The Future of Regulatory T Cell Therapy: Promises and Challenges of Implementing CAR Technology

Abstract

Cell therapy with polyclonal regulatory T cells (Tregs) has been translated into the clinic and is currently being tested in transplant recipients and patients suffering from autoimmune diseases. Moreover, building on animal models, it has been widely reported that antigen-specific Tregs are functionally superior to polyclonal Tregs. Among various options to confer target specificity to Tregs, genetic engineering is a particularly timely one as has been demonstrated in the treatment of hematological malignancies where it is in routine clinical use. Genetic engineering can be exploited to express chimeric antigen receptors (CAR) in Tregs, and this has been successfully demonstrated to be robust in preclinical studies across various animal disease models. However, there are several caveats and a number of strategies should be considered to further improve on targeting, efficacy and to understand the in vivo distribution and fate of CAR-Tregs. Here, we review the differing approaches to confer antigen specificity to Tregs with emphasis on CAR-Tregs. This includes an overview and discussion of the various approaches to improve CAR-Treg specificity and therapeutic efficacy as well as addressing potential safety concerns. We also discuss different imaging approaches to understand the in vivo biodistribution of administered Tregs. Preclinical research as well as suitability of methodologies for clinical translation are discussed.

Cellular therapies in organ transplantation

“…Next‐generation Treg therapeutics are now focused on antigen specificity [73], with chimeric antigen receptor (CAR) Tregs taking centre stage [74]. These cell products allow for intricate modification in antigen recognition, costimulation, and signalling domains, theoretically providing greater control of the desired effects [75,76].…”

Adoptive Immunotherapy beyond CAR T-Cells

“…Single-use bag bioreactors are somewhat similar to the conventional flasks, with the advantage of accurate and sterile medium supply, as well as enhanced sterility during cell growth and various manipulations. Simplicity of the device allows it to be used with the majority of cellular products, e.g., DCs, Tregs, CAR T-cells, TILs [95,96].…”

“…Single-use bag bioreactors are somewhat similar to the conventional flasks, with the advantage of accurate and sterile medium supply, as well as enhanced sterility during cell growth and various manipulations. Simplicity of the device allows it to be used with the majority of cellular products, e.g., DCs, Tregs, CAR T-cells, TILs [95,96]. The most common bioreactors for growing immune cells are suspension-based, such as the G-Rex ® flask by Wilson Wolf Inc. (New Brighton, MN, USA) and Z ® RP cell cultivation platform by Zellwerk GmbH (Oberkrämer, Germany).…”

Potential Application of T-Follicular Regulatory Cell Therapy in Transplantation

“…The latter involves synthetic fusion proteins which typically combine an extracellular antibody-derived antigen targeting moiety and an intracellular TCR complex-derived signaling domain (or domains). The resultant protein is consequently able to bind designated target antigens, in an MHC-independent manner, and translate this engagement into activation of customized T cell signaling cascades [reviewed by us ( 132 )]. The first Phase 1/2 human clinical trial using CAR-Tregs (in a setting other than cancer) will launch in 2020 (STEADFAST study, Sangamo Therapeutics) and will test CAR-Tregs in prevention of immune-mediated rejection following HLA-A2 mismatched kidney transplantation.…”