Chimeric antigen receptor-induced antigen loss protects CD5.CART cells from fratricide without compromising on-target cytotoxicity

• Published in: Cell reports. Medicine Vol. 5; no. 7; p. 101628
• Main Authors: Ma, Royce, Woods, Mae, Burkhardt, Phillip, Crooks, Noah, van Leeuwen, Dayenne G., Shmidt, Daniil, Couturier, Jacob, Chaumette, Alexandre, Popat, Divya, Hill, LaQuisa C., Rouce, Rayne H., Thakkar, Sachin, Orozco, Aaron F., Carisey, Alexandre F., Brenner, Malcolm K., Mamonkin, Maksim
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.07.2024; Elsevier
• Subjects: Animals; CAR; CD5; CD5 Antigens - metabolism; chimeric antigen receptor; clinical trials; Cytotoxicity, Immunologic; fratricide; Humans; Immunotherapy, Adoptive - methods; off-tumor toxicity; Receptors, Antigen, T-Cell - immunology; Receptors, Antigen, T-Cell - metabolism; Receptors, Chimeric Antigen - immunology; Receptors, Chimeric Antigen - metabolism; T cell fratricide; T cell malignancies; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; off-tumor toxicity; CD5; CAR; chimeric antigen receptor; clinical trials; T cell fratricide; T cell malignancies; fratricide
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2024.101628

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. [Display omitted] •CD5 is highly expressed in T cell malignancies and normal T cells•CD5.CAR causes full degradation of CD5 in T cells leading to fratricide resistance•CD5.CAR transiently downmodulates CD5 on target cells in trans•CD5 modulation in trans does not protect target cells from CD5.CART cells long-term CD5 is a pan-T cell marker highly expressed in T cell cancers. Ma et al. show that expression of CD5.CAR in T cells drives full degradation of CD5 to achieve fratricide resistance. While CD5.CAR also transiently downmodulates CD5 in trans on target T cells, this process does not protect them from elimination long term.