Enhancing CAR T cell efficacy: the next step toward a clinical revolution?

ABSTRACT

Introduction

The field of immunotherapy has witnessed considerable progress over the last two decades. Beginning with the ability to conceptualize CAR T cell therapy as immunotherapeutic approach, to effortlessly genetically modifying T cells, we have now reached the stage of mass production for clinical needs, all within less than quarter of a century.

Areas covered

CAR T cell therapy has been tremendously successful in acute leukemia patients, specifically even in relapsed/refractory disease states. However, similar success is yet to be realized in other malignancies. This review article covers the challenges encountered with the current CD19-targeted CARs, as well as specific obstacles faced by adoptive therapy in solid tumors. It also discusses various strategies to counteract these problems.

Expert opinion

CD19-directed trials in the past decade have exposed vulnerabilities in the current CAR T cell design, particularly concerning safety aspects, antigen escape, and T cell persistence. Building on these lessons and factoring in the unique challenges associated with immunotherapy in solid tumors will help generate CARs designed for future trials. Also, research related to the production of allogeneic CAR T cell products will boost the patient reach of this unique technology and possibly reduce financial burden.

KEYWORDS:

• Chimeric antigen therapy
• CAR T cells
• CAR
• immunotherapy
• next steps in adoptive immunotherapy

Article highlights

• CAR T cells in hematologic malignancies: Antigen escape, CAR T cell persistence, and on-target, off-tumor and other toxicities remain important challenges.

• CAR T cells in solid tumors: Paucity of ideal antigen targets, CAR T cell trafficking, tumor microenvironment are the unique roadblocks in this area of CAR T cell use.

• Optimized manufacturing practices, off-the-shelf products, and cost reduction algorithms are needed to increase the scalability of this immunotherapeutic approach.

This box summarizes key points contained in the article.

Declaration of interest

M Namuduri is an adhoc consultant for Cellectar Biosciences and RJ Brentjens is Renier J Brentjens receives royalties and grant support from JUNO Therapeutics and is a consultant for JUNO/Celgene. 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 apart from those disclosed.

Reviewer disclosures

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

Additional information

Funding

This paper was not funded.