New Strategies for the Treatment of Solid Tumors with CAR-T Cells

Abstract

Recent years, we have witnessed significant progresses in both basic and clinical studies regarding novel therapeutic strategies with genetically engineered T cells. Modification with chimeric antigen receptors (CARs) endows T cells with tumor specific cytotoxicity and thus induce anti-tumor immunity against malignancies. However, targeting solid tumors is more challenging than targeting B-cell malignancies with CAR-T cells because of the histopathological structure features, specific antigens shortage and strong immunosuppressive environment of solid tumors. Meanwhile, the on-target/off-tumor toxicity caused by relative expression of target on normal tissues is another issue that should be reckoned. Optimization of the design of CAR vectors, exploration of new targets, addition of safe switches and combination with other treatments bring new vitality to the CAR-T cell based immunotherapy against solid tumors. In this review, we focus on the major obstacles limiting the application of CAR-T cell therapy toward solid tumors and summarize the measures to refine this new cancer therapeutic modality.

Keywords: adoptive immunotherapy; cell therapy; chimeric antigen receptor; solid tumor..

Figure 1

Chimeric antigen receptors (CARs) architecture. (A) CARs consist of an extracellular domain, a hinge, a transmembrane domain, and an intracellular domain. The extracellular domain is typically a scFv fragment that isolated from an antigen-specific monoclonal antibody, with retained specificity and affinity. (B) The intracellular domain, derived from the phosphorylation of immunoreceptor tyrosine based activation motifs (ITAMs) presented in the cytoplasmic CD3-ζ domain of the TCR complex, transmits activation and co-stimulatory signals to T cells. (C) According to the number of signaling molecules, CARs are classified into the 1st generation (one), 2nd generation (two) and 3rd generation (three) CARs. The most applied co-stimulatory signaling molecules are CD28, 4-1BB, ICOS and OX-40.

Figure 2

Schema of adoptive cellular therapy with CAR-T cells. PBLs harvested from specifically selected patients. T cells were isolated, activated and genetically modified to express a transgene encoding tumor-specific CARs. The genetically modified T cells are then expanded on a large scale using a cell processing center in vitro to a sufficient number, and thus infused back into patients, with or without chemo-radio therapeutic preconditioning.