Publications by authors named "Jeffrey A Bluestone"

239 Publications

The CD28-Transmembrane Domain Mediates Chimeric Antigen Receptor Heterodimerization With CD28.

Front Immunol 2021 23;12:639818. Epub 2021 Mar 23.

Department of Surgery, University of California, San Francisco, San Francisco, CA, United States.

Anti-CD19 chimeric antigen receptor (CD19-CAR)-engineered T cells are approved therapeutics for malignancies. The impact of the hinge domain (HD) and the transmembrane domain (TMD) between the extracellular antigen-targeting CARs and the intracellular signaling modalities of CARs has not been systemically studied. In this study, a series of 19-CARs differing only by their HD (CD8, CD28, or IgG) and TMD (CD8 or CD28) was generated. CARs containing a CD28-TMD, but not a CD8-TMD, formed heterodimers with the endogenous CD28 in human T cells, as shown by co-immunoprecipitation and CAR-dependent proliferation of anti-CD28 stimulation. This dimerization was dependent on polar amino acids in the CD28-TMD and was more efficient with CARs containing CD28 or CD8 HD than IgG-HD. The CD28-CAR heterodimers did not respond to CD80 and CD86 stimulation but had a significantly reduced CD28 cell-surface expression. These data unveiled a fundamental difference between CD28-TMD and CD8-TMD and indicated that CD28-TMD can modulate CAR T-cell activities by engaging endogenous partners.
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http://dx.doi.org/10.3389/fimmu.2021.639818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021955PMC
March 2021

Predicting and Preventing Immune Checkpoint Inhibitor Toxicity: Targeting Cytokines.

Trends Immunol 2021 04 10;42(4):293-311. Epub 2021 Mar 10.

Sean N. Parker Autoimmune Research Laboratory and Diabetes Center, University of California San Francisco, San Francisco, CA, USA; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. Electronic address:

Cancer immunotherapies can successfully activate immune responses towards certain tumors. However, this can also result in the development of treatment-induced immune-related adverse events (irAEs) in multiple tissues. Growing evidence suggests that cytokine production in response to these therapeutics potentiates the development of irAEs and may have predictive value as biomarkers for irAE occurrence. In addition, therapeutic agents that inhibit cytokine activity can limit the severity of irAEs, and their use is being tested in the clinical setting. This review provides an in-depth analysis of strategies to uncouple the cytokine response, that precipitates irAEs following cancer immunotherapies, from the benefit gained in promoting antitumor immunity.
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http://dx.doi.org/10.1016/j.it.2021.02.006DOI Listing
April 2021

At the Heart of Immune Checkpoint Inhibitor-Induced Immune Toxicity.

Cancer Discov 2021 Mar;11(3):537-539

Sean N. Parker Autoimmune Research Laboratory and Diabetes Center, University of California, San Francisco, San Francisco, California.

Wei and colleagues showcase a genetic mouse model of immune-mediated myocarditis that shares homology with immune checkpoint inhibitor (CPI)-induced myocarditis in patients with cancer. They demonstrate that abatacept (CTLA4-Ig) limits cardiac toxicity in the mouse model and, thus, may ameliorate the CPI-induced myocarditis in patients with cancer while potentially maintaining antitumor activity..
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http://dx.doi.org/10.1158/2159-8290.CD-21-0091DOI Listing
March 2021

Multi-Omics Resolves a Sharp Disease-State Shift between Mild and Moderate COVID-19.

Cell 2020 12 28;183(6):1479-1495.e20. Epub 2020 Oct 28.

Institute for Systems Biology, Seattle, WA 98109, USA; Department of Bioengineering, University of Washington, Seattle, WA 98105, USA. Electronic address:

We present an integrated analysis of the clinical measurements, immune cells, and plasma multi-omics of 139 COVID-19 patients representing all levels of disease severity, from serial blood draws collected during the first week of infection following diagnosis. We identify a major shift between mild and moderate disease, at which point elevated inflammatory signaling is accompanied by the loss of specific classes of metabolites and metabolic processes. Within this stressed plasma environment at moderate disease, multiple unusual immune cell phenotypes emerge and amplify with increasing disease severity. We condensed over 120,000 immune features into a single axis to capture how different immune cell classes coordinate in response to SARS-CoV-2. This immune-response axis independently aligns with the major plasma composition changes, with clinical metrics of blood clotting, and with the sharp transition between mild and moderate disease. This study suggests that moderate disease may provide the most effective setting for therapeutic intervention.
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http://dx.doi.org/10.1016/j.cell.2020.10.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598382PMC
December 2020

Regulatory T cell control of systemic immunity and immunotherapy response in liver metastasis.

Sci Immunol 2020 10;5(52)

Sean N. Parker Autoimmune Research Laboratory, University of California, San Francisco, San Francisco, CA 94143, USA.

