Transient mTOR inhibition rescues 4-1BB CAR-Tregs from tonic signal-induced dysfunction

Lamarthée, Baptiste; Marchal, A.; Charbonnier, Sylvie; Blein, Tifanie; Léon, Juliette; Martin, Emmanuel; Rabaux, Lucas; Vogt, Katrin; Titeux, Matthias; Delville, Marianne; Vinçon, Hélène; Six, Emmanuelle; Pallet, Nicolas; Michonneau, David; Anglicheau, Dany; Legendre, Christophe; Taupin, Jean‐Luc; Nemazanyy, Ivan; Sawitzki, Birgit; Latour, Sylvain; Cavazzana, Marina; André-Schmutz, Isabelle; Zuber, Julien

doi:10.1038/s41467-021-26844-1

Cited by 41 publications

(53 citation statements)

References 74 publications

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“…Studies in the delivery of chimeric antigen receptor (CAR) T cells in cancer (71, 72) and CAR Tregs in inflammatory models (73) have clearly shown that therapeutic success is reliant on dampening of memory acquisition and hindering the development of cellular exhaustion. CAR Tregs, while proposed for treatment of autoimmunity, likewise require methodological fine-tuning for prevention of exhaustion and loss of lineage stability (74). Future studies should investigate whether the incorporation of IL-2 + IGF1 or IL-7 + IGF1 into CAR Treg or Tconv expansion protocols, respectively, prevents exhaustion to allow for longer duration of efficacy.…”

Section: Discussionmentioning

confidence: 99%

Insulin-like Growth Factor-1 Synergizes with IL-2 to Induce Homeostatic Proliferation of Regulatory T cells

Shapiro

Peters

Brown

et al. 2022

Preprint

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IL-2 has been proposed to restore tolerance via regulatory T cell (Treg) expansion in autoimmunity, yet off-target effects necessitate identification of a combinatorial approach. We recently reported reduced levels of immunoregulatory insulin-like growth factor-1 (IGF1) during type 1 diabetes (T1D) progression. Thus, we hypothesized that IGF1 would synergize with IL-2 to expand Tregs. We observed IGF1R was elevated on murine memory and human naïve Treg subsets. IL-2 and IGF1 promoted murine PI3K/Akt and human STAT5 signaling in Tregs. IL-2 and IGF1 treatment expanded Tregs beyond either agent alone in NOD mice. Incubation of naïve human CD4+T cells with IL-2 and IGF1 enhanced Treg proliferationin vitro, without the need for T cell receptor ligation. This synergism was attributed to increased high-affinity IL-2Rα expression on naïve Tregs, in contrast to intermediate-affinity IL-2Rβ and IL-2Rγ subunit enhancement on naïve conventional T cells (Tconv). We then demonstrated that IGF1 and IL-2 or the IL2Rγ-chain-dependent cytokine, IL-7, can be used to induce proliferation of genetically-engineered naïve Treg or Tconv cells, respectively. These data support the potential use of IGF1 in combination with common γ-chain cytokines to drive T cell expansions bothin vitroandin vivofor cellular therapeutics and genetic modifications.

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Section: Discussionmentioning

confidence: 99%

Insulin-like Growth Factor-1 Synergizes with IL-2 to Induce Homeostatic Proliferation of Regulatory T cells

Shapiro

Peters

Brown

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…4-1BB-containing CARs are more resistant to T-cell exhaustion [48]. Function is improved by exposure to mTOR inhibitors and vitamin C [45].…”

Section: -1bbmentioning

confidence: 99%

“…Furthermore, Lamarthee et al showed 4-1BB CAR Tregs exhibit decreased lineage stability and reduced in vivo suppressive capacities. Yet, transient exposure to mTOR inhibitors and vitamin C improves 4-1BB CAR Treg in vivo function [ 45 ]. In a separate study, Shrestha et al showed CAR Tregs generated with the 4-1BB domain are able to prevent GvHD in murine model [ 46 ].…”

