Systematic testing and specificity mapping of alloantigen-specific chimeric antigen receptors in T regulatory cells

Dawson, Nicholas A.J.; Lamarche, Caroline; Hoeppli, R.; Bergqvist, Peter; Fung, Vivian; McIver, Emma; Huang, Qing; Gillies, Jana; Speck, Madeleine; Orban, Paul C.; Bush, Jonathan W.; Mahdavi, Majid; Levings, Megan K.

doi:10.1172/jci.insight.123672

Cited by 81 publications

(117 citation statements)

References 71 publications

(90 reference statements)

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“…The kinetics of persistence and migration of ex vivo expanded Tregs following adoptive transfer, however, is still not well understood. In murine transplant models Tregs tend to accumulate in the graft and draining lymph nodes, although Lee et al were not able to detect transferred Tregs beyond 14 days after infusion into murine islet transplant recipients . In nontransplanted nonhuman primates, adoptively transferred Tregs were shown to be short‐lived, as their numbers declined rapidly during the first week after infusion, albeit a small number of cells were still detected both in blood and in secondary lymphoid tissues for >50 days .…”

Section: Discussionmentioning

confidence: 99%

Applicability, safety, and biological activity of regulatory T cell therapy in liver transplantation

Sánchez‐Fueyo

Whitehouse

Grageda

et al. 2020

American Journal of Transplantation

153

179

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Regulatory T cells (Tregs) are a lymphocyte subset with intrinsic immunosuppressive properties that can be expanded in large numbers ex vivo and have been shown to prevent allograft rejection and promote tolerance in animal models. To investigate the safety, applicability, and biological activity of autologous Treg adoptive transfer in humans, we conducted an open‐label, dose‐escalation, Phase I clinical trial in liver transplantation. Patients were enrolled while awaiting liver transplantation or 6‐12 months posttransplant. Circulating Tregs were isolated from blood or leukapheresis, expanded under good manufacturing practices (GMP) conditions, and administered intravenously at either 0.5‐1 million Tregs/kg or 3‐4.5 million Tregs/kg. The primary endpoint was the rate of dose‐ limiting toxicities occurring within 4 weeks of infusion. The applicability of the clinical protocol was poor unless patient recruitment was deferred until 6‐12 months posttransplant. Thus, only 3 of the 17 patients who consented while awaiting liver transplantation were dosed. In contrast, all six patients who consented 6‐12 months posttransplant received the cell infusion. Treg transfer was safe, transiently increased the pool of circulating Tregs and reduced anti‐donor T cell responses. Our study opens the door to employing Treg immunotherapy to facilitate the reduction or complete discontinuation of immunosuppression following liver transplantation.

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Section: Discussionmentioning

confidence: 99%

Applicability, safety, and biological activity of regulatory T cell therapy in liver transplantation

Sánchez‐Fueyo

Whitehouse

Grageda

et al. 2020

American Journal of Transplantation

153

179

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“…We selected 9 co-receptor proteins to test in a CAR format in comparison to an existing CAR which encodes an intracellular CD28 domain and an extracellular single chain antibody (scFv) specific for HLA-A2, and stimulates potent Treg suppression in vitro and in vivo (Dawson et al, 2019;MacDonald et al, 2016). Co-receptors were selected from CD28 or TNFR family proteins ( Figure 1A) since these are functionally relevant in T cells and, in some cases, had already been successfully used as CARs in Tconvs.…”

Section: Generation Cell Surface Expression and Selection Of Signalimentioning

confidence: 99%

“…We previously found that circulating CAR Tregs are difficult to detect >7 days after injection (Dawson et al, 2019). Since CARs encoding TNFR family domains can increase CAR T cell longevity (Long et al, 2015;Song et al, 2011), we sought to characterize CAR Treg engraftment and stability by analyzing the proportion of Myc + cells within the hCD45 + gate over time.…”

