10 results on '"Sadelain M"'
Search Results
2. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer.
- Author
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Rojas LA, Sethna Z, Soares KC, Olcese C, Pang N, Patterson E, Lihm J, Ceglia N, Guasp P, Chu A, Yu R, Chandra AK, Waters T, Ruan J, Amisaki M, Zebboudj A, Odgerel Z, Payne G, Derhovanessian E, Müller F, Rhee I, Yadav M, Dobrin A, Sadelain M, Łuksza M, Cohen N, Tang L, Basturk O, Gönen M, Katz S, Do RK, Epstein AS, Momtaz P, Park W, Sugarman R, Varghese AM, Won E, Desai A, Wei AC, D'Angelica MI, Kingham TP, Mellman I, Merghoub T, Wolchok JD, Sahin U, Türeci Ö, Greenbaum BD, Jarnagin WR, Drebin J, O'Reilly EM, and Balachandran VP
- Subjects
- Humans, Adjuvants, Immunologic therapeutic use, CD8-Positive T-Lymphocytes cytology, CD8-Positive T-Lymphocytes immunology, Immunotherapy, mRNA Vaccines, Antigens, Neoplasm immunology, Cancer Vaccines immunology, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal immunology, Carcinoma, Pancreatic Ductal therapy, Lymphocyte Activation immunology, Pancreatic Neoplasms genetics, Pancreatic Neoplasms immunology, Pancreatic Neoplasms therapy, T-Lymphocytes cytology, T-Lymphocytes immunology
- Abstract
Pancreatic ductal adenocarcinoma (PDAC) is lethal in 88% of patients
1 , yet harbours mutation-derived T cell neoantigens that are suitable for vaccines2,3 . Here in a phase I trial of adjuvant autogene cevumeran, an individualized neoantigen vaccine based on uridine mRNA-lipoplex nanoparticles, we synthesized mRNA neoantigen vaccines in real time from surgically resected PDAC tumours. After surgery, we sequentially administered atezolizumab (an anti-PD-L1 immunotherapy), autogene cevumeran (a maximum of 20 neoantigens per patient) and a modified version of a four-drug chemotherapy regimen (mFOLFIRINOX, comprising folinic acid, fluorouracil, irinotecan and oxaliplatin). The end points included vaccine-induced neoantigen-specific T cells by high-threshold assays, 18-month recurrence-free survival and oncologic feasibility. We treated 16 patients with atezolizumab and autogene cevumeran, then 15 patients with mFOLFIRINOX. Autogene cevumeran was administered within 3 days of benchmarked times, was tolerable and induced de novo high-magnitude neoantigen-specific T cells in 8 out of 16 patients, with half targeting more than one vaccine neoantigen. Using a new mathematical strategy to track T cell clones (CloneTrack) and functional assays, we found that vaccine-expanded T cells comprised up to 10% of all blood T cells, re-expanded with a vaccine booster and included long-lived polyfunctional neoantigen-specific effector CD8+ T cells. At 18-month median follow-up, patients with vaccine-expanded T cells (responders) had a longer median recurrence-free survival (not reached) compared with patients without vaccine-expanded T cells (non-responders; 13.4 months, P = 0.003). Differences in the immune fitness of the patients did not confound this correlation, as responders and non-responders mounted equivalent immunity to a concurrent unrelated mRNA vaccine against SARS-CoV-2. Thus, adjuvant atezolizumab, autogene cevumeran and mFOLFIRINOX induces substantial T cell activity that may correlate with delayed PDAC recurrence., (© 2023. The Author(s).)- Published
- 2023
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3. TET2 guards against unchecked BATF3-induced CAR T cell expansion.
