Chimeric Antigen Receptor-Induced Antigen Loss Protects CD5CART Cells From Fratricide Without Compromising On-Target Cytotoxicity

Authors

Royce Ma
Mae Woods
Phillip Burkhardt
Noah Crooks
Dayenne G van Leeuwen
Daniil Shmidt
Jacob Couturier
Alexandre Chaumette
Divya Popat
LaQuisa C Hill
Rayne H Rouce
Sachin Thakkar
Aaron F Orozco
Alexandre F Carisey
Malcolm K Brenner
Maksim Mamonkin

Publication Date

7-16-2024

Journal

Cell Reports Medicine

DOI

10.1016/j.xcrm.2024.101628

PMID

38986621

PMCID

PMC11293353

PubMedCentral® Posted Date

7-16-2024

PubMedCentral® Full Text Version

Post-Print

Published Open-Access

yes

Keywords

CD5 Antigens, Humans, Receptors, Chimeric Antigen, Cytotoxicity, Immunologic, T-Lymphocytes, Immunotherapy, Adoptive, Animals, Receptors, Antigen, T-Cell/, chimeric antigen receptor, T cell fratricide, CD5, T cell malignancies, off-tumor toxicity, clinical trials, CAR, fratricide

Abstract

Chimeric antigen receptor T cells (CART) targeting lymphocyte antigens can induce T cell fratricide and require additional engineering to mitigate self-damage. We demonstrate that the expression of a chimeric antigen receptor (CAR) targeting CD5, a prominent pan-T cell antigen, induces rapid internalization and complete loss of the CD5 protein on T cells, protecting them from self-targeting. Notably, exposure of healthy and malignant T cells to CD5.CART cells induces similar internalization of CD5 on target cells, transiently shielding them from cytotoxicity. However, this protection is short-lived, as sustained activity of CD5.CART cells in patients with T cell malignancies results in full ablation of CD5+ T cells while sparing healthy T cells naturally lacking CD5. These results indicate that continuous downmodulation of the target antigen in CD5.CART cells produces effective fratricide resistance without undermining their on-target cytotoxicity.