CAR T-cell therapy for B-cell lymphomas: outcomes and resistance mechanisms.

in Cancer metastasis reviews by Tyce J Kearl, Fateeha Furqan, Nirav N Shah

TLDR

  • CAR T-cell therapy is a promising treatment for NHL, but some patients don't respond or relapse due to resistance mechanisms. Researchers are working to develop new approaches to improve treatment outcomes.

Abstract

Chimeric antigen receptor (CAR) T cells are an exciting curative intent approach to the treatment of non-Hodgkin lymphomas (NHLs). Several products have received FDA approval for 2nd or 3rd line indications, and studies are underway for their use earlier in the disease course. These CAR T cells are ex vivo manufactured autologous cell products that specifically target tumor antigens to optimize tumor specificity and minimize off-tumor side effects-in NHLs, this is typically achieved by targeting B-cell antigens. Engagement of the CAR and corresponding antigen is designed to result in T-cell activation and subsequent tumor clearance. While curative for many NHL patients, too many patients fail to respond to or relapse following CAR T-cell treatment, and salvage options post CAR T-cell therapy are limited. Treatment failures occur because of myriad resistance mechanisms including CAR T-cell dysfunction, generalized immune dysregulation, and intrinsic tumor resistance. Focusing on patients with NHL, we review the clinical outcomes of CAR T-cell therapy and the major resistance mechanisms that lead to poor outcomes. We also review the many innovative and encouraging strategies that are being developed to improve CAR T-cell therapy for NHL.

Overview

  • The study reviews the clinical outcomes of CAR T-cell therapy in non-Hodgkin lymphomas (NHLs) and the major resistance mechanisms that lead to poor outcomes.
  • CAR T cells are autologous cell products that target tumor antigens to optimize tumor specificity and minimize off-tumor side effects.
  • The study focuses on patients with NHL and aims to review current clinical outcomes, resistance mechanisms, and innovative strategies to improve CAR T-cell therapy.

Comparative Analysis & Findings

  • CAR T-cell therapy is curative for many NHL patients, but too many patients fail to respond or relapse due to various resistance mechanisms.
  • Major resistance mechanisms include CAR T-cell dysfunction, generalized immune dysregulation, and intrinsic tumor resistance.
  • The study finds that while CAR T-cell therapy is effective, treatment failures occur due to the complexity of resistance mechanisms.

Implications and Future Directions

  • The study highlights the need for innovative strategies to improve CAR T-cell therapy for NHL, including overcoming resistance mechanisms.
  • Future directions include developing new CAR T-cell constructs, combination therapies, and adoptive T-cell transfer approaches to improve treatment outcomes.
  • Elucidating the underlying mechanisms of resistance to CAR T-cell therapy could lead to the development of more effective and durable treatments for NHL patients.
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