodepleting chemotherapy.8 This argument was consistently cited as an additional justification—alongside technical constraints—for the < 6 kg limitation. Beyond these initial considerations, additional waivers were informed by the study component of the PIPs. A total of 19 studies were proposed across all PIPs (5 quality, 2 non-clinical, and 12 clinical). All nonclinical studies (2/2) and several quality studies (3/5) were conducted and led to a waiver, the former highlighting heterogeneous and low B-cell maturation antigen (BCMA) expression, and the latter revealing formulation challenges specific to pediatric use. In contrast, of the 12 clinical studies initially planned, seven were conducted and five were deleted during subsequent PIP modifications, following the results obtained from the earlier quality and nonclinical phases. Two waivers were additionally based on nonclinical study findings, such as antigen heterogeneity for certain tumor types, both relating to B-NHL, while one waiver was supported by clinical trial results demonstrating no significant advantage over existing therapies.5, 6 Our findings underscore the dual challenge of disease rarity and significant technical barriers to the extension of CAR-T cell therapy in pediatric populations. As in adults, recruitment difficulties and technological limitations prevail. This emphasizes the urgent need to adapt manufacturing and procedural frameworks to children. Potential solutions include accelerating the development of allogeneic or universal CAR-T products and employing adaptive clinical trial designs specifically tailored for pediatric needs.9 At the regulatory level, in 2023, the EMA introduced the stepwise PIP (sPIP),10 a flexible framework designed for situations in which the full pediatric development plan cannot yet be defined due to insufficient evidence. Under this approach, applicants may submit an initial, partial program containing only those elements that can already be justified, with the remaining components to be provided through subsequent, preplanned PIP modifications. This progressive structure establishes clear timelines for the delivery of the complete PIP and is expected to facilitate early pediatric planning for innovative therapies developed in areas of high uncertainty. From this review, several clinical recommendations can be proposed to address challenges unique to pediatric CAR-T therapy. It is critical to implement recruitment strategies designed for rare disease settings, including the establishment of international collaborative trial networks to enhance statistical power and expedite evidence generation. Early and sustained involvement of patient families within trial planning and conduct should be prioritized as it reinforces both scientific integrity and long-term follow-up. Furthermore, the adoption of adaptive trial designs tailored to pediatric populations may accelerate development timelines while maintaining rigorous safety monitoring, ultimately improving access to these transformative therapies. Despite these advances, certain limitations of this review must be acknowledged. The analysis relied on EMA regulatory documents, which may exclude relevant data from therapies developed outside the European Union or under alternative pathways. Additionally, the largely qualitative nature of waiver justifications limits the possibility of a detailed quantitative assessment of safety and efficacy outcomes. Reporting bias or incomplete records within regulatory submissions could further constrain the generalizability of these findings. Beyond these regulatory and methodological considerations, recent advances in pediatric oncology encompass not only CAR-T cell therapies, but also a wider spectrum of cellular and gene-modifying interventions.6 A comparative analysis including allogeneic CAR-T approaches and gene-editing technologies may also provide valuable context for the limitations encountered in current clinical development. Altogether, the findings point to the urgent need for a harmonized European approach that integrates scientific, regulatory, and ethical dimensions to facilitate timely and equitable access to CAR-T therapies for children. Future strategies must integrate early identification of limitations, embrace innovative manufacturing solutions, and consider the ethical dimension of clinical research in small patient populations to ensure broader and more equitable access to advanced therapies for children.4, 5 Additionally, the involvement of patient families and attention to ethical considerations are essential in the design and conduct of future trials, supporting not only scientific advancement but also the acceptability, equity, and long-term benefit of these therapies.7 This study was funded by the European Union. Views and opinions expressed are, however, those of the author(s) only and do not necessarily reflect those of the European Union or the European Health and Digital Executive Agency. Neither the European Union nor the granting authority can be held responsible for them. Generative artificial intelligence tools have been used in a limited way for the reformulation and correction of the text, without substitution for the scientific expertise of the authors. This work was supported by the ERAMET project, funded by the European Health and Digital Executive Agency through grant number 101137141. The authors declared no competing interests for this work.