Suppression of Murine Colitis and its Associated Cancer by Carcinoembryonic Antigen-Specific Regulatory T Cells

Abstract

The adoptive transfer of regulatory T cells (Tregs) offers a promising strategy to combat pathologies that are characterized by aberrant immune activation, including graft rejection and autoinflammatory diseases. Expression of a chimeric antigen receptor (CAR) gene in Tregs redirects them to the site of autoimmune activity, thereby increasing their suppressive efficiency while avoiding systemic immunosuppression. Since carcinoembryonic antigen (CEA) has been shown to be overexpressed in both human colitis and colorectal cancer, we treated CEA-transgenic mice that were induced to develop colitis with CEA-specific CAR Tregs. Two disease models were employed: T-cell-transfer colitis as well as the azoxymethane-dextran sodium sulfate model for colitis-associated colorectal cancer. Systemically administered CEA-specific (but not control) CAR Tregs accumulated in the colons of diseased mice. In both model systems, CEA-specific CAR Tregs suppressed the severity of colitis compared to control Tregs. Moreover, in the azoxymethane-dextran sodium sulfate model, CEA-specific CAR Tregs significantly decreased the subsequent colorectal tumor burden. Our data demonstrate that CEA-specific CAR Tregs exhibit a promising potential in ameliorating ulcerative colitis and in hindering colorectal cancer development. Collectively, this study provides a proof of concept for the therapeutic potential of CAR Tregs in colitis patients as well as in other autoimmune inflammatory disorders.

A Novel Carcinoembryonic Antigen T-Cell Bispecific Antibody (CEA TCB) for the Treatment of Solid Tumors

“…Similar differences in the ability to induce toxicities of T cells targeting CEA but expressing TCRs or CARs (Chimeric Antigen Receptor) were recently described by Magee and Snook (40). This and other studies also highlighted that the CEA expression level in the target organ is a key determinant in the development of toxicity and concluded that, similarly to CEA TCB antibody, CAR T cells can discriminate between cells with varying levels of antigen expression in vivo, providing a potential avenue to target antigens that are highly expressed by tumor cells but have lower expression in normal tissues (40,41).…”

Tumor Regression and Delayed Onset Toxicity Following B7-H4 CAR T Cell Therapy

“…Transfer of regulatory T cells expressing a carcinoembryonic antigen-specific CAR lessens the severity of colitis in preclinical animal models. 54 Since pancreatic islet cells express B7-H4, investigation of B7-H4 CAR-bearing regulatory T cells could have therapeutic potential in Type-1 diabetes.…”

Combination Therapy Using IL-2/IL-2 Monoclonal Antibody Complexes, Rapamycin, and Islet Autoantigen Peptides Increases Regulatory T Cell Frequency and Protects against Spontaneous and Induced Type 1 Diabetes in Nonobese Diabetic Mice

“…Recently, Tregs have also been investigated in clinical trials to prevent/treat T1D, graft-versushost diseases, and organ transplant rejection (16). Notably, it is well established in several models that Ag-specific Tregs are more effective than polyclonal Tregs in immunosuppression in vitro and control of autoimmunity in vivo (e.g., T1D, arthritis, multiple sclerosis, arthritis, colitis) (17)(18)(19)(20)(21)(22)(23)(24); particularly, injection of small numbers of Ag-specific Tregs selectively expanded in vitro can reverse diabetes even after disease onset (17,18). However, whether Ag-specific Tregs can be expanded in vivo, whether these cells retain their immunosuppressive function following expansion, and the stability of their Foxp3 expression have not yet been elucidated.…”