Chimeric antigen receptor costimulation domains modulate human regulatory T cell function

Boroughs, Angela C.; Larson, Rebecca C.; Choi, Bryan D.; Bouffard, Amanda A.; Riley, Lauren S.; Schiferle, Erik; Kulkarni, Anupriya S.; Cetrulo, Curtis L.; Ting, David T.; Blazar, Bruce R.; Demehri, Shadmehr; Maus, Marcela V.

doi:10.1172/jci.insight.126194

Cited by 100 publications

(98 citation statements)

References 62 publications

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“…Given the extensive evidence for the benefit of 4-1BB encoding CARs in anti-tumour-CAR T cell function, we were surprised to find that inclusion of this domain provided no apparent benefit for Tregs. This finding is consistent with a recent report from Boroughs et al who used a CD19 CAR system to compare the function of first generation, CD28 or 4-1BB encoding CARs in Tregs (Boroughs et al, 2019). They found that a 4-1BB CD19-CAR stimulated expression of CTLA-4 and LAP but had diminished suppressive function in vitro.…”

Section: Discussionsupporting

confidence: 92%

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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Section: Discussionsupporting

confidence: 92%

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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show abstract

“…These results coupled with our data support the notion that CB Tregs represent a population with increased phenotypic homogeneity alongside increased receptor diversity compared to APB Treg, thus serving as an ideal candidate for ACT in autoimmune diseases. Additionally, the potential to generate TCR redirected or chimeric antigen receptor (CAR) Treg has become a topic of great interest in the immunotherapy space (138)(139)(140). Our data suggest that the phenotypic stability and homogeneity of CB Tregs relative to APB might ameliorate concerns over lineage stability with TCR or CAR-directed Treg therapies.…”

Section: Discussionmentioning

confidence: 90%

Human Regulatory T Cells From Umbilical Cord Blood Display Increased Repertoire Diversity and Lineage Stability Relative to Adult Peripheral Blood

et al. 2020

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Tregs. Interestingly, expression of canonical Treg markers, such as FOXP3, TIGIT, and IKZF2, were increased in CB CD4 + CD127 + conventional T cells (Tconv) compared to APB Tconv, post-expansion, implying perinatal T cells may adopt a default regulatory program. Collectively, these data identify surface markers (namely CXCR3) that could be depleted to improve purity and stability of APB Tregs, and support the use of expanded CB Tregs as a potentially optimal ACT modality for the treatment of autoimmune and inflammatory diseases.

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“…They found that CAR-Tregs with the CD28 endodomain maintained their inhibitory function whereas CAR-Tregs with the 4-1BB endodomain did not. Furthermore, only CD28 CAR-Tregs and not 4-1BB CAR-Tregs were effective suppressors of T-effector cells in vivo and were the most effective at inhibiting EGFR-CAR Teff mediated damage on EGFR + skin transplant (90). This is in contrast with what has been published with CAR-T cells, in which the 4-1BB endodomain but not the CD28 endodomain reduced CAR-T cell exhaustion resulting in enhanced CAR-T cell persistence and longevity (57,91).…”

Section: Car Co-stimulatory Endodomain Function In Tregsmentioning

confidence: 93%

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

et al. 2020

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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.

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Chimeric antigen receptor costimulation domains modulate human regulatory T cell function

Cited by 100 publications

References 62 publications

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

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

Human Regulatory T Cells From Umbilical Cord Blood Display Increased Repertoire Diversity and Lineage Stability Relative to Adult Peripheral Blood

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

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