Challenges and strategies in relation to effective CAR-T cell immunotherapy for solid tumors.

Chimeric Antigen Receptor T cell (CAR-T) therapy has revolutionized cancer treatment, but its application to solid tumors is limited. CAR-T cells have poor incapability of entering, surviving, proliferating, and finally exerting function in the tumor microenvironment. This review summarizes the main strategies related to enhancing the infiltration, efficacy, antigen recognition, and production of CAR-T in solid tumors. Additional applications of CAR-γδ T and macrophages are also discussed. We believe CAR-T will be a milestone in treating solid tumors once these problems are solved.

Cyclosporine A-resistant CAR-T cells mediate antitumour immunity in the presence of allogeneic cells.

Chimeric antigen receptor (CAR)-T therapy requires autologous T lymphocytes from cancer patients, a process that is both costly and complex. Universal CAR-T cell treatment from allogeneic sources can overcome this limitation but is impeded by graft-versus-host disease (GvHD) and host versus-graft rejection (HvGR). Here, we introduce a mutated calcineurin subunit A (CNA) and a CD19-specific CAR into the T cell receptor α constant (TRAC) locus to generate cells that are resistant to the widely used immunosuppressant, cyclosporine A (CsA). These immunosuppressant-resistant universal (IRU) CAR-T cells display improved effector function in vitro and anti-tumour efficacy in a leukemia xenograft mouse model in the presence of CsA, compared with CAR-T cells carrying wild-type CNA. Moreover, IRU CAR-T cells retain effector function in vitro and in vivo in the presence of both allogeneic T cells and CsA. Lastly, CsA withdrawal restores HvGR, acting as a safety switch that can eliminate IRU CAR-T cells. These findings demonstrate the efficacy of CsA-resistant CAR-T cells as a universal, 'off-the-shelf' treatment option.