Patients with cancer with liver metastasis demonstrate significantly worse outcomes than those without liver metastasis when treated with anti-PD-1 immunotherapy. The mechanism of liver metastases-induced reduction in systemic antitumor immunity is unclear. Using a dual-tumor immunocompetent mouse model, we found that the immune response to tumor antigen presence within the liver led to the systemic suppression of antitumor immunity. The immune suppression was antigen specific and associated with the coordinated activation of regulatory T cells (T) and modulation of intratumoral CD11b monocytes. The dysfunctional immune state could not be reversed by anti-PD-1 monotherapy unless T cells were depleted (anti-CTLA-4) or destabilized (EZH2 inhibitor). Thus, this study provides a mechanistic understanding and rationale for adding T and CD11b monocyte targeting agents in combination with anti-PD-1 to treat patients with cancer with liver metastasis.
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http://dx.doi.org/10.1126/sciimmunol.aba0759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755924PMC
October 2020

Solving the Puzzle of Immune Tolerance for β-Cell Replacement Therapy for Type 1 Diabetes.

Cell Stem Cell 2020 10;27(4):505-507

Diabetes Center, University of California San Francisco, San Francisco, CA 94143, USA; Department of Surgery, University of California San Francisco, San Francisco, CA 94143, USA. Electronic address:

Type 1 diabetes mellitus results from autoimmune destruction of pancreatic β cells. Insulin treatment is often inadequate in preventing devastating complications. Replacing β cells using stem cell-derived islets while fostering immune tolerance, exemplified in Yoshihara et al., holds the promise of a curative therapy for this disease.
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http://dx.doi.org/10.1016/j.stem.2020.09.008DOI Listing
October 2020

Functional CRISPR dissection of gene networks controlling human regulatory T cell identity.

Nat Immunol 2020 11 28;21(11):1456-1466. Epub 2020 Sep 28.

Department of Microbiology and Immunology, University of California, San Francisco, CA, USA.

Human regulatory T (T) cells are essential for immune homeostasis. The transcription factor FOXP3 maintains T cell identity, yet the complete set of key transcription factors that control T cell gene expression remains unknown. Here, we used pooled and arrayed Cas9 ribonucleoprotein screens to identify transcription factors that regulate critical proteins in primary human T cells under basal and proinflammatory conditions. We then generated 54,424 single-cell transcriptomes from T cells subjected to genetic perturbations and cytokine stimulation, which revealed distinct gene networks individually regulated by FOXP3 and PRDM1, in addition to a network coregulated by FOXO1 and IRF4. We also discovered that HIVEP2, to our knowledge not previously implicated in T cell function, coregulates another gene network with SATB1 and is important for T cell-mediated immunosuppression. By integrating CRISPR screens and single-cell RNA-sequencing profiling, we have uncovered transcriptional regulators and downstream gene networks in human T cells that could be targeted for immunotherapies.
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http://dx.doi.org/10.1038/s41590-020-0784-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577958PMC
November 2020

Tolerance in the Age of Immunotherapy.

N Engl J Med 2020 09;383(12):1156-1166

From the Sean N. Parker Autoimmune Research Laboratory (J.A.B.) and the Diabetes Center (J.A.B., M.A.), University of California, San Francisco, San Francisco.

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http://dx.doi.org/10.1056/NEJMra1911109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534289PMC
September 2020

Multiomic Immunophenotyping of COVID-19 Patients Reveals Early Infection Trajectories.

bioRxiv 2020 Jul 31. Epub 2020 Jul 31.

Host immune responses play central roles in controlling SARS-CoV2 infection, yet remain incompletely characterized and understood. Here, we present a comprehensive immune response map spanning 454 proteins and 847 metabolites in plasma integrated with single-cell multi-omic assays of PBMCs in which whole transcriptome, 192 surface proteins, and T and B cell receptor sequence were co-analyzed within the context of clinical measures from 50 COVID19 patient samples. Our study reveals novel cellular subpopulations, such as proliferative exhausted CD8 and CD4 T cells, and cytotoxic CD4 T cells, that may be features of severe COVID-19 infection. We condensed over 1 million immune features into a single immune response axis that independently aligns with many clinical features and is also strongly associated with disease severity. Our study represents an important resource towards understanding the heterogeneous immune responses of COVID-19 patients and may provide key information for informing therapeutic development.
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http://dx.doi.org/10.1101/2020.07.27.224063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402042PMC
July 2020

CRISPR screen in regulatory T cells reveals modulators of Foxp3.

Nature 2020 06 29;582(7812):416-420. Epub 2020 Apr 29.

Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Regulatory T (T) cells are required to control immune responses and maintain homeostasis, but are a significant barrier to antitumour immunity. Conversely, T instability, characterized by loss of the master transcription factor Foxp3 and acquisition of proinflammatory properties, can promote autoimmunity and/or facilitate more effective tumour immunity. A comprehensive understanding of the pathways that regulate Foxp3 could lead to more effective T therapies for autoimmune disease and cancer. The availability of new functional genetic tools has enabled the possibility of systematic dissection of the gene regulatory programs that modulate Foxp3 expression. Here we developed a CRISPR-based pooled screening platform for phenotypes in primary mouse T cells and applied this technology to perform a targeted loss-of-function screen of around 500 nuclear factors to identify gene regulatory programs that promote or disrupt Foxp3 expression. We identified several modulators of Foxp3 expression, including ubiquitin-specific peptidase 22 (Usp22) and ring finger protein 20 (Rnf20). Usp22, a member of the deubiquitination module of the SAGA chromatin-modifying complex, was revealed to be a positive regulator that stabilized Foxp3 expression; whereas the screen suggested that Rnf20, an E3 ubiquitin ligase, can serve as a negative regulator of Foxp3. T-specific ablation of Usp22 in mice reduced Foxp3 protein levels and caused defects in their suppressive function that led to spontaneous autoimmunity but protected against tumour growth in multiple cancer models. Foxp3 destabilization in Usp22-deficient T cells could be rescued by ablation of Rnf20, revealing a reciprocal ubiquitin switch in T cells. These results reveal previously unknown modulators of Foxp3 and demonstrate a screening method that can be broadly applied to discover new targets for T immunotherapies for cancer and autoimmune disease.
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http://dx.doi.org/10.1038/s41586-020-2246-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305989PMC
June 2020

Regulatory cell therapy in kidney transplantation (The ONE Study): a harmonised design and analysis of seven non-randomised, single-arm, phase 1/2A trials.

Lancet 2020 05;395(10237):1627-1639

Department of Surgery, University of Regensburg, University Hospital Regensburg, Regensburg, Germany; Division of Personalized Tumor Therapy, Fraunhofer Institute for Experimental Medicine and Toxicology, Regensburg, Germany; Regensburg Center for Interventional Immunology, University of Regensburg, Regensburg, Germany. Electronic address:

Background: Use of cell-based medicinal products (CBMPs) represents a state-of-the-art approach for reducing general immunosuppression in organ transplantation. We tested multiple regulatory CBMPs in kidney transplant trials to establish the safety of regulatory CBMPs when combined with reduced immunosuppressive treatment.

Methods: The ONE Study consisted of seven investigator-led, single-arm trials done internationally at eight hospitals in France, Germany, Italy, the UK, and the USA (60 week follow-up). Included patients were living-donor kidney transplant recipients aged 18 years and older. The reference group trial (RGT) was a standard-of-care group given basiliximab, tapered steroids, mycophenolate mofetil, and tacrolimus. Six non-randomised phase 1/2A cell therapy group (CTG) trials were pooled and analysed, in which patients received one of six CBMPs containing regulatory T cells, dendritic cells, or macrophages; patient selection and immunosuppression mirrored the RGT, except basiliximab induction was substituted with CBMPs and mycophenolate mofetil tapering was allowed. None of the trials were randomised and none of the individuals involved were masked. The primary endpoint was biopsy-confirmed acute rejection (BCAR) within 60 weeks after transplantation; adverse event coding was centralised. The RTG and CTG trials are registered with ClinicalTrials.gov, NCT01656135, NCT02252055, NCT02085629, NCT02244801, NCT02371434, NCT02129881, and NCT02091232.

Findings: The seven trials took place between Dec 11, 2012, and Nov 14, 2018. Of 782 patients assessed for eligibility, 130 (17%) patients were enrolled and 104 were treated and included in the analysis. The 66 patients who were treated in the RGT were 73% male and had a median age of 47 years. The 38 patients who were treated across six CTG trials were 71% male and had a median age of 45 years. Standard-of-care immunosuppression in the recipients in the RGT resulted in a 12% BCAR rate (expected range 3·2-18·0). The overall BCAR rate for the six parallel CTG trials was 16%. 15 (40%) patients given CBMPs were successfully weaned from mycophenolate mofetil and maintained on tacrolimus monotherapy. Combined adverse event data and BCAR episodes from all six CTG trials revealed no safety concerns when compared with the RGT. Fewer episodes of infections were registered in CTG trials versus the RGT.

Interpretation: Regulatory cell therapy is achievable and safe in living-donor kidney transplant recipients, and is associated with fewer infectious complications, but similar rejection rates in the first year. Therefore, immune cell therapy is a potentially useful therapeutic approach in recipients of kidney transplant to minimise the burden of general immunosuppression.

Funding: The 7th EU Framework Programme.
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http://dx.doi.org/10.1016/S0140-6736(20)30167-7DOI Listing
May 2020

Pooled Knockin Targeting for Genome Engineering of Cellular Immunotherapies.

Cell 2020 04 16;181(3):728-744.e21. Epub 2020 Apr 16.

Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA; Diabetes Center, University of California, San Francisco, San Francisco, CA, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA, USA; UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. Electronic address:

Adoptive transfer of genetically modified immune cells holds great promise for cancer immunotherapy. CRISPR knockin targeting can improve cell therapies, but more high-throughput methods are needed to test which knockin gene constructs most potently enhance primary cell functions in vivo. We developed a widely adaptable technology to barcode and track targeted integrations of large non-viral DNA templates and applied it to perform pooled knockin screens in primary human T cells. Pooled knockin of dozens of unique barcoded templates into the T cell receptor (TCR)-locus revealed gene constructs that enhanced fitness in vitro and in vivo. We further developed pooled knockin sequencing (PoKI-seq), combining single-cell transcriptome analysis and pooled knockin screening to measure cell abundance and cell state ex vivo and in vivo. This platform nominated a novel transforming growth factor β (TGF-β) R2-41BB chimeric receptor that improved solid tumor clearance. Pooled knockin screening enables parallelized re-writing of endogenous genetic sequences to accelerate discovery of knockin programs for cell therapies.
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http://dx.doi.org/10.1016/j.cell.2020.03.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219528PMC
April 2020

Cutting Edge: IL-6-Driven Immune Dysregulation Is Strictly Dependent on IL-6R α-Chain Expression.

