Abstract:
Despite its remarkable success in the treatment of several hematological malignancies, cellular immunotherapy using chimeric antigen receptor (CAR) T cells faces significant challenges when treating refractory/relapsed or myeloid malignancies such as AML, CML or multiple myeloma. To overcome the pronounced heterogeneity of such diseases, the search for suitable tumor-associated antigens recently led to surface antigens of the B7 protein family as potential CAR-T cell targets. Using the example of CD86-targeting, we highlight a considerable pitfall of CAR-T therapy which utilizes B7-family proteins as a prominent group of T cell (activation) associated antigens. In a consistent set of in vitro and in vivo experiments we could demonstrate that fratricide among pre-activated CD86-specific CAR-T cells strongly reduces their overall survival and efficacy in tumor killing as recently shown for B7-H3/CD276-targeting CARs. Therefore, we propose a defined combinatorial antigen recognition concept via dual-chain CAR-T cells that incorporate an “AND-gate” mechanism through CD19 primary CAR activation and CD86 conditional co-stimulation to circumvent a severely limited outcome.
Congrats to the co-authors of the B05 project, Tobias Riet and Markus Chmielewski, on this excellent work and important contribution to the field.
Read the full article:
Riet T, Lennartz S, Bösing N, Prinz LF, Dähn L, Scheid C, Hallek M, Chmielewski MM. Overcoming fratricide of CD86 targeting CAR-T cells by defined logic-gate CAR strategy. Exp Hematol Oncol. 2026 Jun 18;15(1):53. doi: 10.1186/s40164-026-00791-3.
