Innovative CAR-T Cell Therapy for Solid Tumor; Current Duel between CAR-T Spear and Tumor Shield

Abstract

Novel engineered T cells containing chimeric antigen receptors (CAR-T cells) that combine the benefits of antigen recognition and T cell response have been developed, and their effect in the anti-tumor immunotherapy of patients with relapsed/refractory leukemia has been dramatic. Thus, CAR-T cell immunotherapy is rapidly emerging as a new therapy. However, it has limitations that prevent consistency in therapeutic effects in solid tumors, which accounts for over 90% of all cancer patients. Here, we review the literature regarding various obstacles to CAR-T cell immunotherapy for solid tumors, including those that cause CAR-T cell dysfunction in the immunosuppressive tumor microenvironment, such as reactive oxygen species, pH, O2, immunosuppressive cells, cytokines, and metabolites, as well as those that impair cell trafficking into the tumor microenvironment. Next-generation CAR-T cell therapy is currently undergoing clinical trials to overcome these challenges. Therefore, novel approaches to address the challenges faced by CAR-T cell immunotherapy in solid tumors are also discussed here.

Harnessing the chemokine system to home CAR-T cells into solid tumors

“…Solid tumors present numerous challenges that are absent in disseminated hematological cancers such as: heterogeneous antigen expression, physical and molecular barriers that block T cell entry, acidic and hypoxic conditions, and a highly immunosuppressive TME. 88 These features are illustrated in Figure 1 . While there are a growing number of clinical trials currently investigating CAR-T cell therapies against solid tumors, this is disproportionate to the large number of those investigating these therapies in hematological cancers.…”

Current Strategies for Tumor Photodynamic Therapy Combined With Immunotherapy

“…Immunosuppressive cells such as MDSCs and regulatory T cells (Tregs) in the TME suppress the antitumor immune responses and promote tumor progression and invasion ( 112 , 113 ). Specifically, MDSCs suppress T-cell function through multiple mechanisms, including production of nitric oxide and immunosuppressive metabolites, secretion of immunosuppressive cytokines such as TGF-β and IL-10, and upregulation of cyclo-oxygenase 2 (Cox2) and prostaglandin E2 (PGE2) ( 114 , 115 ), while Tregs suppress T-cell function through CTL antigen 4 to inhibit the expression of DC co-stimulatory molecules including CD80 and CD86 ( 116 ).…”

Chimeric antigen receptor natural killer (CAR-NK) cell design and engineering for cancer therapy

“…A reduction of immune suppressor cells that are abundantly present in the TME (Treg [ 199 ], MDSC [ 200 ], TAM [ 201 ]) also is directed towards an improved clinical outcome and increased overall survival. The challenges posed by the tumor microenvironment and possible solutions using CAR-engineered cells have been covered extensively in various recent reviews [ 193 , 202 ].…”