- Author
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Jain N, Zhao Z, Feucht J, Koche R, Iyer A, Dobrin A, Mansilla-Soto J, Yang J, Zhan Y, Lopez M, Gunset G, and Sadelain M
- Subjects
- Humans, Male, Cell Differentiation genetics, Leukemia immunology, Prostatic Neoplasms immunology, Epigenesis, Genetic, Immunologic Memory, Cell Proliferation, Dioxygenases metabolism, DNA-Binding Proteins metabolism, Immunotherapy, Adoptive methods, Immunotherapy, Adoptive standards, Lymphocyte Activation, Receptors, Chimeric Antigen immunology, Receptors, Chimeric Antigen metabolism, T-Lymphocytes cytology, T-Lymphocytes immunology, T-Lymphocytes pathology, Basic-Leucine Zipper Transcription Factors metabolism
- Abstract
Further advances in cell engineering are needed to increase the efficacy of chimeric antigen receptor (CAR) and other T cell-based therapies
1-5 . As T cell differentiation and functional states are associated with distinct epigenetic profiles6,7 , we hypothesized that epigenetic programming may provide a means to improve CAR T cell performance. Targeting the gene that encodes the epigenetic regulator ten-eleven translocation 2 (TET2)8 presents an interesting opportunity as its loss may enhance T cell memory9,10 , albeit not cause malignancy9,11,12 . Here we show that disruption of TET2 enhances T cell-mediated tumour rejection in leukaemia and prostate cancer models. However, loss of TET2 also enables antigen-independent CAR T cell clonal expansions that may eventually result in prominent systemic tissue infiltration. These clonal proliferations require biallelic TET2 disruption and sustained expression of the AP-1 factor BATF3 to drive a MYC-dependent proliferative program. This proliferative state is associated with reduced effector function that differs from both canonical T cell memory13,14 and exhaustion15,16 states, and is prone to the acquisition of secondary somatic mutations, establishing TET2 as a guardian against BATF3-induced CAR T cell proliferation and ensuing genomic instability. Our findings illustrate the potential of epigenetic programming to enhance T cell immunity but highlight the risk of unleashing unchecked proliferative responses., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2023
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4. Neoantigen quality predicts immunoediting in survivors of pancreatic cancer.
- Author
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Łuksza M, Sethna ZM, Rojas LA, Lihm J, Bravi B, Elhanati Y, Soares K, Amisaki M, Dobrin A, Hoyos D, Guasp P, Zebboudj A, Yu R, Chandra AK, Waters T, Odgerel Z, Leung J, Kappagantula R, Makohon-Moore A, Johns A, Gill A, Gigoux M, Wolchok J, Merghoub T, Sadelain M, Patterson E, Monasson R, Mora T, Walczak AM, Cocco S, Iacobuzio-Donahue C, Greenbaum BD, and Balachandran VP
- Subjects
- Humans, T-Lymphocytes immunology, Tumor Escape immunology, Antigens, Neoplasm genetics, Antigens, Neoplasm immunology, Cancer Survivors, Pancreatic Neoplasms genetics, Pancreatic Neoplasms immunology, Pancreatic Neoplasms pathology
- Abstract
Cancer immunoediting
1 is a hallmark of cancer2 that predicts that lymphocytes kill more immunogenic cancer cells to cause less immunogenic clones to dominate a population. Although proven in mice1,3 , whether immunoediting occurs naturally in human cancers remains unclear. Here, to address this, we investigate how 70 human pancreatic cancers evolved over 10 years. We find that, despite having more time to accumulate mutations, rare long-term survivors of pancreatic cancer who have stronger T cell activity in primary tumours develop genetically less heterogeneous recurrent tumours with fewer immunogenic mutations (neoantigens). To quantify whether immunoediting underlies these observations, we infer that a neoantigen is immunogenic (high-quality) by two features-'non-selfness' based on neoantigen similarity to known antigens4,5 , and 'selfness' based on the antigenic distance required for a neoantigen to differentially bind to the MHC or activate a T cell compared with its wild-type peptide. Using these features, we estimate cancer clone fitness as the aggregate cost of T cells recognizing high-quality neoantigens offset by gains from oncogenic mutations. With this model, we predict the clonal evolution of tumours to reveal that long-term survivors of pancreatic cancer develop recurrent tumours with fewer high-quality neoantigens. Thus, we submit evidence that that the human immune system naturally edits neoantigens. Furthermore, we present a model to predict how immune pressure induces cancer cell populations to evolve over time. More broadly, our results argue that the immune system fundamentally surveils host genetic changes to suppress cancer., (© 2022. The Author(s).)- Published
- 2022
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5. Senolytic CAR T cells reverse senescence-associated pathologies.
