Recent Advances in CAR-Based Solid Tumor Immunotherapy

Abstract

Adoptive cell therapy using chimeric antigen receptor (CAR) technology is one of the most advanced engineering platforms for cancer immunotherapy. CAR-T cells have shown remarkable efficacy in the treatment of hematological malignancies. However, their limitations in solid tumors include an immunosuppressive tumor microenvironment (TME), insufficient tumor infiltration, toxicity, and the absence of tumor-specific antigens. Although recent advances in CAR-T cell design-such as the incorporation of co-stimulatory domains and the development of armored CAR-T cells-have shown promising results in treating solid tumors, there are still challenges that need to be addressed. To overcome these limitations, other immune cells, such as natural killer (NK) cells and macrophages (M), have been developed as attractive options for efficient cancer immunotherapy of solid tumors. CAR-NK cells exhibit substantial clinical improvements with "off-the-shelf" availability and low toxicity. CAR-M cells have promising therapeutic potential because macrophages can infiltrate the TME of solid tumors. Here, we review the recent advances and future perspectives associated with engineered immune cell-based cancer immunotherapies for solid tumors. We also summarize ongoing clinical trials investigating the safety and efficacy of engineered immune cells, such as CAR-T, CAR-NK, and CAR-M, for targeting solid tumors.

Keywords: CAR-M; CAR-NK; CAR-T; cancer immunotherapy.

Figure 1

Schematic diagram of the CAR-T cell cytotoxic mechanisms against the cancer cells. Activated CAR-T cells can specifically recognize the tumor antigen and secrete perforin, granzyme, and IFN-γ to mediate anti-tumor activity. Death receptor pathway via Fas/Fas-L mediates the anti-tumor activity of CAR-T cells and leads to cancer cell apoptosis.

Figure 2

Progressive evolution of the CAR structure with modifications from the 1st to 5th generation. The central part of the CAR consists of three domains (extracellular, transmembrane, and intracellular domains). Components of the extracellular domain scFv region include heavy and light chains. Intracellular domains comprise CD3ζ signaling and co-stimulatory domains, such as CD28, 2B4, and 4-1BB. The fourth generation of CAR contains a nuclear factor of the activated T cells (NFAT) domain, which inducibly expresses cytokines such as IL-12. The fifth generation of CAR contains a JAK-STAT activation domain induced from IL-2Rβ.