Engineering Chimeric Antigen Receptor T-Cells for Racing in Solid Tumors: Don’t Forget the Fuel

Abstract

T-cells play a critical role in tumor immunity. Indeed, the presence of tumor-infiltrating lymphocytes is a predictor of favorable patient prognosis for many indications and is a requirement for responsiveness to immune checkpoint blockade therapy targeting programmed cell death 1. For tumors lacking immune infiltrate, or for which antigen processing and/or presentation has been downregulated, a promising immunotherapeutic approach is chimeric antigen receptor (CAR) T-cell therapy. CARs are hybrid receptors that link the tumor antigen specificity and affinity of an antibody-derived single-chain variable fragment with signaling endodomains associated with T-cell activation. CAR therapy targeting CD19 has yielded extraordinary clinical responses against some hematological tumors. Solid tumors, however, remain an important challenge to CAR T-cells due to issues of homing, tumor vasculature and stromal barriers, and a range of obstacles in the tumor bed. Protumoral immune infiltrate including T regulatory cells and myeloid-derived suppressor cells have been well characterized for their ability to upregulate inhibitory receptors and molecules that hinder effector T-cells. A critical role for metabolic barriers in the tumor microenvironment (TME) is emerging. High glucose consumption and competition for key amino acids by tumor cells can leave T-cells with insufficient energy and biosynthetic precursors to support activities such as cytokine secretion and lead to a phenotypic state of anergy or exhaustion. CAR T-cell expansion protocols that promote a less differentiated phenotype, combined with optimal receptor design and coengineering strategies, along with immunomodulatory therapies that also promote endogenous immunity, offer great promise in surmounting immunometabolic barriers in the TME and curing solid tumors.

Macrophage targeting: opening new possibilities for cancer immunotherapy

“…Chimeric antigen receptor (CAR) is a genetically engineered T‐cell receptor where the intracellular signalling domain is activated by extracellular single‐chain variable fragments upon direct binding to a specific protein expressed on the surface of tumour cells. Therefore, CAR‐T cells can exert cytotoxicity against tumour cells expressing the target surface molecules without MHC‐I‐restricted antigen presentation . The CAR‐T‐cell transfer therapy has been successful for B lymphoma, but its applicability to solid tumours is still under investigation .…”

Programming CAR-T cells to kill cancer

“…After infusion into a patient, the T cells must traffic to the tumour site, infiltrate the tumour stroma and engage the specific TAA on malignant cells. Then, they must rapidly expand to high numbers in response to an antigen and mount the attack on cancer cells within a harsh tumour microenvironment that features multiple physical barriers 97-99 , a biochemical and metabolic milieu that is unfavourable to T-cell effector function [100][101][102] , and immunosuppression signals from an arsenal of inhibitory molecules displayed or secreted by cancer cells and supporting stromal cells alike 103-105 (Fig. 6).…”

“…Consequently, the metabolic profile of T cells is intimately linked to the regulation of T-cell function and differentiation stage. The aberrant metabolic milieu in tumour microenvironments, as a result of the high metabolic activity of tumour cells and dysfunctional tumour vasculature, is both hypoxic and acidic, depleted of nutrients such as glucose and glutamine, and lacks key amino acids such as arginine and tryptophan due to the upregulation of the inhibitory enzymes indoleamine 2,3-dioxygenase-1 (IDO-1) and arginase by the tumour stroma 100 . This unfavourable environment inhibits T-cell effector functions and promotes a defective T-cell state.…”

Regulation of Memory CD8+ T Cell Differentiation by MicroRNAs

“…However, current T cell therapies had a limited clinical response in solid tumors [83]. Therefore, there are emerging challenges in the field of T cell-based immunotherapy for solid tumors: (1) how can we expand less-differentiated engineered T cell subsets in vitro; and (2) [84].…”