Second Primary Cancer After Chimeric Antigen Receptor-T-Cell Therapy: A Review.

in JAMA oncology by Shyam A Patel, Jay Y Spiegel, Saurabh Dahiya

TLDR

  • The review summarizes the literature on second primary cancers after CAR-T therapy, highlighting the risk and potential mitigation strategies.
  • The study finds limited evidence associating inadvertent transgene insertion with SPCs and suggests optimizing T-cell manufacturing and genomic testing to minimize risk.
  • The review recommends evidence-based practical solutions for risk mitigation in future CAR-T products, improving the risk-benefit profile and patient outcomes.

Abstract

The commercialization of chimeric antigen receptor-T-cell (CAR-T) therapy has changed the landscape of treatment of hematological cancers. Numerous studies from the early 2000s paved the way for cell-based targeted therapeutics, which have been established as practice-changing therapies in lymphoma, leukemia, and multiple myeloma. However, there has been some recent concern about the risk for second primary cancers (SPCs). Multiple cases of SPCs arising after CAR-T therapy have been reported to the US Food and Drug Administration. Most SPCs have been negative for the chimeric antigen receptor transgene, with rare reports of transgene-positive cancers. This review summarizes the most salient literature on epidemiology and pathobiology of SPCs after CAR-T therapy. Additionally, a discussion is provided on potential mitigation strategies for SPCs after CAR-T therapies. The results of this review suggest that there are limited data to suggest that inadvertent transgene insertion is associated with SPCs in the post-CAR-T setting. Nonetheless, evidence-based practical solutions and scientific strategies for risk mitigation can be implemented. These include optimization of T-cell manufacturing, application of safer synthetic immunobiology, and implementation of high-fidelity genomic testing, including baseline screening for clonal hematopoiesis. These strategies may inform optimal design of the next generation of CAR-T products that confer minimal risk for SPCs such that the risk-benefit profile remains favorable to proceed with CAR-T administration for eligible patients.

Overview

  • The review aims to summarize the literature on second primary cancers (SPCs) after chimeric antigen receptor-T-cell (CAR-T) therapy, including epidemiology, pathobiology, and potential mitigation strategies.
  • The study explores the concern about the risk of SPCs after CAR-T therapy, including cases reported to the US Food and Drug Administration.
  • The review focuses on optimizing T-cell manufacturing, safer synthetic immunobiology, and high-fidelity genomic testing to minimize the risk of SPCs and improve the risk-benefit profile of CAR-T therapy.

Comparative Analysis & Findings

  • The review finds limited evidence associating inadvertent transgene insertion with SPCs after CAR-T therapy.
  • Most SPCs reported have been negative for the chimeric antigen receptor transgene, with rare reports of transgene-positive cancers.
  • The study suggests that optimization of T-cell manufacturing, application of safer synthetic immunobiology, and implementation of high-fidelity genomic testing can minimize the risk of SPCs.

Implications and Future Directions

  • The review highlights the importance of implementing evidence-based practical solutions and scientific strategies for risk mitigation in CAR-T therapy.
  • The study recommends optimization of T-cell manufacturing, application of safer synthetic immunobiology, and implementation of high-fidelity genomic testing to minimize the risk of SPCs in future CAR-T products.
  • The review implies that the risk-benefit profile of CAR-T therapy can be improved by implementing these strategies, making it a safer and more effective treatment option for eligible patients.
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