CAR T-cell therapy landscape in pediatric, adolescent and young adult oncology – A comprehensive analysis of clinical trials

Chimeric Antigen Receptor (CAR) T-cell therapy has emerged as a transformative approach in cancer treatment, particularly for hematologic malignancies. This therapy involves the genetic modification of patients' T-cells to target specific tumor antigens, bypassing the traditional MHC-TCR-mediated recognition. This innovation marks a significant step toward personalized medicine and precision oncology. In the pediatric, adolescent, and young adult (P-AYA) populations, Tisagenlecleucel (Kymriah®) exemplifies the success of CAR T-cell therapy, demonstrating significant efficacy in treating relapsed or refractory acute lymphoblastic leukemia (r/r ALL). However, the development of CAR T-cell therapies for P-AYA patients has not progressed as rapidly as for adults, with only one FDA approval for pediatric applications compared to six for adults up to 2024. Several challenges hinder the development of pediatric CAR T-cell therapies, including complex production logistics, limited clinical site access, restrictive patient eligibility criteria, and financial constraints, necessitating more effective incentives for pediatric oncology drug development independent of adult indications. To assess the current landscape of CAR T-cell therapy in P-AYA oncology, we conducted a comprehensive review of clinical trials registered on ClinicalTrials.gov up to May 2024. Our analysis included 77 trials exclusively targeting the P-AYA population from an initial pool of 40,690 studies filtered by age, dates, and specific criteria related to CAR T-cell interventions in cancer therapy. We found that 45 % of these trials originated from the USA and 30 % from China. The data retrieved from these trials provided insights into various aspects, including histological categories, antigenic targets, CAR-T generations, costimulatory domains, manufacturing processes, geographical distribution, and funding sources. This review highlighted a predominant focus on hematologic malignancies, particularly B-cell acute lymphoblastic leukemia (B-ALL), with significant attention to dual antigen targeting (CD19 and CD22) to address resistance mechanisms. Emerging targets such as GD2 for solid tumors and B7-H3 for various cancers also showed promise. Additionally, most trials still utilize second-generation CAR-T constructs with 4-1BB costimulatory domains, reflecting a conservative approach in pediatric populations. Our findings underscore the disparity in CAR T-cell therapy development between pediatric and adult populations, driven by distinct biological, ethical, and economic considerations. Pediatric cancers require specialized treatments tailored to the unique biology and genetic makeup of pediatric oncology. However, research and drug development have historically focused less on pediatric needs. Despite legislative efforts to promote pediatric oncology drug development, significant gaps remain. Clinical trials for P-AYA populations face challenges in patient enrollment, trial design, and funding, often relying on academic and non-profit institutions. Addressing these barriers is critical for advancing CAR T-cell therapy in pediatric oncology, improving outcomes, and ensuring equitable access to innovative treatments for these vulnerable populations. This review aims to inform future research and policy decisions, promoting advancements in CAR T-cell therapy for P-AYA cancer patients.