Chimeric Antigen Receptor (CAR) T-Cell Products for Pediatric Cancers: Why Alternative Development Paths Are Needed

Effective multimodal therapies for pediatric cancers today achieve long-term survival in about 80% of patients.1 Prospective randomized, multicenter trials performed by academic study groups since the 1970s have resulted in stepwise improvements of therapy and increased rates of cure.2 The mainstays of therapy have been intensive combinations of cytotoxic drugs, with surgical resection and radiotherapy in solid cancers and allogeneic hematopoietic stem-cell transplantation (HSCT) in high-risk leukemias. Event-free survival rates have now plateaued, illustrating that major advances can no longer be achieved with these conventional treatment modalities. Novel agents that target specific molecular hallmarks improve outcomes of some cancers.3 However, they are not widely applicable as the majority of pediatric malignancies lack relevant and targetable molecular drivers, and responses are often not sustained.4 Off-the-shelf immunotherapeutic agents block inhibitory checkpoints in the tumor microenvironment, and this activates the host immune system for T-cell–mediated tumor cell rejection. Although these agents can produce long-term remissions in solid tumors in adults,5 this Nobel prize winning breakthrough could not be reproduced in pediatric cancers.6 A major reason is the scarcity of somatic mutations in tumors arising in children and adolescents, with consequent lack of tumor-associated neoantigens recognizable as nonself by endogenous T cells.7 Despite this, targeted immunotherapeutic interventions have also started making an impact on pediatric cancers. Antibodies against tumor-associated target antigens and T-cell engaging derivatives have successfully complemented cytotoxic chemotherapy in selected indications.8-10 An impressive immunotherapeutic advance in pediatric leukemia has been the introduction of chimeric antigen receptor (CAR) T-cell therapy.11-13 Autologous T cells are ex vivo gene-engineered with recombinant CARs to recognize leukemic cells via surface expression of the B-lineage antigen CD19. Treatment with CAR T cells has achieved high rates of complete remissions in refractory populations of pediatric patients with ALL.12-14 Even more remarkable, remissions in around 40% of patients treated with CAR T cells containing 4-1BB–derived costimulation have been durable without further therapy both in early-phase clinical studies15 and in real-world databases.16-19 It has been demonstrated that immune control of leukemia relies on the memory capacity of the CAR T cells which is reflected by persistent absence of the (CD19-positive) B-cell compartment.

Journal of Clinical Oncology , article en libre accès, 2022

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