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 CART 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 CART , that differ from B cell malignancies. For instance, intravenously infused CARTs 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 CART 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 CART therapy against solid tumors. Key Points Chimeric antigen receptor-T cell (CAR-T) therapy for the treatment of solid tumors is currently being evaluated in approximately one-third of all CART clinical trials. CART therapies targeting solid cancers have yet to demonstrate similar levels of clinical response as those being achieved in hematological indications. Developing methods and technologies to overcome the immune-suppressive tumor environment, tumor accessibility and infiltration, as well as optimization of CART function are the current focus of the CART field in order to improve therapy for solid tumors.

Immunotherapeutic approaches for small-cell lung cancer

“…Thus far, CAR T cells have demonstrated efficacy in patients with several forms of haematological cancer, although this approach has not achieved promising results in early trials in patients with solid tumours. This early lack of efficacy of CAR T cells in patients with solid tumours most likely reflects the difficulties in assuring that CAR T cells are able to come into contact with solid tumour cells within their respective organs and/or immunosuppressive microenvironments 57 .…”

CAR-T Cell Therapy in Cancer: Tribulations and Road Ahead

“…It is difficult to select targets that can cover all tumor cells [45]. Importantly, studies have shown that even if antigenpositive tumor cells are cleared, a large number of antigennegative cells still remain in the body, resulting in an especially high rate of tumor recurrence [46].…”

Advancing CAR T-Cell Therapy for Solid Tumors: Lessons Learned from Lymphoma Treatment

“…These T-cells also achieved better persistence within tumors than unconditioned cells resulting in prolonged survival and better tumor regression in a melanoma mouse model. Other strategies to limit the cell differentiation include pharmacological blockade of phosphoinositide 3-kinase (PI3K) or shortening the duration of ex vivo expansion [121].…”