Chimeric Antigen Receptor (CAR)-T Cell Immunotherapy Against Thoracic Malignancies: Challenges and Opportunities

Abstract

Different from surgery, chemical therapy, radio-therapy and target therapy, Chimeric antigen receptor-modified T (CAR-T) cells, a novel adoptive immunotherapy strategy, have been used successfully against both hematological tumors and solid tumors. Although several problems have reduced engineered CAR-T cell therapeutic outcomes in clinical trials for the treatment of thoracic malignancies, including the lack of specific antigens, an immunosuppressive tumor microenvironment, a low level of CAR-T cell infiltration into tumor tissues, off-target toxicity, and other safety issues, CAR-T cell treatment is still full of bright future. In this review, we outline the basic structure and characteristics of CAR-T cells among different period, summarize the common tumor-associated antigens in clinical trials of CAR-T cell therapy for thoracic malignancies, and point out the current challenges and new strategies, aiming to provide new ideas and approaches for preclinical experiments and clinical trials of CAR-T cell therapy for thoracic malignancies.

Cancer Nano-Immunotherapy: The Novel and Promising Weapon to Fight Cancer

“…In this line, image-guided insertion of these T cells is being tested in patients with pleural malignancies [91] or in combination with the anti-PD-1 agent pembrolizumab [92]. Even though, in this type of tumor, the search of an adequate, specific TAA that directs the immune reaction towards the tumor cells and causes minimal damage to healthy cells is very complex, unlike what occurs in hematological neoplasms with CD19, and the solution of this problem will be in the numerous clinical trials with such different approaches [93].…”

Design and Application of Hybrid Polymer-Protein Systems in Cancer Therapy

“…At present, the field of immunotherapy is mainly focused on chimeric antigen receptor T cell immunotherapy (CAR-T) and checkpoint inhibitors (ICI), both of which aim to target cytotoxic T cells for the elimination of tumor cells. However, several problems reduce the therapeutic effect, including an immunosuppressive tumor microenvironment, a low level of drug infiltration into tumor tissues, off-target toxicity and other safety issues [143][144][145]. Furthermore, studies have shown that in order to achieve more powerful anti-tumor immune responses combined with immunotherapy, which can stimulate several different types of immune cells, needs to be considered [146,147].…”

Fine-tuning the antigen sensitivity of CAR T cells: emerging strategies and current challenges

“…The canonical “second generation” CAR recognizes target antigen by an extracellular single chain fragment of variable region (scFv) antibody that is composed of the variable domains of the antibody heavy (VH) and light (VL) chains tethered together by a short flexible linker in the order VH-VL or VL-VH ( 16 , 17 ). A hinge region physically connects the scFv to the transmembrane domain and is usually derived from the IgG1 CH2-CH3 region, the extracellular part of CD28 or from the hinge domain of the CD8α molecule ( 18 ). Generally, the intracellular signaling part of a CAR comprises the CD3ζ chain to provide the primary signal and a costimulatory domain to augment and prolong activation, frequently derived of the intracellular part of CD28 or 4-1BB ( 18 ).…”

“…A hinge region physically connects the scFv to the transmembrane domain and is usually derived from the IgG1 CH2-CH3 region, the extracellular part of CD28 or from the hinge domain of the CD8α molecule ( 18 ). Generally, the intracellular signaling part of a CAR comprises the CD3ζ chain to provide the primary signal and a costimulatory domain to augment and prolong activation, frequently derived of the intracellular part of CD28 or 4-1BB ( 18 ). To enhance the antigen sensitivity, each CAR component can accordingly modified ( Figure 1 ).…”