J Immunol 2020 02 10;204(4):747-751. Epub 2020 Jan 10.

Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.

IL-6 binds to the IL-6R α-chain (IL-6Rα) and signals via the signal transducer gp130. Recently, IL-6 was found to also bind to the cell surface glycoprotein CD5, which would then engage gp130 in the absence of IL-6Rα. However, the biological relevance of this alternative pathway is under debate. In this study, we developed a mouse model, in which murine IL-6 is overexpressed in a CD11c-Cre-dependent manner. Transgenic mice developed a lethal immune dysregulation syndrome with increased numbers of Ly-6G neutrophils and Ly-6C monocytes/macrophages. IL-6 overexpression promoted activation of CD4 T cells while suppressing CD5 B-1a cell development. However, additional ablation of IL-6Rα protected IL-6-overexpressing mice from IL-6-triggered inflammation and fully phenocopied IL-6Rα-deficient mice without IL-6 overexpression. Mechanistically, IL-6Rα deficiency completely prevented downstream activation of STAT3 in response to IL-6. Altogether, our data clarify that IL-6Rα is the only biologically relevant receptor for IL-6 in mice.
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http://dx.doi.org/10.4049/jimmunol.1900876DOI Listing
February 2020

New Frontiers in the Treatment of Type 1 Diabetes.

Cell Metab 2020 01 12;31(1):46-61. Epub 2019 Dec 12.

Endocrine Division, Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA; Diabetes Center, University of California San Francisco, San Francisco, CA 94143, USA. Electronic address:

Type 1 diabetes is an autoimmune disease caused by the immune-mediated destruction of pancreatic β cells that results in lifelong absolute insulin deficiency. For nearly a century, insulin replacement has been the only therapy for most people living with this disease. Recent advances in technology and our understanding of β cell development, glucose metabolism, and the underlying immune pathogenesis of the disease have led to innovative therapeutic and preventative approaches. A paradigm shift in immunotherapy development toward the targeting of islet-specific immune pathways involved in tolerance has driven the development of therapies that may allow for the prevention or reversal of this disease while avoiding toxicities associated with historical approaches that were broadly immunosuppressive. In this review, we discuss successes, failures, and emerging pharmacological therapies for type 1 diabetes that are changing how we approach this disease, from improving glycemic control to developing the "holy grail" of disease prevention.
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http://dx.doi.org/10.1016/j.cmet.2019.11.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986815PMC
January 2020

Polymer-stabilized Cas9 nanoparticles and modified repair templates increase genome editing efficiency.

Nat Biotechnol 2020 01 9;38(1):44-49. Epub 2019 Dec 9.

Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.

Versatile and precise genome modifications are needed to create a wider range of adoptive cellular therapies. Here we report two improvements that increase the efficiency of CRISPR-Cas9-based genome editing in clinically relevant primary cell types. Truncated Cas9 target sequences (tCTSs) added at the ends of the homology-directed repair (HDR) template interact with Cas9 ribonucleoproteins (RNPs) to shuttle the template to the nucleus, enhancing HDR efficiency approximately two- to fourfold. Furthermore, stabilizing Cas9 RNPs into nanoparticles with polyglutamic acid further improves editing efficiency by approximately twofold, reduces toxicity, and enables lyophilized storage without loss of activity. Combining the two improvements increases gene targeting efficiency even at reduced HDR template doses, yielding approximately two to six times as many viable edited cells across multiple genomic loci in diverse cell types, such as bulk (CD3) T cells, CD8 T cells, CD4 T cells, regulatory T cells (Tregs), γδ T cells, B cells, natural killer cells, and primary and induced pluripotent stem cell-derived hematopoietic stem progenitor cells (HSPCs).
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http://dx.doi.org/10.1038/s41587-019-0325-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954310PMC
January 2020

T cell-based therapies: challenges and perspectives.

Nat Rev Immunol 2020 03 6;20(3):158-172. Epub 2019 Dec 6.

Sean N. Parker Autoimmune Research Laboratory, Diabetes Center, University of California, San Francisco, San Francisco, CA, USA.

Cellular therapies using regulatory T (T) cells are currently undergoing clinical trials for the treatment of autoimmune diseases, transplant rejection and graft-versus-host disease. In this Review, we discuss the biology of T cells and describe new efforts in T cell engineering to enhance specificity, stability, functional activity and delivery. Finally, we envision that the success of T cell therapy in autoimmunity and transplantation will encourage the clinical use of adoptive T cell therapy for non-immune diseases, such as neurological disorders and tissue repair.
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http://dx.doi.org/10.1038/s41577-019-0232-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814338PMC
March 2020

Thymically-derived Foxp3+ regulatory T cells are the primary regulators of type 1 diabetes in the non-obese diabetic mouse model.

