T cells expressing CD26-specific chimeric antigen receptors exhibit extensive self-antigen-driven fratricide

Abstract

Background: Immunotherapy utilizing T cells genetically modified to express chimeric antigen receptors (CARs) is rapidly emerging as a promising novel treatment for hematological and nonhematological malignancies. In order to target the TKI-insensitive leukemia stem cells (LSCs) in chronic myeloid leukemia (CML) by CAR T cells, we chose CD26 as a cell surface tumor-associated antigen due to preferentially expression on LSCs. Additionally, CD26 has also been suggested to be a multipurpose therapeutic target for other cancer. Therefore, developing the CD26-targeting CAR T cells may be a promising therapy for not only LSCs but also other CD26+ cancer cells.

Methods: We designed the second-generation CD26-targeting CAR utilizing 4-1BB (CD137) as costimulatory domain, and transduced T cells with CD26-CAR containing lentiviral. Then we evaluated the transduction efficiency and expansion ability, and demonstrated the existence of self-antigen-driven fratricide by cytokine assay and cytotoxicity assay.

Results: Anti-CD26-4-1BB-CAR T cells exhibited poor viability, multiple cytokine secretion, down-regulation of CD26 and direct cytotoxicity against themselves, indicating self-antigen-driven fratricide.

Conclusion: Eradicating CML-LSCs via anti-CD26-4-1BB-CAR T cells is not applicable, and optimized design or alternative target is needed.

Keywords:

• Chimeric antigen receptor T cells
• chronic myeloid leukemia
• leukemia stem cells
• cancer
• CD26
• fratricide

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The work was supported by grants from the National Natural Science Foundation of China (NSFC) (Nos. 81500136, 81700142 and 81670145).