Anti-melanoma activity of T cells redirected with a TCR-like chimeric antigen receptor

Abstract

Genetically modified T cells to recognize tumor-associated antigens by transgenic TCRs or chimeric antigen receptors (CAR) have been successfully applied in clinical trials. However, the disadvantages of either TCR mismatching or the requirement of a surface tumor antigen limit their wider applications in adoptive T cell therapy. A TCR-like chimeric receptor, specific for the melanoma-related gp100/HLA-A2 complex was created by joining a TCR-like antibody GPA7 with the endodomains of CD28 and CD3-ζ chain. This TCR-like CAR, GPA7-28z, was subsequently introduced into human T cells. Retargeted T cells expressing GPA7-28z could exhibit efficient cytotoxic activities against human melanoma cells in vitro in the context with HLA-A2. Furthermore, infusion of GPA7-28z-transduced T cells suppressed melanoma progression in a xenograft mouse model. Redirecting human T cells with TCR-like CARs would be a promising alternative approach to TCR-mediated therapy for melanoma patients, which is also feasible for targeting a variety of other tumor antigens.

Blockade of Programmed Death 1 Augments the Ability of Human T Cells Engineered to Target NY-ESO-1 to Control Tumor Growth after Adoptive Transfer

“…These T cells are genetically altered to express optimized TCRs that operate under restriction of the TCR-peptide-MHC complex, but offer the benefits of the full spectrum of activation signals that are exhibited by the wild-type receptor(4, 5), show more physiologically-relevant levels of affinity for their cognate antigen(6), and can also be directed against antigen-expressing stromal cells and intracellular TAAs(7). Antigens that have been targeted by TCR engineering, to date, have included relatively immunogenic antigens derived from spontaneously occurring tumor-specific T cells in patients, such as the melanocyte differentiation antigens MART-1(8), glycoprotein 100 (gp100)(9), the melanoma-associated antigen (MAGE)(10), and New York esophageal squamous cell carcinoma antigen (NYESO1)(11). Using these targets, anti-tumor responses have been reported in a subset of patients enrolled in early phase clinical trials of TCR-engineered T cells targeting melanoma(1, 9), colon cancer(12), and synovial cell sarcoma(13).…”

“…Antigens that have been targeted by TCR engineering, to date, have included relatively immunogenic antigens derived from spontaneously occurring tumor-specific T cells in patients, such as the melanocyte differentiation antigens MART-1(8), glycoprotein 100 (gp100)(9), the melanoma-associated antigen (MAGE)(10), and New York esophageal squamous cell carcinoma antigen (NYESO1)(11). Using these targets, anti-tumor responses have been reported in a subset of patients enrolled in early phase clinical trials of TCR-engineered T cells targeting melanoma(1, 9), colon cancer(12), and synovial cell sarcoma(13). …”

A therapeutic T cell receptor mimic antibody targets tumor-associated PRAME peptide/HLA-I antigens

“…Therefore, the present study on Pr20 adds additional proof-of-concept that TCRm can be potent and selective therapeutic agents. Finally, due to the well-characterized mAb format of TCRm, they can be readily engineered into alternative formats such as Fc-enhanced forms, as shown in this study, and BiTE (56,57) forms, as done with a TCRm to WT1, or transduced as chimeric antigen constructs (CARs) in T cells (58,59). These additional formats may be required for effective targeting of these ultra-low density targets.…”

Engineering CAR-T cells: Design concepts

“…Developing CAR recognition domains that more closely mimic TCRs is an intriguing strategy for enhancing T cell functionality. Several groups have employed phage display and hybridoma strategies to isolate “TCR-like” antibodies, which bind tumor-derived peptides in an HLA-restricted manner [63,73]. These antibodies imitate the specificity of TCRs in their ability to recognize intracellular tumor antigens expressed on MHC; however, they still exhibit the kinetics and high-affinity binding properties of antibodies rather than TCRs [63].…”