TAC Engineered γδ T cells for Multiple Myeloma

Abstract

Engineered T cell therapies have had unprecedented success in treating hematological malignancies. However, their use is limited by expensive treatment costs – priced at approximately $500,000 CAD for a single-dose of CAR-T cell therapy. γδ T cells are a candidate for allogeneic engineered T cell therapies, which can be mass manufactured to reduce the cost of goods. In this thesis we investigate γδ T cells engineered with a T cell Antigen Coupler targeting BCMA (BCMA-TAC) for the treatment of Multiple Myeloma – an incurable hematological malignancy. We optimized a manufacturing method to transduce γδ T cells with a GaLV-pseudotyped γ-retrovirus encoding BCMA-TAC and demonstrated that BCMA-TAC γδ T cells rapidly and specifically kill Multiple Myeloma tumour cells. We also investigated the potential for a combination therapy using engineered γδ T cells and monoclonal antibodies. Such a combination therapy may be synergistic, because γδ T cells express CD16 and can respond to antibody opsonized cells via direct cytotoxicity or phagocytosis. While degranulation of BCMA-TAC γδ T cells was enhanced by CD16 stimulation, we did not observe any improvements in direct cytotoxicity against antibody-opsonized tumour cells. Overall, our results demonstrate that BCMA-TAC γδ T cells can directly target and kill Multiple Myeloma tumour cells, but whether monoclonal antibodies can be used to further enhance their anti-tumour properties remains unclear.