PLoS One 2019 24;14(10):e0217728. Epub 2019 Oct 24.

Diabetes Center, University of California, San Francisco, San Francisco, CA, United States of America.

Regulatory T cells (Tregs) are an immunosuppressive population that are identified based on the stable expression of the fate-determining transcription factor forkhead box P3 (Foxp3). Tregs can be divided into distinct subsets based on whether they developed in the thymus (tTregs) or in the periphery (pTregs). Whether there are unique functional roles that distinguish pTregs and tTregs remains largely unclear. To elucidate these functions, efforts have been made to specifically identify and modify individual Treg subsets. Deletion of the conserved non-coding sequence (CNS)1 in the Foxp3 locus leads to selective impairment of pTreg generation without disrupting tTreg generation in the C57BL/6J background. Using CRISPR-Cas9 genome editing technology, we removed the Foxp3 CNS1 region in the non-obese diabetic (NOD) mouse model of spontaneous type 1 diabetes mellitus (T1D) to determine if pTregs contribute to autoimmune regulation. Deletion of CNS1 impaired in vitro induction of Foxp3 in naïve NOD CD4+ T cells, but it did not alter Tregs in most lymphoid and non-lymphoid tissues analyzed except for the large intestine lamina propria, where a small but significant decrease in RORγt+ Tregs and corresponding increase in Helios+ Tregs was observed in NOD CNS1-/- mice. CNS1 deletion also did not alter the development of T1D or glucose tolerance despite increased pancreatic insulitis in pre-diabetic female NOD CNS1-/- mice. Furthermore, the proportions of autoreactive Tregs and conventional T cells (Tconvs) within pancreatic islets were unchanged. These results suggest that pTregs dependent on the Foxp3 CNS1 region are not the dominant regulatory population controlling T1D in the NOD mouse model.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217728PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812862PMC
March 2020

Next-generation regulatory T cell therapy.

Nat Rev Drug Discov 2019 10 20;18(10):749-769. Epub 2019 Sep 20.

Department of Surgery, University of California, San Francisco, San Francisco, CA, USA.

Regulatory T cells (T cells) are a small subset of immune cells that are dedicated to curbing excessive immune activation and maintaining immune homeostasis. Accordingly, deficiencies in T cell development or function result in uncontrolled immune responses and tissue destruction and can lead to inflammatory disorders such as graft-versus-host disease, transplant rejection and autoimmune diseases. As T cells deploy more than a dozen molecular mechanisms to suppress immune responses, they have potential as multifaceted adaptable smart therapeutics for treating inflammatory disorders. Indeed, early-phase clinical trials of T cell therapy have shown feasibility, tolerability and potential efficacy in these disease settings. In the meantime, progress in the development of chimeric antigen receptors and in genome editing (including the application of CRISPR-Cas9) over the past two decades has facilitated the genetic optimization of primary T cell therapy for cancer. These technologies are now being used to enhance the specificity and functionality of T cells. In this Review, we describe the key advances and prospects in designing and implementing T cell-based therapy in autoimmunity and transplantation.
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http://dx.doi.org/10.1038/s41573-019-0041-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773144PMC
October 2019

An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes.

N Engl J Med 2019 08 9;381(7):603-613. Epub 2019 Jun 9.

From the Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT (K.C.H.); the Departments of Epidemiology and Pediatrics, University of South Florida, Tampa (B.N.B., J.P.K., H.R.), the Department of Medicine, University of Miami, Miami (J.B.M., J.S.S.), and the Department of Pediatrics, University of Florida, Gainesville (D.S.) - all in Florida; Benaroya Research Institute, Seattle (S.A.L., M.J.D., P.S.L., C.J.G.); the Diabetes Center, University of California at San Francisco, San Francisco (J.A.B., S.E.G.); the Department of Pediatrics, Indiana University, Indianapolis (L.A.D.); the Barbara Davis Diabetes Center, University of Colorado, Anschultz (P.A.G.); Children's Mercy Hospital, Kansas City, MO (W.M.); the Department of Pediatrics, University of Minnesota, Minneapolis (A.M.); the Department of Pediatrics and Cell and Developmental Biology, Vanderbilt University, Nashville (W.E.R.); the Department of Pediatrics, University of Iowa, Iowa City (E.T.); the Hospital for Sick Children, University of Toronto, Toronto (D.K.W.); and Forschergruppe Diabetes, Technical University Munich, at Klinikum rechts der Isar, Munich, Germany (A.-G.Z.).

Background: Type 1 diabetes is a chronic autoimmune disease that leads to destruction of insulin-producing beta cells and dependence on exogenous insulin for survival. Some interventions have delayed the loss of insulin production in patients with type 1 diabetes, but interventions that might affect clinical progression before diagnosis are needed.

