1. CD33-CD123 IF-THEN gating reduces toxicity while enhancing the specificity and memory phenotype of AML-targeting CAR-T cells.
- Author
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Jambon S, Sun J, Barman S, Muthugounder S, Bito XR, Shadfar A, Kovach AE, Wood BL, Thoppey Manoharan V, Morrissy AS, Bhojwani D, Wayne AS, Pulsipher MA, Kim YM, Asgharzadeh S, Parekh C, and Moghimi B
- Abstract
CAR T-cell therapy has remarkably succeeded in treating lymphoblastic leukemia. However, its success in AML remains elusive due to the risk of on-target off-tumor toxicity to hematopoietic stem and progenitor cells (HSPC) and insufficient T-cell persistence and longevity. Using a SynNotch circuit, we generated a high-precision "IF-THEN" gated logical circuit against the combination of CD33 and CD123 AML antigens and demonstrated anti-tumor efficacy against AML cell lines and patient-derived xenografts. Unlike constitutively expressed CD123 CAR-T cells, those expressed through the CD33 SynNotch circuit could preserve HSPCs and lower the risk of on-target off-tumor hematopoietic toxicity. These gated CAR-T cells exhibited lower expression of exhaustion markers (PD1, Tim3, LAG3, and CD39), higher frequency of memory T cells (CD62L+CD45RA+), and enhanced expansion. While targeting AML, the moderated circuit CAR signal also helped to mitigate cytokine release syndrome, potentially addressing one of the ongoing challenges in CAR-T immunotherapy.
- Published
- 2024
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