Post-infusion CAR TReg cells identify patients resistant to CD19-CAR therapy

Good, Zinaida; Spiegel, Jay Y.; Sahaf, Bita; Malipatlolla, Meena; Ehlinger, Zachary; Kurra, Sreevidya; Desai, Manan; Reynolds, Warren; Lin, Anita; Vandris, Panayiotis; Wu, Fang; Prabhu, Snehit; Hamilton, Mark; Tamaresis, John; Hanson, P. J.; Patel, Shabnum; Feldman, Steven A.; Frank, Matthew J.; Baird, John H.; Muffly, Lori; Claire, Gursharan K.; Craig, Juliana; Kong, Katherine A.; Wagh, Dhananjay; Coller, John A.; Bendall, Sean C.; Tibshirani, Robert; Plevritis, Sylvia K.; Miklos, David B.; Mackall, Crystal L.

doi:10.1038/s41591-022-01960-7

Cited by 117 publications

(102 citation statements)

References 75 publications

(106 reference statements)

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“…Recently, it has further been shown that T reg /chimeric antigen receptor T-cell ratios in favor of T reg impair the therapeutic efficacy of chimeric antigen receptor T cells. 6 This highlights the complexity of the T reg compartment within chronic inflammatory diseases including cancer. Consequently, T reg are extensively studied as targets for immunotherapies with the aim to reduce immunosuppression by tumorinfiltrating T reg and to promote antitumor immunity.…”

Section: Introductionmentioning

confidence: 99%

“…The other side of this coin is that T reg suppressive activity in solid tumors is generally associated with reduced antitumor responses. Recently, it has further been shown that T reg /chimeric antigen receptor T‐cell ratios in favor of T reg impair the therapeutic efficacy of chimeric antigen receptor T cells 6 . This highlights the complexity of the T reg compartment within chronic inflammatory diseases including cancer.…”

Section: Introductionmentioning

confidence: 99%

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Regulatory T‐cell stability and functional plasticity in health and disease

et al. 2022

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FOXP3-expressing regulatory T cells (T reg ) are indispensable for immune homeostasis and tolerance, and in addition tissue-resident T reg have been found to perform noncanonical, tissue-specific functions. For optimal tolerogenic function during inflammatory disease, T reg are equipped with mechanisms that assure lineage stability. T reg lineage stability is closely linked to the installation and maintenance of a lineage-specific epigenetic landscape, specifically a T regspecific DNA demethylation pattern. At the same time, for local and directed immune regulation T reg must possess a level of functional plasticity that requires them to partially acquire T helper cell (T H ) transcriptional programsthen referred to as T H -like T reg . Unleashing T H programs in T reg , however, is not without risk and may threaten the epigenetic stability of T reg with consequently pathogenic ex-T reg contributing to (auto-) inflammatory conditions. Here, we review how the T reg -stabilizing epigenetic landscape is installed and maintained, and further discuss the development, necessity and lineage instability risks of T H 1-, T H 2-, T H 17-like T reg and follicular T reg .

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Regulatory T‐cell stability and functional plasticity in health and disease

et al. 2022

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“…Given the nature of our question, the role of chronic CAR stimulation on T cell dysfunction, we prioritized sequencing of cells undergoing chronic stimulation for a prolonged period. Most studies evaluate CAR T cells collected between days 7-30 after infusion ( 41, 42 ), or cells collected at later time points from patients with durable responses, a clinical setting in which CAR T cells are not chronically stimulated and persist longer ( 37, 43 ). To our knowledge, this is the first study to report data on CAR T cells isolated months after infusion from a patient with progressive lymphoma, a scenario in which CAR T cell persistence is highly limited beyond 30 days.…”

Section: Discussionmentioning

confidence: 99%

Costimulatory domains direct distinct fates of CAR-driven T cell dysfunction

Selli¹,

Landmann²,

Terekhova³

et al. 2023

Preprint

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Chimeric antigen receptor (CAR) engineered T cells often fail to enact effector functions after infusion into patients. Understanding the biological pathways that lead CAR T cells to failure is of critical importance in the design of more effective therapies. We developed and validated an in vitro model that drives T cell dysfunction through chronic CAR activation and interrogated how CAR costimulatory domains contribute to T cell failure. We found that dysfunctional CD28-based CARs targeting CD19 bear hallmarks of classical T cell exhaustion while dysfunctional 41BB-based CARs are phenotypically, transcriptionally and epigenetically distinct. We confirmed activation of this unique transcriptional program in CAR T cells that failed to control clinical disease. Further, we demonstrate that 41BB-dependent activation of the transcription factor FOXO3 is a significant contributor to this dysfunction and disruption of FOXO3 improves CAR T cell function. These findings identify that chronic activation of 41BB leads to novel state of T cell dysfunction that can be alleviated by genetic modification of FOXO3.

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“…Exposure to phosphatidylinositol-3-kinase (PI3K) inhibitors during the CAR-T manufacturing process can improve T-cell fitness and reduce T-cell exhaustion, and bb21217 incorporated PI3K inhibition during the manufacturing of bb2121 (equivalent to ide-cel) with this goal in mind ( 65 , 66 ). Although bb21217 is no longer under development, a more recent publication has suggested that the transduction of regulatory T cells (T reg ) with CARs predicts shorter responses to CD19-directed CAR-T therapy ( 67 ). Because PI3K inhibitors are known to suppress T reg cells ( 68 ), future research may shed additional insights on the merits of T reg manipulation.…”

Section: Better Mileage: Longer Duration Of Responsesmentioning

confidence: 99%

Innovation in BCMA CAR-T therapy: Building beyond the Model T

2022

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Autologous chimeric antigen receptor T-cell (CAR-T) therapies targeting B-cell maturation antigen (BCMA) have revolutionized the field of multiple myeloma in the same way that the Ford Model T revolutionized the original CAR world a century ago. However, we are only beginning to understand how to improve the efficacy and usability of these cellular therapies. In this review, we explore three automotive analogies for innovation with BCMA CAR-T therapies: stronger engines, better mileage, and hassle-free delivery. Firstly, we can build stronger engines in terms of BCMA targeting: improved antigen binding, tools to modulate antigen density, and armoring to better reach the antigen itself. Secondly, we can improve “mileage” in terms of response durability through ex vivo CAR design and in vivo immune manipulation. Thirdly, we can implement hassle-free delivery through rapid manufacturing protocols and off-the-shelf products. Just as the Model T set a benchmark for car manufacturing over 100 years ago, idecabtagene vicleucel and ciltacabtagene autoleucel have now set the starting point for BCMA CAR-T therapy with their approvals. As with any emerging technology, whether automotive or cellular, the best in innovation and optimization is yet to come.

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Post-infusion CAR TReg cells identify patients resistant to CD19-CAR therapy

Cited by 117 publications

References 75 publications

Regulatory T‐cell stability and functional plasticity in health and disease

Regulatory T‐cell stability and functional plasticity in health and disease

Costimulatory domains direct distinct fates of CAR-driven T cell dysfunction

Innovation in BCMA CAR-T therapy: Building beyond the Model T

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