Challenges of CAR-T Therapy in Solid Tumors: Immune Exclusion and Treatment Resistance

Biomedical Sci & Biotechnology, Hong Kong Metropolitan University, 999077 Ho Man Tin, Kowloon, Hong Kong, China

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Abstract

Chimeric antigen receptor (CAR) -T cell therapy is an advanced form of treatment in the cellular immunotherapy field for cancer. T cells’s Major Histocompatibility Complex (MHC) restrictions and directly target could kill tumour cells. This is an approach in which autologous T lymphocytes are modified to express synthetic CAR molecules, which are capable of identifying tumour-associated antigens in a MHC unrestricted way. While CAR-T therapy has been highly successful in the treatment of haematological cancers, particularly B-cells, CAR-T therapy for the treatment of solid tumours has been less than satisfactory with overall response rates usually less than 20%. The reasons for this dilemma so far stem primarily from the complex immunosuppressive network and the spatial barriers in the tumour microenvironment (TME) of solid tumours and the major obstacles are the highly immunosuppressive tumour microenvironment as well as the physical barriers causing immune exclusion, prohibiting the infiltration and antitumor activity of CAR-T cells. This review presents the principles of CAR T therapy analyses important mechanisms of immune exclusion and therapeutic resistance and the summary of advanced engineering strategies to overcome these challenges and treat solid tumours.