Current advances and challenges in CAR T-Cell therapy for solid tumors: tumor-associated antigens and the tumor microenvironment

Abstract

The past decade has witnessed ongoing progress in immune therapy to ameliorate human health. As an emerging technique, chimeric antigen receptor (CAR) T-cell therapy has the advantages of specific killing of cancer cells, a high remission rate of cancer-induced symptoms, rapid tumor eradication, and long-lasting tumor immunity, opening a new window for tumor treatment. However, challenges remain in CAR T-cell therapy for solid tumors due to target diversity, tumor heterogeneity, and the complex microenvironment. In this review, we have outlined the development of the CAR T-cell technique, summarized the current advances in tumor-associated antigens (TAAs), and highlighted the importance of tumor-specific antigens (TSAs) or neoantigens for solid tumors. We also addressed the challenge of the TAA binding domain in CARs to overcome off-tumor toxicity. Moreover, we illustrated the dominant tumor microenvironment (TME)-induced challenges and new strategies based on TME-associated antigens (TMAs) for solid tumor CAR T-cell therapy.

The Efficacy of Tumor Mutation Burden as a Biomarker of Response to Immune Checkpoint Inhibitors

“…Similarly, chimeric antigen receptor (CAR) T cell therapies have emerged since 2017 as immunotherapies for hematological tumors ( Figure 3 A) [ 85 ]. This therapy involves the adoptive transfer of T lymphocytes that have been reprogrammed to specifically attack tumor cells by targeting CD19, CD20, and CD22, as well as the B cell maturation antigen (BCMA) [ 86 ]. CAR T cell therapies have shown potential for solid tumors as well, demonstrating rapid tumor eradication and long-lasting response, but challenges have arisen due to the complexity of the TME [ 86 ].…”

“…This therapy involves the adoptive transfer of T lymphocytes that have been reprogrammed to specifically attack tumor cells by targeting CD19, CD20, and CD22, as well as the B cell maturation antigen (BCMA) [ 86 ]. CAR T cell therapies have shown potential for solid tumors as well, demonstrating rapid tumor eradication and long-lasting response, but challenges have arisen due to the complexity of the TME [ 86 ]. Due to the immunosuppressive TME, the CAR T cells struggle to penetrate the dense fibrotic stroma of solid tumors, are inadequately activated due to a lack of chemokine expression, and become exhausted.…”

“…Due to the immunosuppressive TME, the CAR T cells struggle to penetrate the dense fibrotic stroma of solid tumors, are inadequately activated due to a lack of chemokine expression, and become exhausted. However, specific tumor-associated antigens (TAAs) for solid tumors such as mucin-1, B7H3, human epidermal growth factor receptor 2, epidermal growth factor receptor, and carcinoembryonic antigen, have been applied to CAR T cells for use in solid tumors [ 86 ]. Tumor neoantigens also have potential for utilization in CAR T cell therapies; for example, anti-EGFRvIII-CAR T cells have been utilized for high-grade glioblastoma cells [ 86 ].…”

Tumor microenvironment and CAR‐T cell immunotherapy in B‐cell lymphoma

“…In contrast to hematological malignancies, solid tumors often present a challenging barrier for T cells to migrate and infiltrate into the tumor sites by the immunosuppressive microenvironment 14 . On the other hand, tumor‐associated antigens (TAAs) are frequently targeted in solid tumors, as they are overexpressed in tumors and low present in normal non‐tumor tissues at physiological levels 15 . Examples of TAAs commonly targeted in solid tumors include epidermal growth factor receptor (EGFR), carcinoembryonic antigen (CEA), human epidermal growth factor receptor 2 (HER2), prostate‐specific membrane antigen (PSMA), and mesothelin, among others 15 .…”

“…On the other hand, tumor‐associated antigens (TAAs) are frequently targeted in solid tumors, as they are overexpressed in tumors and low present in normal non‐tumor tissues at physiological levels 15 . Examples of TAAs commonly targeted in solid tumors include epidermal growth factor receptor (EGFR), carcinoembryonic antigen (CEA), human epidermal growth factor receptor 2 (HER2), prostate‐specific membrane antigen (PSMA), and mesothelin, among others 15 . Besides, CAR‐T cell treatment can also be accompanied by serious side effects such as neurotoxicity and cytokine release syndrome (CRS) 16 .…”