Section: Introductionmentioning

confidence: 99%

CAR-T Regulatory (CAR-Treg) Cells: Engineering and Applications

2022

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Regulatory T cells are critical for maintaining immune tolerance. Recent studies have confirmed their therapeutic suppressive potential to modulate immune responses in organ transplant and autoimmune diseases. However, the unknown and nonspecific antigen recognition of polyclonal Tregs has impaired their therapeutic potency in initial clinical findings. To address this limitation, antigen specificity can be conferred to Tregs by engineering the expression of transgenic T-cell receptor (TCR) or chimeric antigen receptor (CAR). In contrast to TCR Tregs, CAR Tregs are major histocompatibility complex (MHC) independent and less dependent on interleukin-2 (IL-2). Furthermore, CAR Tregs maintain Treg phenotype and function, home to the target tissue and show enhanced suppressive efficacy compared to polyclonal Tregs. Additional development of engineered CAR Tregs is needed to increase Tregs’ suppressive function and stability, prevent CAR Treg exhaustion, and assess their safety profile. Further understanding of Tregs therapeutic potential will be necessary before moving to broader clinical applications. Here, we summarize recent studies utilizing CAR Tregs in modulating immune responses in autoimmune diseases, transplantation, and gene therapy and future clinical applications.

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“…Dawson et al generated 10 CARs with different co‐receptor signaling domains and observed that CAR encoding CD28 were markedly superior to all other CARs in a murine model of CAR Treg therapy 35 . Interestingly, the 4‐1BB signaling domain was shown to be associated with tonic signaling in CAR Tregs which led to a decreased lineage stability and reduced in vivo suppressive capacities compared with CD28 CAR‐Tregs 36 . Transient ex vivo mitigation of 4‐1BB tonic signaling through mTOR inhibition significantly improved CAR‐Treg stability and function.…”

Section: Car Tregs Stability and Functionmentioning

confidence: 99%

“…35 Interestingly, the 4-1BB signaling domain was shown to be associated with tonic signaling in CAR Tregs which led to a decreased lineage stability and reduced in vivo suppressive capacities compared with CD28 CAR-Tregs. 36 Transient ex vivo mitigation of 4-1BB tonic signaling through mTOR inhibition significantly improved CAR-Treg stability and function. Because CAR Tregs stability and function depends on many parameters such as the characteristics of the cell donor, the source of Tregs, the isolation strategy and/or the CAR structure, each different CAR-Treg product can have a different stability and function.…”

Section: Car Tregs Stability and Functionmentioning

confidence: 99%

Overcoming barriers to widespread use of CAR‐Treg therapy in organ transplant recipients

Crémoni¹,

Massa

Sicard

2022

HLA

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Preventing allograft rejection has been the main challenge of transplantation medicine since the discovery of immune responses against foreign HLA molecules in the mid-20th century. Prevention of rejection currently relies on immunosuppressive drugs, which lack antigen specificity and therefore increase the risk for infections and cancers. Adoptive cell therapy with donorreactive regulatory T cells (Tregs) has progressively emerged as a promising approach to reduce the need for pan-immunosuppressive drugs and minimize morbidity and mortality in solid-organ transplant recipients. Chimeric antigen receptor (CAR) technology has recently been used successfully to generate Tregs specific for donor HLA molecules and overcome the limitations of Tregs enrichment protocols based on repetitive stimulations with alloantigens. While this novel approach opens new possibilities to make Tregs therapy more feasible, it also creates additional challenges. It is essential to determine which source of therapeutic Tregs, CAR constructs, target alloantigens, safety strategies, patients and immunosuppressive regimens are optimal for the success of CAR Treg therapy. Here, we discuss unmet needs and strategies to bring donor-specific CAR Treg therapy to the clinic and make it as accessible as possible.

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Transient mTOR inhibition rescues 4-1BB CAR-Tregs from tonic signal-induced dysfunction

Cited by 41 publications

References 74 publications

Insulin-like Growth Factor-1 Synergizes with IL-2 to Induce Homeostatic Proliferation of Regulatory T cells

Insulin-like Growth Factor-1 Synergizes with IL-2 to Induce Homeostatic Proliferation of Regulatory T cells

CAR-T Regulatory (CAR-Treg) Cells: Engineering and Applications

Overcoming barriers to widespread use of CAR‐Treg therapy in organ transplant recipients

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