Mechanisms of resistance to CAR T cell therapy

We provide an overview of potential strategies to overcome these obstacles in an effort to more effectively incorporate this unique therapeutic strategy into standard treatment paradigms

Nirali N. Shah; Terry J. Fry

2019

Scholarcy highlights

  • In April 2012, following successes first experienced with CD19-directed chimeric antigen receptor T cell therapy in adults with follicular lymphoma or chronic lymphocytic leukaemia, the first child with acute lymphoblastic leukaemia was infused
  • As antigen-directed CAR T cells become more widely used, understanding the limitations of CAR T cell therapy and overcoming these obstacles will be crucial to harnessing the full potential of this highly effective treatment modality
  • With the FDA approval of axicabtagene ciloleucel and subsequently tisagenlecleucel, CAR T cell therapies provide a highly effective approach to the treatment of relapsed and/or refractory large B cell lymphoma; unique challenges exist in this setting, including lower remission rates and a limited understanding of the mechanisms of relapse
  • CAR T cell manufacturing considerations — from patient selection to the characteristics of the infused product and the potential for subsequent cell expansion — reflect one particular aspect of efforts to improve outcomes, and advances in cell manufacturing will certainly make these products accessible for a greater number of patients. For those with response, confirming CAR T cell persistence and monitoring for antigen loss are necessary for relapse prediction and prevention strategies; antigennegative disease relapse is currently difficult to treat, and even antigen-positive relapsed disease might not respond to CAR T cell re-infusion
  • Akin to multi-agent chemotherapy, multi-antigen-targeting strategies might address these mechanisms of relapse and, might be a pathway to more durable remissions
  • Using a competing risks analysis, the 24-month cumulative incidence of post-alloHSCT relapse in all 25 patients and in the 19 patients who underwent HSCT for the first time was 13.5% and 11.3%, respectively
  • Optimizing this therapeutic approach in patients with non-B cell malignancies is the frontier for research in this field of immunotherapy, but many obstacles need to be overcome, and close attention to the design of novel CAR constructs will be informative in identifying further barriers, such as those in solid tumours
  • In this fast-paced field of research, a shift in focus to overcome the obstacles identified will be imperative to make this promising therapy more broadly available, more effective and potentially curative for all those treated

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