CAR T-cells and macrophages in large B-cell lymphoma: impact on toxicity and efficacy

Abstract

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 is the current standard of care for the treatment of relapsed refractory large B cell lymphoma, demonstrating impressive response rates in the second- and third-line setting. Despite these advances, this treatment strategy can result in significant toxicities, such as cytokine release syndrome or immune effector cell associated neurotoxicity syndrome. While the exact mechanisms of these immune-mediated toxicities are not clearly understood, emerging pre-clinical and clinical studies have revealed the pivotal role of myeloid cells, particularly macrophages, as key contributors to the efficacy of treatments and as crucial mediators of toxicity. In this review, we discuss the current understanding of how macrophages mediate these effects, highlighting specific mechanisms of macrophage biology relevant to CAR T-cell therapy activity and side effects. These findings are resulting in novel treatment strategies that target macrophages, and able to mitigate toxicity while preserving CAR T-cell therapy efficacy.

Keywords:

• CAR T-cell
• macrophages
• ICANS
• CRS

Acknowledgments

PS salary is supported by the Lymphoma Research Foundation Career Development Award, the Leukemia Lymphoma Society Scholar in Clinical Research Career Development Program, the Gilead Scholar in Clinical Research Award, the Sabin Family Fellowship Award, and by an R21 NIH grant.

Author contributions

AA, DM and PS have coauthored the paper.

Disclosure statement

PS is a consultant for Kite-Gilead, Astrazeneca, Roche-Genentech, Hutchinson MediPharma, ADC Therapeutics, Incyte Morphosis and TG Therapeutics; and received research funds from Sobi Pharmaceuticals, Astrazeneca-Acerta, ALX Oncology and ADC Therapeutics. No potential conflict of interest was reported by the author(s).

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.