Methods: We conducted a phase 2, randomized, placebo-controlled, double-blind trial of teplizumab (an Fc receptor-nonbinding anti-CD3 monoclonal antibody) involving relatives of patients with type 1 diabetes who did not have diabetes but were at high risk for development of clinical disease. Patients were randomly assigned to a single 14-day course of teplizumab or placebo, and follow-up for progression to clinical type 1 diabetes was performed with the use of oral glucose-tolerance tests at 6-month intervals.

Results: A total of 76 participants (55 [72%] of whom were ≤18 years of age) underwent randomization - 44 to the teplizumab group and 32 to the placebo group. The median time to the diagnosis of type 1 diabetes was 48.4 months in the teplizumab group and 24.4 months in the placebo group; the disease was diagnosed in 19 (43%) of the participants who received teplizumab and in 23 (72%) of those who received placebo. The hazard ratio for the diagnosis of type 1 diabetes (teplizumab vs. placebo) was 0.41 (95% confidence interval, 0.22 to 0.78; P = 0.006 by adjusted Cox proportional-hazards model). The annualized rates of diagnosis of diabetes were 14.9% per year in the teplizumab group and 35.9% per year in the placebo group. There were expected adverse events of rash and transient lymphopenia. KLRG1+TIGIT+CD8+ T cells were more common in the teplizumab group than in the placebo group. Among the participants who were HLA-DR3-negative, HLA-DR4-positive, or anti-zinc transporter 8 antibody-negative, fewer participants in the teplizumab group than in the placebo group had diabetes diagnosed.

Conclusions: Teplizumab delayed progression to clinical type 1 diabetes in high-risk participants. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01030861.).
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http://dx.doi.org/10.1056/NEJMoa1902226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776880PMC
August 2019

NextGen cell-based immunotherapies in cancer and other immune disorders.

Curr Opin Immunol 2019 08 6;59:79-87. Epub 2019 May 6.

Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA; UCSF Diabetes Center, University of California, San Francisco, San Francisco, CA, USA. Electronic address:

T lymphocyte and other cell therapies have the potential to transform how we treat cancers and other diseases that have few therapeutic options. Here, we review the current progress in engineered T cell therapies and look to the future of what will establish cell therapy as the next pillar of medicine. The tools of synthetic biology along with fundamental knowledge in cell biology and immunology have enabled the development of approaches to engineer cells with enhanced capacity to recognize and treat disease safely and effectively. This along with new modes of engineering cells with CRISPR and strategies to make universal 'off-the-shelf' cell therapies will provide more rapid, flexible, and cheaper translation to the clinic.
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http://dx.doi.org/10.1016/j.coi.2019.03.007DOI Listing
August 2019

A Mutation in the Transcription Factor Foxp3 Drives T Helper 2 Effector Function in Regulatory T Cells.

Immunity 2019 02 29;50(2):362-377.e6. Epub 2019 Jan 29.

Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA; Sean N. Parker Autoimmune Research Laboratory, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address:

Regulatory T (Treg) cells maintain immune tolerance through the master transcription factor forkhead box P3 (FOXP3), which is crucial for Treg cell function and homeostasis. We identified an IPEX (immune dysregulation polyendocrinopathy enteropathy X-linked) syndrome patient with a FOXP3 mutation in the domain swap interface of the protein. Recapitulation of this Foxp3 variant in mice led to the development of an autoimmune syndrome consistent with an unrestrained T helper type 2 (Th2) immune response. Genomic analysis of Treg cells by RNA-sequencing, Foxp3 chromatin immunoprecipitation followed by high-throughput DNA sequencing (ChIP-sequencing), and H3K27ac-HiChIP revealed a specific de-repression of the Th2 transcriptional program leading to the generation of Th2-like Treg cells that were unable to suppress extrinsic Th2 cells. Th2-like Treg cells showed increased intra-chromosomal interactions in the Th2 locus, leading to type 2 cytokine production. These findings identify a direct role for Foxp3 in suppressing Th2-like Treg cells and implicate additional pathways that could be targeted to restrain Th2 trans-differentiated Treg cells.
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http://dx.doi.org/10.1016/j.immuni.2018.12.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6476426PMC
February 2019

Cytokines, Chemokines, and Other Biomarkers of Response for Checkpoint Inhibitor Therapy in Skin Cancer.

Front Med (Lausanne) 2018 12;5:351. Epub 2018 Dec 12.

Sean N. Parker Autoimmune Research Laboratory, Diabetes Center, University of California, San Francisco, San Francisco, CA, United States.

