From barriers to novel strategies: smarter CAR T therapy hits hard to tumors

Abstract

Chimeric antigen receptor (CAR) T cell therapy for solid tumors shows promise, but several hurdles remain. Strategies to overcome barriers such as CAR T therapy-related toxicities (CTT), immunosuppression, and immune checkpoints through research and technology are needed to put the last nail to the coffin and offer hope for previously incurable malignancies. Herein we review current literature and infer novel strategies for the mitigation of CTT while impeding immune suppression, stromal barriers, tumor heterogeneity, on-target/off-tumor toxicities, and better transfection strategies with an emphasis on clinical research and prospects.

Cancer/Testis Antigens as Targets for RNA-Based Anticancer Therapy

“…CARs are generated by fusing the antigen-binding domain to membranespanning and intracellular signaling domains, which enables T cells to recognize and eliminate cancer cells with CTAs. Although CAR-T therapy been effective for leukemia, it has not been successful in solid tumors [60]. Current applications of cancer/testis antigen-X (CT-X) in the CAR-T strategy are mainly limited to preclinical studies or early-phase clinical trials.…”

CAR T Therapies: Game Changer or Culprit in Cancer Treatment?‎

“…Chimeric Antigen Receptor (CAR) T cell therapy introduces potential challenges, including fratricide, where the engineered cells intended for targeting malignant T cells may inadvertently harm non-malignant T cells, hindering their necessary expansion for effective tumor eradication (Cinquina et al, 2022). Additionally, concerns arise regarding T-cell deficiency, as CAR T cells directed towards T-cell markers may compromise both malignant and non-malignant cells, increasing the risk of opportunistic infections (Khawar et al, 2023a). Another complication involves potential contamination of collected T-cells with malignant counterparts, heightening the risk of T cell malignancy (Stewart & Henden, 2021).…”

“…Navigating the complexities of CAR T cell therapy and the disclosed risks underscores the importance of finding a balance between advancing therapeutic strategies, such as using specialized CAR T cells, and maintaining vigilant monitoring to minimize potential adverse outcomes. Formerly, we have discussed the potential of nanoengineered formulations in clinical trials (Khawar et al, 2023c) and CAR associated toxicities (Khawar, et al, 2023a).…”

Steering the course of CAR T cell therapy with lipid nanoparticles

“…Given this success, the U.S. Food and Drug Administration (FDA) approves six CAR products, as outlined in Table 1 . Earlier, we showcased nanoengineering of better performing CAR T cells [ 17 ], mitigating the barriers of the tumor microenvironment (TME) [ 18 ] and precision in targeting hematological and solid cancers [ 19 ] (Fig. 1 A).…”

“…Moreover, there are several potential drawbacks and side effects associated with CAR T-cell therapy. For example, cytokine release syndrome and neurotoxicity, [ 21 ] which we have reviewed recently and discussed potential insights to mitigate the CRS using CAR T cells for future research [ 18 ].…”