Chimeric Antigen Receptor-T Cells for Targeting Solid Tumors: Current Challenges and Existing Strategies

Abstract

Chimeric antigen receptor-T cells (CAR-Ts) are an exciting new cancer treatment modality exemplified by the recent regulatory approval of two CD19-targeted CAR-T therapies for certain B cell malignancies. However, this success in the hematological setting has yet to translate to a significant level of objective clinical responses in the solid tumor setting. The reason for this lack of translation undoubtedly lies in the substantial challenges raised by solid tumors to all therapies, including CAR-T, that differ from B cell malignancies. For instance, intravenously infused CAR-Ts are likely to make rapid contact with cancerous B cells since both tend to reside in the same vascular compartments within the body. By contrast, solid cancers tend to form discrete tumor masses with an immune-suppressive tumor microenvironment composed of tumor cells and non-tumor stromal cells served by abnormal vasculature that restricts lymphocyte infiltration and suppresses immune function, expansion, and persistence. Moreover, the paucity of uniquely and homogeneously expressed tumor antigens and inherent plasticity of cancer cells provide major challenges to the specificity, potency, and overall effectiveness of CAR-T therapies. This review focuses on the major preclinical and clinical strategies currently being pursued to tackle these challenges in order to drive the success of CAR-T therapy against solid tumors.

Fig. 1

Estimated proportion of new cancer cases in the USA in 2019 (left) and CAR-T clinical trials per organ class (right). Based on Cancer Facts and Figures, 2019 (American Cancer Society) [129] and the U.S. National Library of Medicine (ClinicalTrials.gov; excluding long-term follow-up and retrospective studies). CAR-T chimeric antigen receptor T cell

Fig. 2

CAR-T clinical trials targeting solid tumors. Based on the US National Library of Medicine (ClinicalTrials.gov; excluding long-term follow-up and retrospective studies). AFP α-fetoprotein,  CAR chimeric antigen receptor, CAR-T chimeric antigen receptor T cell, CEA carcinoembryonic antigen, DLL-3 delta-like protein 3, DR5 death receptor 5, EGFR epidermal growth factor receptor, EGFRvIII variant III of the epidermal growth factor receptor, EPCAM epithelial cell adhesion molecule, EpHA2 Ephrin type A receptor 2, FAP fibroblast activation protein, FR-alpha folate receptor-α, GD2 disialoganglioside, gp100 glycoprotein 100, GPC3 glypican 3, HER2 human epidermal growth factor receptor 2, IL-13Rα2 interleukin-13 receptor α2, LMP1 latent membrane protein 1, MAGE melanoma associated antigen, MMP matrix metalloproteinase, MUC1 mucin 1, NKG2D natural killer group 2 member D, NY-ESO-1 New York esophageal squamous cell carcinoma 1, PD-L1 programmed death-ligand 1, PSCA prostate stem cell antigen, PSMA prostate-specific membrane antigen, ROR1/2 receptor tyrosine kinase-like orphan receptor 1/2, TME tumor microenvironment, VEGFR-2 vascular epidermal growth factor receptor-2