Immunotherapy for skin malignancies has ushered in a new era for cancer treatments by demonstrating unprecedented durable responses in the setting of metastatic Melanoma. Consequently, checkpoint inhibitors are now the first-line treatment of metastatic melanoma and widely used as adjuvant therapy for stage III disease. With the observation that higher tumor mutational burden correlates with a better response, checkpoint inhibitors are tested in other skin cancer types of known high tumor mutational burden with promising results and recently became the first-ever FDA-approved treatment for metastatic Merkel cell carcinoma. The emerging new standards-of-care will necessitate more precise biomarkers and predictors for treatment response and immune-related adverse events. Measurable immune-related mediators are currently under investigation as factors that promote or block the response to cancer immunotherapy and may provide insights into the underlying immune response to the tumor. Cytokines and chemokines are such mediators and are crucial for facilitating the recruitment and activation of specific subsets of leukocytes within the microenvironment of skin cancers. The exact mechanisms of how these meditators, both immunological and non-immunological, operate in the tumor microenvironment is an area of active research, so to reliable biomarkers of responses to cancer immunotherapy. Here, we will review and summarize the expanding body of literature for immune-related biomarkers pertaining to Melanoma, Basal cell carcinoma, Squamous cell carcinoma, and Merkel cell carcinoma, highlighting clinically relevant checkpoint inhibitor therapy biomarker advancements.
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http://dx.doi.org/10.3389/fmed.2018.00351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315146PMC
December 2018

The Balancing Act between Cancer Immunity and Autoimmunity in Response to Immunotherapy.

Cancer Immunol Res 2018 12;6(12):1445-1452

Diabetes Center and Sean N. Parker Autoimmune Research Laboratory, University of California San Francisco, San Francisco, California.

The explosion in novel cancer immunotherapies has resulted in extraordinary clinical successes in the treatment of multiple cancers. Checkpoint inhibitors (CPIs) that target negative regulatory molecules have become standard of care. However, with the growing use of CPIs, alone or in combination with chemotherapy, targeted therapies, or other immune modulators, a significant increase in immune-related adverse events (irAEs) has emerged. The wide-ranging and currently unpredictable spectrum of CPI-induced irAEs can lead to profound pathology and, in some cases, death. Growing evidence indicates that many irAEs are a consequence of a breakdown in self-tolerance, but the influence of genetics, the environment, and the mechanisms involved remains unclear. This review explores key questions in this emerging field, summarizing preclinical and clinical experiences with this new generation of cancer drugs, the growing understanding of the role of the immune response in mediating these toxicities, the relationship of CPI-induced autoimmunity to conventional autoimmune diseases, and insights into the mechanism of irAE development and treatment.
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http://dx.doi.org/10.1158/2326-6066.CIR-18-0487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281171PMC
December 2018

Recent advances in immunotherapies: from infection and autoimmunity, to cancer, and back again.

Genome Med 2018 10 31;10(1):79. Epub 2018 Oct 31.

Parker Institute of Cancer Immunotherapy, 1 Letterman Drive, San Francisco, CA, USA.

For at least 300 years the immune system has been targeted to improve human health. Decades of work advancing immunotherapies against infection and autoimmunity paved the way for the current explosion in cancer immunotherapies. Pathways targeted for therapeutic intervention in autoimmune diseases can be modulated in the opposite sense in malignancy and infectious disease. We discuss the basic principles of the immune response, how these are co-opted in chronic infection and malignancy, and how these can be harnessed to treat disease. T cells are at the center of immunotherapy. We consider the complexity of T cell functional subsets, differentiation states, and extrinsic and intrinsic influences in the design, success, and lessons from immunotherapies. The integral role of checkpoints in the immune response is highlighted by the rapid advances in FDA approvals and the use of therapeutics that target the CTLA-4 and PD-1/PD-L1 pathways. We discuss the distinct and overlapping mechanisms of CTLA-4 and PD-1 and how these can be translated to combination immunotherapy treatments. Finally, we discuss how the successes and challenges in cancer immunotherapies, such as the collateral damage of immune-related adverse events following checkpoint inhibition, are informing treatment of autoimmunity, infection, and malignancy.
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http://dx.doi.org/10.1186/s13073-018-0588-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208073PMC
October 2018

Regulatory T-cell therapy for autoimmune and autoinflammatory diseases: The next frontier.

J Allergy Clin Immunol 2018 12 25;142(6):1710-1718. Epub 2018 Oct 25.

Department of Surgery at the University of California, San Francisco, Calif; Diabetes Center at the University of California, San Francisco, Calif. Electronic address:

Forkhead box P3-expressing regulatory T (Treg) cells are essential for self-tolerance, with an emerging role in tissue repair and regeneration. Their ability to traffic to tissue and perform complex therapeutic tasks in response to the tissue microenvironment make them an attractive candidate for drug development. Early experiences of Treg cell therapy in patients with graft-versus-host disease, type 1 diabetes, and organ transplantation have shown that it is feasible, safe, and potentially efficacious in some settings. Many ongoing trials in patients with a wide variety of diseases will further enhance our knowledge about the optimal approaches for Treg cell manufacturing and dosing. We review the current preclinical rationale supporting Treg cell therapy in a variety of disease settings ranging from tissue transplantation, autoimmune diseases, and non-immune-mediated inflammatory settings. We point out challenges in development of Treg cell therapy and speculate how synthetic biology can be used to enhance the feasibility and efficacy of Treg cell therapy for autoimmune and autoinflammatory diseases.
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http://dx.doi.org/10.1016/j.jaci.2018.10.015DOI Listing
December 2018

T cells-the next frontier of cell therapy.

