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.

DNA origami assembled spheroid for evaluating cytotoxicity and infiltration of chimeric antigen receptor macrophage (CAR-M)

“…(3) Mimicking solid tumor microenvironment: The 3D NACs-origami assembled tumor spheroids also mimic a simplified version of the solid tumor microenvironment. Obviously, trafficking and infiltration barrier and tumor heterogeneity in solid tumors partially resulted in the failure of CAR-T [33]. In this respect, our study had outlined that our immune cell or CAR-M could infiltrate into tumor micro-spheroid, and CAR-Ms could specifically target the solid tumor more effectively than macrophage alone.…”

Chimeric Antigen Receptor T Cell Therapy for Pancreatic Cancer: A Review of Current Evidence

“…Nevertheless, high hopes are associated with the prospective use of CAR-T strategy against solid cancers, especially the ones resistant to standard oncological therapies, such as PC. Indeed, current pre-clinical and clinical studies evaluate potential tumor-associated antigens (TAA), cancer markers, CAR-T cell toxicities, and efficacy in PC [ 56 , 57 ].…”

Mesenchymal stromal cells in myeloid malignancies: Immunotherapeutic opportunities

“…The extracellular domain comprises a single-chain variable fragment (scFv) derived from an antitumor antigen-antibody. The intracellular domain primarily contains CD3ζ, CD28, and 4-1BB [ [212] , [213] , [214] ]. To carry out CART cell immunotherapy, autologous T-cells are genetically modified to express a specific CAR, expanded in vitro, and then reinfused into the same patients to eliminate neoplastic cells.…”