CAR-cell therapy in the era of solid tumor treatment: current challenges and emerging therapeutic advances

Abstract

In the last decade, Chimeric Antigen Receptor (CAR)-T cell therapy has emerged as a promising immunotherapeutic approach to fight cancers. This approach consists of genetically engineered immune cells expressing a surface receptor, called CAR, that specifically targets antigens expressed on the surface of tumor cells. In hematological malignancies like leukemias, myeloma, and non-Hodgkin B-cell lymphomas, adoptive CAR-T cell therapy has shown efficacy in treating chemotherapy refractory patients. However, the value of this therapy remains inconclusive in the context of solid tumors and is restrained by several obstacles including limited tumor trafficking and infiltration, the presence of an immunosuppressive tumor microenvironment, as well as adverse events associated with such therapy. Recently, CAR-Natural Killer (CAR-NK) and CAR-macrophages (CAR-M) were introduced as a complement/alternative to CAR-T cell therapy for solid tumors. CAR-NK cells could be a favorable substitute for CAR-T cells since they do not require HLA compatibility and have limited toxicity. Additionally, CAR-NK cells might be generated in large scale from several sources which would suggest them as promising off-the-shelf product. CAR-M immunotherapy with its capabilities of phagocytosis, tumor-antigen presentation, and broad tumor infiltration, is currently being investigated. Here, we discuss the emerging role of CAR-T, CAR-NK, and CAR-M cells in solid tumors. We also highlight the advantages and drawbacks of CAR-NK and CAR-M cells compared to CAR-T cells. Finally, we suggest prospective solutions such as potential combination therapies to enhance the efficacy of CAR-cells immunotherapy.

Injectable Supramolecular Hydrogels for In Situ Programming of Car‐T Cells toward Solid Tumor Immunotherapy

“…Contrary to CD3‐PPP/pCAR@α‐CD supramolecular hydrogel‐treated ones, the proportion of native CAR‐T cells in solid tumors was low, while the proportion study showed a significant decline with the extension of treatment time in the blood and tumor tissues, in terms of mice treated with intravenous infusion of CAR‐T cells, which is consistent with previous report. [ 17 ] These results can be attributed to two factors: 1) CD3‐PPP/pCAR@α‐CD provides a “factory” for cell generation, wherein the nanocomplexes released by the slow degradation of hydrogel continually in situ produced CAR‐T cells, while these CAR‐T cells could directly enrich in solid tumor rather than supplying bolus administration like intravascular infusion. 2) CD3‐PPP/pCAR@α‐CD‐generated CAR‐T cells bypassed in vitro expansion, while the enhanced production of these self‐renewing T cell populations might further contribute to increased cellular persistence.…”

Application of adoptive cell therapy in hepatocellular carcinoma

“…The mononuclear phagocyte system (MPS) consists mainly of monocytes and monocyte-derived macrophages. They both have phagocytic functions [139]. Phagocytes are highly plastic cells.…”

Harnessing Phagocytosis for Cancer Treatment

“…Additionally, CAR-M that were administered intravenously (IV) were found to localize to tumors in several xenograft models and persisted in tumor-free mice (primarily within the liver) for at least 62 days, as detected by whole-body bioluminescent imaging. In vitro analysis further demonstrated that CAR-M were capable of coordinating an antitumor T cell response by recruiting T cells and cross-presenting antigens from phagocytosed cells [19,86,87].…”