The current landscape of CAR T-cell therapy for solid tumors: Mechanisms, research progress, challenges, and counterstrategies

Abstract

The successful outcomes of chimeric antigen receptor (CAR) T-cell therapy in treating hematologic cancers have increased the previously unprecedented excitement to use this innovative approach in treating various forms of human cancers. Although researchers have put a lot of work into maximizing the effectiveness of these cells in the context of solid tumors, few studies have discussed challenges and potential strategies to overcome them. Restricted trafficking and infiltration into the tumor site, hypoxic and immunosuppressive tumor microenvironment (TME), antigen escape and heterogeneity, CAR T-cell exhaustion, and severe life-threatening toxicities are a few of the major obstacles facing CAR T-cells. CAR designs will need to go beyond the traditional architectures in order to get over these limitations and broaden their applicability to a larger range of malignancies. To enhance the safety, effectiveness, and applicability of this treatment modality, researchers are addressing the present challenges with a wide variety of engineering strategies as well as integrating several therapeutic tactics. In this study, we reviewed the antigens that CAR T-cells have been clinically trained to recognize, as well as counterstrategies to overcome the limitations of CAR T-cell therapy, such as recent advances in CAR T-cell engineering and the use of several therapies in combination to optimize their clinical efficacy in solid tumors.

Keywords: CAR T-cell; challenges; chimeric antigen receptor; clinical trials; immunotherapy; solid tumors.

Figure 1

Challenges and counterstrategies of CAR-T-cell therapy. Although CAR T-cell therapy confronts several challenges, such as CAR T-cell trafficking to the tumor site, hypoxia and metabolism impairment, CAR T-cell exhaustion, tumor heterogeneity, and immunosuppressive tumor microenvironment, potential engineering methods and combinational therapies have shown promise in overcoming these obstacles. ATR, All-trans retinoic; CAF, Cancer-associated fibroblast; CAR, Chimeric antigen receptor; CTLA-4, Cytotoxic T lymphocyte-associated antigen 4; DC, Dendritic cell; DNR, Dominant negative receptor; FAP, Fibroblast-activation protein; IDO, Indoleamine 2,3-dioxygenase; IFN-γ, Interferon-gamma; JAK, Janus kinase; LAG-3, Lymphocyte activation gene-3; NFAT, Nuclear factor of activated T-cells; NF-κB, Nuclear factor-κB; PD-1, Programmed death-1; PDE5, Phosphodiesterase 5; PI3K, Phosphoinositide 3-kinases; RIAD, Regulatory subunit I anchoring disruptor; ROS, Reactive oxygen specimens; ScFv, Single chain variable fragment; STAT5, Signal transducer and activator of transcription 5; TGF-β, Transforming growth factor-beta; TOX, Thymocyte selection-associated HMGB; TRAF, TNF receptor associated factor; TSA, Tumor-specific antigen; Treg, Regulatory T cell.