Overcoming the challenges of primary resistance and relapse after CAR-T cell therapy

ABSTRACT

Introduction

While CAR T-cell therapy has led to remarkable responses in relapsed B-cell hematologic malignancies, only 50% of patients ultimately have a complete, sustained response. Understanding the mechanisms of resistance and relapse after CAR T-cell therapy is crucial to future development and improving outcomes.

Areas covered

We review reasons for both primary resistance and relapse after CAR T-cell therapies. Reasons for primary failure include CAR T-cell manufacturing problems, suboptimal fitness of autologous T-cells themselves, and intrinsic features of the underlying cancer and tumor microenvironment. Relapse after initial response to CAR T-cell therapy may be antigen-positive, due to CAR T-cell exhaustion or limited persistence, or antigen-negative, due to antigen-modulation on the target cells. Finally, we discuss ongoing efforts to overcome resistance to CAR T-cell therapy with enhanced CAR constructs, manufacturing methods, alternate cell types, combinatorial strategies, and optimization of both pre-infusion conditioning regimens and post-infusion consolidative strategies.

Expert opinion

There is a continued need for novel approaches to CAR T-cell therapy for both hematologic and solid malignancies to obtain sustained remissions. Opportunities for improvement include development of new targets, optimally combining existing CAR T-cell therapies, and defining the role for adjunctive immune modulators and stem cell transplant in enhancing long-term survival.

KEYWORDS:

• CAR T-cell
• B-cell acute lymphoblastic leukemia
• B-cell lymphoma
• resistance
• relapse

Article highlights

• Although CD19 CAR T-cell therapy has shown broad efficacy, primary resistance or relapse after CAR T-cell therapy remain a risk for about 50% of treated patients.

• Primary failure of CAR T-cells is most likely to occur either due to inadequate T-cell fitness or high-risk leukemia features, while manufacturing failures are rare.

• Relapse following an initial response to CAR T-cells is caused either by antigen modulation or by inadequate persistence of CAR T-cells.

• Improving efficacy of existing CAR T-cell products will depend not only on engineering novel constructs, but also on optimizing risk stratification, combination, and consolidation therapies.

• Strategies for optimization of CD19 CAR T-cells can also be applied in the context of novel CAR products that are currently in development for T-cell, myeloid, and solid malignancies.

Declaration of interest

N Shah receives research funding from Lentigen, VOR Bio and CARGO therapeutics and has participated in Advisory Boards for Sobi, Allogene, invoX, VOR, and ImmunoACT. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Authorship contributions

All authors contributed to the concept and writing of the first draft. No non-author wrote the first draft or any part of the paper. All authors contributed to reviewing the final manuscript and have agreed to be coauthors.

Disclaimer

The content of this publication does not necessarily reflect the views of policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

Additional information

Funding

This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, the Warren Grant Magnuson Clinical Center [ZIA BC 011823, N. Shah], and the Hyundai Hope on Wheels Foundation (AD).