Science 2018 10;362(6411):154-155

Department of Surgery, University of California, San Francisco, CA 94143, USA.

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http://dx.doi.org/10.1126/science.aau2688DOI Listing
October 2018

Adoptive Treg Cell Therapy in a Patient With Systemic Lupus Erythematosus.

Arthritis Rheumatol 2019 03 24;71(3):431-440. Epub 2019 Jan 24.

University of California, San Francisco.

Objective: Adoptive Treg cell therapy has great potential to treat autoimmune disease. Currently, very little is known about how these cells impact inflamed tissues. This study was undertaken to elucidate how autologous Treg cell therapy influences tissue inflammation in human autoimmune disease.

Methods: We describe a systemic lupus erythematosus (SLE) patient with active skin disease who received adoptive Treg therapy. We comprehensively quantified Treg cells and immune activation in peripheral blood and skin, with data obtained at multiple time points posttreatment.

Results: Deuterium tracking of infused Treg cells revealed the transient presence of cells in peripheral blood, accompanied by increased percentages of highly activated Treg cells in diseased skin. Flow cytometric analysis and whole transcriptome RNA sequencing revealed that Treg cell accumulation in skin was associated with a marked attenuation of the interferon-γ pathway and a reciprocal augmentation of the interleukin-17 (IL-17) pathway. This phenomenon was more pronounced in skin relative to peripheral blood. To validate these findings, we investigated Treg cell adoptive transfer of skin inflammation in a murine model and found that it also resulted in a pronounced skewing away from Th1 immunity and toward IL-17 production.

Conclusion: We report the first case of a patient with SLE treated with autologous adoptive Treg cell therapy. Taken together, our results suggest that this treatment leads to increased activated Treg cells in inflamed skin, with a dynamic shift from Th1 to Th17 responses.
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http://dx.doi.org/10.1002/art.40737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447289PMC
March 2019

Engineering a Single-Agent Cytokine/Antibody Fusion That Selectively Expands Regulatory T Cells for Autoimmune Disease Therapy.

J Immunol 2018 10 13;201(7):2094-2106. Epub 2018 Aug 13.

Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305;

IL-2 has been used to treat diseases ranging from cancer to autoimmune disorders, but its concurrent immunostimulatory and immunosuppressive effects hinder efficacy. IL-2 orchestrates immune cell function through activation of a high-affinity heterotrimeric receptor (composed of IL-2Rα, IL-2Rβ, and common γ [γ]). IL-2Rα, which is highly expressed on regulatory T (T) cells, regulates IL-2 sensitivity. Previous studies have shown that complexation of IL-2 with the JES6-1 Ab preferentially biases cytokine activity toward T cells through a unique mechanism whereby IL-2 is exchanged from the Ab to IL-2Rα. However, clinical adoption of a mixed Ab/cytokine complex regimen is limited by stoichiometry and stability concerns. In this study, through structure-guided design, we engineered a single agent fusion of the IL-2 cytokine and JES6-1 Ab that, despite being covalently linked, preserves IL-2 exchange, selectively stimulating T expansion and exhibiting superior disease control to the mixed IL-2/JES6-1 complex in a mouse colitis model. These studies provide an engineering blueprint for resolving a major barrier to the implementation of functionally similar IL-2/Ab complexes for treatment of human disease.
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http://dx.doi.org/10.4049/jimmunol.1800578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173196PMC
October 2018

Chance favours the prepared mind.

Nat Rev Immunol 2018 09;18(9):541

Diabetes Center, University of California, San Francisco, USA.

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http://dx.doi.org/10.1038/s41577-018-0043-1DOI Listing
September 2018

Revisiting IL-2: Biology and therapeutic prospects.

Sci Immunol 2018 07;3(25)

Diabetes Center, University of California, San Francisco, San Francisco, CA, USA.

Interleukin-2 (IL-2), the first cytokine that was molecularly cloned, was shown to be a T cell growth factor essential for the proliferation of T cells and the generation of effector and memory cells. On the basis of this activity, the earliest therapeutic application of IL-2 was to boost immune responses in cancer patients. Therefore, it was a surprise that genetic deletion of the cytokine or its receptor led not only to the expected immune deficiency but also to systemic autoimmunity and lymphoproliferation. Subsequent studies established that IL-2 is essential for the maintenance of Foxp3 regulatory T cells (T cells), and in its absence, there is a profound deficiency of T cells and resulting autoimmunity. We now know that IL-2 promotes the generation, survival, and functional activity of T cells and thus has dual and opposing functions: maintaining T cells to control immune responses and stimulating conventional T cells to promote immune responses. It is well documented that certain IL-2 conformations result in selective targeting of T cells by increasing reliance on CD25 binding while compromising CD122 binding. Recent therapeutic strategies have emerged to use IL-2, monoclonal antibodies to IL-2, or IL-2 variants to boost T cell numbers and function to treat autoimmune diseases while dealing with the continuing challenges to minimize the generation of effector and memory cells, natural killer cells, and other innate lymphoid populations.
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http://dx.doi.org/10.1126/sciimmunol.aat1482DOI Listing
July 2018