Chimeric non-antigen receptors in T cell-based cancer therapy

Abstract

Adoptively transferred T cell-based cancer therapies have shown incredible promise in treatment of various cancers. So far therapeutic strategies using T cells have focused on manipulation of the antigen-recognition machinery itself, such as through selective expression of tumor-antigen specific T cell receptors or engineered antigen-recognition chimeric antigen receptors (CARs). While several CARs have been approved for treatment of hematopoietic malignancies, this kind of therapy has been less successful in the treatment of solid tumors, in part due to lack of suitable tumor-specific targets, the immunosuppressive tumor microenvironment, and the inability of adoptively transferred cells to maintain their therapeutic potentials. It is critical for therapeutic T cells to overcome immunosuppressive environmental triggers, mediating balanced antitumor immunity without causing unwanted inflammation or autoimmunity. To address these hurdles, chimeric receptors with distinct signaling properties are being engineered to function as allies of tumor antigen-specific receptors, modulating unique aspects of T cell function without directly binding to antigen themselves. In this review, we focus on the design and function of these chimeric non-antigen receptors, which fall into three broad categories: ‘inhibitory-to-stimulatory’ switch receptors that bind natural ligands, enhanced stimulatory receptors that interact with natural ligands, and synthetic receptor-ligand pairs. Our intent is to offer detailed descriptions that will help readers to understand the structure and function of these receptors, as well as inspire development of additional novel synthetic receptors to improve T cell-based cancer therapy.

Boosting the integration of cell membrane-nanomaterial hybrids via dextran-mediated dynamic dispersion system to capture bioactive compounds in natural products

“…5,6 In particular, natural cells have abundant specific receptors that are thought to function in chemical signal recognition and response. [7][8][9][10] In this case, taking advantage of the receptor-ligand interactions, CN hybrids with targeting capability can be designed to capture bioactive compounds from natural products. 11,12 However, effective target recognition is crucial for improving the performance of CN hybrids, which largely depends on the efficient coating of the recognition element-cell membrane.…”

Implementing Logic Gates for Safer Immunotherapy of Cancer

“…Here we examine different classes of such cues as potential components of tumor-specific signatures and review various strategies used to exploit the AND and NOT gates for their immunotargeting. Other powerful genetic approaches implementing the OR logic gate (12)(13)(14)(15), TRUCKs (16)(17)(18) or switch receptors (19)(20)(21)(22) address additional critical challenges in ACT and are not dealt with in this review.…”

Double Strike Approach for Tumor Attack: Engineering T Cells Using a CD40L:CD28 Chimeric Co-Stimulatory Switch Protein for Enhanced Tumor Targeting in Adoptive Cell Therapy

“…Thus, CD40L:CD28 CSPs can be triggered in the TME and should, thereby, activate the co-stimulation in CD40L: CD28-engineered T cells while additionally supporting the antitumor response indirectly by inducing tumor cell apoptosis (43,44), and counteracting various suppressive mechanisms of tumor-stroma components, including immune stimulatory polarization of DCs and tumor-associated macrophages (45)(46)(47)(48), counteracting T regulatory cells (49), and modulating the tumor endothelium for improved T cell infiltration (40,42) (Figure 1). In this way, the CD40L:CD28 CSPs should differ to other switch receptors, such as PD1:CD28, CTLA4:CD28 and anti-TGFb:CD28, which exert their effects mainly on the expressing T cells (50).…”