CAR-T Cells and Oncolytic Viruses: Joining Forces to Overcome the Solid Tumor Challenge

Abstract

Adoptive transfer of chimeric antigen receptor (CAR)-modified T cells has resulted in unprecedented rates of long-lasting complete responses in patients with leukemia and lymphoma. However, despite the impressive results in patients with hematologic malignancies, CAR-T cells have showed limited effect against solid cancers. New approaches will need to simultaneously overcome the multiple challenges that CAR-T cells encounter in solid tumors, including the immunosuppressive tumor microenvironment and heterogeneity of antigen expression. Oncolytic viruses are lytic and immunogenic anti-cancer agents with the potential to synergize with CAR-T cells for the treatment of solid tumors. In addition, viruses can be further modified to deliver therapeutic transgenes selectively to the tumor microenvironment, which could enhance the effector functions of tumor-specific T cells. This review summarizes the major limitations of CAR-T cells in solid tumors and discusses the potential role for oncolytic viruses as partners for CAR-T cells in the fight against cancer.

TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors

“…One of the main reasons for the poor clinical efficacy of CAR T cells in treating solid tumor is the lack of robust in vivo proliferation (34)(35)(36)(37). In this study, we demonstrated that knocking out TGFBR2 enables CAR T cells to survive and proliferate better in tumor xenograft mouse models, leading to significantly improved antitumor efficacy.…”

Single residue in CD28-costimulated CAR-T cells limits long-term persistence and antitumor durability

“…Persistence is perhaps even more critical for the clinical success of CAR-T cells in solid tumors, due to a multitude of immunosuppressive obstacles to overcome, the need to eliminate micrometastatic niches, as well as the kinetics required to eradicate significant masses of tumor. Substantial effort has been invested in developing novel approaches to enhance persistence and expansion of adoptively transferred CAR-T cells (35), including selection of specific T cell subsets (36)(37)(38), optimized T cell culture conditions (39,40), combination therapies (41,42), genetic modifications and alternative methods of integration to reduce tonic signaling (43,44), introduction of both CD28-YMFM and ICOS CAR-T cells than in CD28 CAR-T cells. Similarly, Pik3cd and Dusp6, genes associated with reduced exhaustion or downregulated in effector cells, were more highly expressed in CD28-YMFM CAR-T cells compared with CD28 or ICOS CAR-T cells.…”

Combination Immunotherapy Using Oncolytic Virus for the Treatment of Advanced Solid Tumors

“…The immunosuppressive TME is another hurdle against effective oncolytic virotherapy. Tumor cells continuously secrete immunosuppressive chemokines and cytokines such as IL-10, TFG-β, and arginase-1 to reduce the amplitude of OV-induced anti-cancer immune responses [ 19 , 93 , 94 ]. To overcome the immunosuppressive TME, many OVs, including adenovirus, type I HSV, reovirus, and poxvirus have been genetically engineered to express GM-CSF to promote the maturation and differentiation of innate immune cells, thereby triggering immunostimulatory signals within the TME [ 24 , 27 , 83 ].…”