CAR T-Cell-Based gene therapy for cancers: new perspectives, challenges, and clinical developments

Abstract

Chimeric antigen receptor (CAR)-T cell therapy is a progressive new pillar in immune cell therapy for cancer. It has yielded remarkable clinical responses in patients with B-cell leukemia or lymphoma. Unfortunately, many challenges remain to be addressed to overcome its ineffectiveness in the treatment of other hematological and solidtumor malignancies. The major hurdles of CAR T-cell therapy are the associated severe life-threatening toxicities such as cytokine release syndrome and limited anti-tumor efficacy. In this review, we briefly discuss cancer immunotherapy and the genetic engineering of T cells and, In detail, the current innovations in CAR T-cell strategies to improve efficacy in treating solid tumors and hematologic malignancies. Furthermore, we also discuss the current challenges in CAR T-cell therapy and new CAR T-cell-derived nanovesicle therapy. Finally, strategies to overcome the current clinical challenges associated with CAR T-cell therapy are included as well.

Keywords: CAR T-cell therapy; gene therapy; hematologic malignancies; immunotherapy; solid cancers.

Figure 1

Generation and administration of CAR T-cells in patients with cancer. (A) T cells are collected from patients’ blood via apheresis. They are genetically engineered to express CAR and cultured ex vivo for expansion. CAR T-cells are then administered to patients. The cells identify their target and kill the tumor cells expressing that target. (B) Illustration of basic structure of four generations of CAR T-cells. Created with BioRender.com.

Figure 2

T cell-mediated antitumor effects by chimeric antigen receptors (CAR). Engineered CAR T-cells can recognize tumor cells by CAR binding to tumor-associated antigen (TAA), signaling activation and targeting the tumor cells by secreting granzymes, and perforins, and inducing TRAIL and FasL expression. CAR T-cells can be used as an ideal platform to deliver immune checkpoint therapeutic antibodies, such as anti-PD1 and CTLA-4 antibodies. CC-chemokine receptor 2; CD, cluster of differentiation; CTLA-4, cytotoxic T-lymphocyte associated protein 4; MHC, major histocompatibility complex; PD-1, programmed cell death protein-1; PD-L1, programmed death-ligand 1; and TCR, T cell receptor. Immune cells invade the tumor by activating proinflammatory cytokines and chemokines. Created with BioRender.com.

Figure 3

CAR-T EV-based therapy for cancer CAR-T EVs containing catalytic proteins (perforin and granzyme B). CAR-T EVs’ interacting and internalizing into cancer cells and leading to apoptotic blebbing and apoptosis. Created with BioRender.com.