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

Yuna Jo, Laraib Amir Ali, Ju A Shim, Byung Ha Lee, Changwan Hong, Yuna Jo, Laraib Amir Ali, Ju A Shim, Byung Ha Lee, Changwan Hong

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.

Keywords: CAR-T; T cell responses; immunotherapy; solid tumor; tumor microenvironment.

Conflict of interest statement

B.H.L. is a full-time employee of NeoImmuneTech, Inc. The other authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The journey of chimeric antigen receptor T (CAR-T) cell from the bloodstream to the tumor microenvironment and the immunosuppressive challenges it faces. A CAR-T cell starts its journey in the bloodstream, which is the common site of administration. It faces challenges regarding infiltration because of the lack of cognate chemokine signaling, aberrant vasculature, and extracellular matrix (ECM) proteins, such as heparan sulfate proteoglycans (HSPGs). Eventually, after infiltration, it encounters complications in recognizing tumors because of the shortage of TSA. It further faces an inhibitory environment because of soluble immunosuppressive factors produced by tumor-associated macrophages (TAMs), regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs), and its cytotoxic efficacy is thus attenuated. The factors that interfere with the effective anti-tumor response of CAR-T cells are controllable, either individually or in combination, to improve CAR-T cell infiltration, persistence, and cytotoxicity. CCR, cognate chemokine receptor; TSA, tumor-specific antigen; IL, interleukin; TGFβ, transforming growth factor-β; IDO, indoleamine-2,3-dioxygenase; CAF, cancer-associated fibroblast; ROS, reactive oxygen species; MG, methylglyoxal; iNOS, inducible nitric oxide synthase.
Figure 2
Figure 2
Approaches for improved CAR-T cell therapy. Innovative approaches of CAR-T cell therapy for solid tumors. Inverted chimeric receptors convert the inhibitory signals from cytokines (IL-4 or TGFβ) or immune checkpoint to stimulatory one via intracellular stimulatory domain. Engineered expression of cognate chemokine receptors (CCRs) with matching of chemokines (CCL), fibroblast activated protein (FAP), and heparanase (HPSE) induces trafficking signals and T cell infiltration into tumor microenvironment (TME). As immune checkpoints, such as PD-1 or CTLA-4, suppress T cell activation, blocking their signals with immune checkpoint inhibitors (anti-PD-1 or anti-CTLA-4) enhances CAR-T cell cytotoxicity. Multi-specific CARs and tandem CARs target multiple tumor antigens to boost its function. Genetic engineering of responsible transcription factors (TFs) to regulatory signals of oxidative stress (ROS and iNOS) and immunosuppressive metabolites (MG and ARG1), from either tumor cells or immune suppressor cells, provides CAR-T cells the resistance to TME. NAbs or sDNR against inhibitory cytokines, such as IL-10 and TGFβ, prevent inhibitory signals via inhibitory cytokine receptors (ICR). Anti-angiogenic antibodies (anti-vascular endothelial growth factor (VEGF)) block angiogenesis and then improve T cell infiltration into the tumor bed. MSCs or CAR-T cells engineered to express survival or inflammatory cytokines, IL-2, IL-12, IL-7, and IL-15, enhance T cells function and maintenance. Combinations of these approaches in a solid tumor models enhance T cell cytotoxicity. CR: cytokine receptor, iNOS: inducible nitric oxide synthase, sDNR: soluble dominant negative receptors, NAb: neutralizing antibody, ICR; inhibitory cytokine receptor, SCR: stimulatory cytokine receptor, MSCs: mesenchymal stem cells.

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