Section: Wild Type Cd28 Signaling Is Required For Optimal Treg Supprementioning

confidence: 99%

“…A notable limitation of our study is due to the paucity of models in which to test human Treg function in vivo. We elected to use the well-established GVHD model because it is a system in which the advantage of CAR Tregs has previously been observed (Dawson et al, 2019;MacDonald et al, 2016) and it is significantly more high throughput than other humanized mouse models, and thus amenable to testing multiple CAR Treg groups in parallel.…”

Section: Previous Reports On the Function Of 4-1bb In Tregs Have Beenmentioning

confidence: 99%

“…We and others developed an approach to generate Ag-specific Tregs with known specificity using chimeric antigen receptors (CARs) which combine extracellular antigen binding domains and intracellular signaling domains (Boardman and Levings, 2019). In comparison to polyclonal cells, the resulting CAR Tregs have enhanced potency, as demonstrated in a variety of models, including colitis (Blat et al, 2014;Elinav et al, 2009;Elinav et al, 2008), experimental autoimmune encephalomyelitis (Fransson et al, 2012), transplantation (Boardman et al, 2017;Dawson et al, 2019;MacDonald et al, 2016;Noyan et al, 2017;Pierini et al, 2017), and immunity to therapeutic proteins (Kim et al, 2015b;Yoon et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Functional effects of chimeric antigen receptor co-receptor signaling domains in human Tregs

Dawson

Rosado‐Sánchez

Novakovsky

et al. 2019

Preprint

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Antigen-specific regulatory T cells (Tregs) engineered with chimeric antigen receptor (CARs) are a potent immunosuppressive cellular therapy in multiple disease models. To date the majority of CAR Treg studies employed second generation CARs, encoding a CD28 or 4-1BB co-receptor signaling domain and CD3z, but it was not known if this CAR design was optimal for Tregs.Using an HLA-A2-specific CAR platform and human Tregs, we compared ten CARs with different co-receptor signaling domains and systematically tested their function. Tregs expressing a CAR encoding wild-type CD28 were markedly superior to all other CARs tested in an in vivo model of graft-versus-host disease. In vitro assays revealed stable expression of Helios and ability to suppress CD80 expression on DCs as key in vitro predictors of in vivo function.This comprehensive study of CAR signaling-domain variants in Tregs can be leveraged to optimize CAR design for use in antigen-specific Treg therapy.

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Cross talk between human regulatory T cells and antigen‐presenting cells: Lessons for clinical applications

et al. 2020

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Regulatory T cells (Tregs) have a critical role in maintaining self‐tolerance and immune homeostasis. There is much interest in using Tregs as a cell therapy to re‐establish tolerance in conditions such as inflammatory bowel disease and type 1 diabetes, with many ongoing clinical studies testing the safety and efficacy of this approach. Manufacturing of Tregs for therapy typically involves ex vivo expansion to obtain sufficient cell numbers for infusion and comes with the risk of altering the activity of key biological processes. However, this process also offers an opportunity to tailor Treg function to maximize in vivo activity. In this review, we focus on the roles of antigen‐presenting cells (APCs) in the generation and function of Tregs in humans. In addition to stimulating the development of Tregs, APCs activate Tregs and provide signals that induce specialized functional and homing marker expression. Cross talk between Tregs and APCs is a critical, often under‐appreciated, aspect of Treg biology, with APCs mediating the key properties of infectious tolerance and bystander suppression. Understanding the biology of human Treg‐APC interactions will reveal new ways to optimize Treg‐based therapeutic approaches.

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Systematic testing and specificity mapping of alloantigen-specific chimeric antigen receptors in T regulatory cells

Cited by 81 publications

References 71 publications

Applicability, safety, and biological activity of regulatory T cell therapy in liver transplantation

Applicability, safety, and biological activity of regulatory T cell therapy in liver transplantation

Functional effects of chimeric antigen receptor co-receptor signaling domains in human Tregs

Cross talk between human regulatory T cells and antigen‐presenting cells: Lessons for clinical applications

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