Chimeric antigen receptor‐modified human regulatory T cells that constitutively express IL‐10 maintain their phenotype and are potently suppressive

Abstract

Clinical trials of Treg therapy in transplantation are currently entering phases IIa and IIb, with the majority of these employing polyclonal Treg populations that harbor a broad specificity. Enhancing Treg specificity is possible with the use of chimeric antigen receptors (CARs), which can be customized to respond to a specific human leukocyte antigen (HLA). In this study, we build on our previous work in the development of HLA-A2 CAR-Tregs by further equipping cells with the constitutive expression of interleukin 10 (IL-10) and an imaging reporter as additional payloads. Cells were engineered to express combinations of these domains and assessed for phenotype and function. Cells expressing the full construct maintained a stable phenotype after transduction, were specifically activated by HLA-A2, and suppressed alloresponses potently. The addition of IL-10 provided an additional advantage to suppressive capacity. This study therefore provides an important proof-of-principle for this cell engineering approach for next-generation Treg therapy in transplantation.

Chimeric Antigen Receptor (CAR) Regulatory T-Cells in Solid Organ Transplantation

“…At the same time, CAR Tregs were demonstrated to produce the anti-inflammatory interleukin 10 (IL-10) in the presence of alloantigens in vitro, suggesting that they contribute to a graft-specific immunosuppressive environment (27). Interestingly, the constitutive co-expression of IL-10 in CAR Tregs has been shown to be advantageous to the suppressive capacity (73).…”

Multipurposing CARs: Same engine, different vehicles

“… 71 Furthermore, co-expressing IL-10 by A2-CAR Tregs enhanced the suppressive capacity of these cells. 72 In a more flexible and modular approach, CAR Tregs were designed to bind monoclonal antibodies to MHC I molecules, and this system promoted allograft tolerance in multiple preclinical tissue transplantation settings. 73 Immune cells besides MHC I-expressing T cells can also be targeted by CAR Tregs; for example, expression of CD19-targeted CARs in Tregs suppressed differentiation and IgG antibody production by CD19+ B cells, thereby reducing GvHD 74 in one model system.…”

Imaging cellular immunotherapies and immune cell biomarkers: from preclinical studies to patients

“…In vitro , cells maintained their phenotype and gained an additional suppressive advantage, while NIS could be used for their non-invasive in vivo monitoring. 34 …”

“…In vitro, cells maintained their phenotype and gained an additional suppressive advantage, while NIS could be used for their non-invasive in vivo monitoring. 34 Gamma delta T cells. They exert their cytotoxic activity through antigens recognition and indirectly enhance the anti-tumor activity of other immune cells by secreting multiple cytokines.…”