Improved Antitumor Efficacy of Chimeric Antigen Receptor T Cells that Secrete Single Domain Antibody Fragments
CAR T cells that target the tumor microenvironment are designed to secrete immune modulating single domain antibodies that can engage the innate immune system, cause epitope spreading, and evade checkpoint immunosuppression by the tumor. Chimeric antigen receptor (CAR) T cell therapy is effective in the treatment of cancers of hematopoietic origin. In the immunosuppressive solid tumor environment, CAR T cells encounter obstacles that compromise their efficacy. We developed a strategy to address these barriers by having CAR T cells secrete single domain antibody fragments [variable heavy domain of heavy chain antibodies (VHH) or nanobodies] that can modify the intratumoral immune landscape and thus support CAR T cell function in immunocompetent animals. VHHs are small in size and able to avoid domain swapping when multiple nanobodies are expressed simultaneously features that can endow CAR T cells with desirable properties. The secretion of an anti CD47 VHH by CAR T cells improves engagement of the innate immune system, enables epitope spreading, and can enhance the antitumor response. CAR T cells that secrete anti PD L1 or anti CTLA 4 nanobodies show improved persistence and demonstrate the versatility of this approach. Furthermore, local delivery of secreted anti CD47 VHH Fc fusions by CAR T cells at the tumor site limits their systemic toxicity. CAR T cells can be further engineered to simultaneously secrete multiple modalities, allowing for even greater tailoring of the antitumor immune response.
Cancer Immunology Research