Abstract
Adoptive transfer of T cells transduced with Chimeric Antigen Receptors (CAR) are now FDA-approved for the treatment of B-cell malignancies. Yet, the functionality of the endogenous TCR in CART cells has not been fully assessed. Here, we demonstrate that CART cells progressively upregulate Fas, FasL, DR5 and TRAIL, which result in their programmed cell death, independently of antigen-mediated TCR or CAR activation. CART cell apoptosis occurs even when the CAR contains a single (co-)activatory domain such as CD3ζ, CD28 or 4-1BB. Importantly, the dominant role of the Fas and DR5 pathways in CART cell apoptosis is demonstrated by the significant rescue of CART cells upon in vivo blockade by combined Fas-Fc and DR5-Fc recombinant proteins. These observations are of crucial importance for the long-term persistence of CART cells and for the development of new applications including the combined TCR and CAR activation against solid tumors.
Highlights
Adoptive T cell immunotherapies involving Chimeric antigen receptor-transduced T cells (CART) cells show impressive clinical responses in advanced cancer [1,2,3,4,5]
Two CART cell products were recently FDA-approved for the treatment of B cell malignancies, and ongoing research aims to extend this approach for the treatment of acute myeloid leukemia [6], multiple myeloma [7] and solid tumors [8, 9]
CART cell therapy applied to solid tumors is facing additional challenges, such as multiple mechanisms of tumor escape, including the highly immunosuppressive tumor microenvironment, and the selection of tumor-specific antigens causing minimal off- and on-target toxicity
Summary
Adoptive T cell immunotherapies involving CART cells show impressive clinical responses in advanced cancer [1,2,3,4,5]. Two CART cell products were recently FDA-approved for the treatment of B cell malignancies, and ongoing research aims to extend this approach for the treatment of acute myeloid leukemia [6], multiple myeloma [7] and solid tumors [8, 9]. CART cell therapy applied to solid tumors is facing additional challenges, such as multiple mechanisms of tumor escape, including the highly immunosuppressive tumor microenvironment, and the selection of tumor-specific antigens causing minimal off- and on-target toxicity. With the aim to enhance the effectiveness of CART cell therapy, we and others have evaluated the transduction of a CAR into tumor antigen-specific T cells, so as to attack the tumor via combined TCR and CAR activation.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