- Author
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Amor C, Feucht J, Leibold J, Ho YJ, Zhu C, Alonso-Curbelo D, Mansilla-Soto J, Boyer JA, Li X, Giavridis T, Kulick A, Houlihan S, Peerschke E, Friedman SL, Ponomarev V, Piersigilli A, Sadelain M, and Lowe SW
- Subjects
- Adenocarcinoma immunology, Adenocarcinoma pathology, Adenocarcinoma therapy, Animals, Carbon Tetrachloride, Female, Heterografts, Humans, Liver Cirrhosis chemically induced, Liver Cirrhosis immunology, Liver Cirrhosis pathology, Lung Neoplasms immunology, Lung Neoplasms pathology, Male, Mice, Receptors, Cell Surface genetics, Receptors, Cell Surface metabolism, Receptors, Chimeric Antigen metabolism, Receptors, Urokinase Plasminogen Activator genetics, Receptors, Urokinase Plasminogen Activator metabolism, T-Lymphocytes metabolism, T-Lymphocytes, Cytotoxic immunology, T-Lymphocytes, Cytotoxic metabolism, Aging pathology, Cellular Senescence immunology, Liver Cirrhosis therapy, Longevity immunology, Lung Neoplasms therapy, Receptors, Chimeric Antigen immunology, Rejuvenation, T-Lymphocytes immunology
- Abstract
Cellular senescence is characterized by stable cell-cycle arrest and a secretory program that modulates the tissue microenvironment
1,2 . Physiologically, senescence serves as a tumour-suppressive mechanism that prevents the expansion of premalignant cells3,4 and has a beneficial role in wound-healing responses5,6 . Pathologically, the aberrant accumulation of senescent cells generates an inflammatory milieu that leads to chronic tissue damage and contributes to diseases such as liver and lung fibrosis, atherosclerosis, diabetes and osteoarthritis1,7 . Accordingly, eliminating senescent cells from damaged tissues in mice ameliorates the symptoms of these pathologies and even promotes longevity1,2,8-10 . Here we test the therapeutic concept that chimeric antigen receptor (CAR) T cells that target senescent cells can be effective senolytic agents. We identify the urokinase-type plasminogen activator receptor (uPAR)11 as a cell-surface protein that is broadly induced during senescence and show that uPAR-specific CAR T cells efficiently ablate senescent cells in vitro and in vivo. CAR T cells that target uPAR extend the survival of mice with lung adenocarcinoma that are treated with a senescence-inducing combination of drugs, and restore tissue homeostasis in mice in which liver fibrosis is induced chemically or by diet. These results establish the therapeutic potential of senolytic CAR T cells for senescence-associated diseases.- Published
- 2020
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6. CAR T cell trogocytosis and cooperative killing regulate tumour antigen escape.
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Hamieh M, Dobrin A, Cabriolu A, van der Stegen SJC, Giavridis T, Mansilla-Soto J, Eyquem J, Zhao Z, Whitlock BM, Miele MM, Li Z, Cunanan KM, Huse M, Hendrickson RC, Wang X, Rivière I, and Sadelain M
- Subjects
- 4-1BB Ligand immunology, Animals, CD28 Antigens immunology, Cytotoxicity, Immunologic, Female, Immunotherapy, Adoptive, Leukemia pathology, Male, Mice, Mice, Inbred NOD, Neoplasm Recurrence, Local immunology, T-Lymphocytes cytology, Antigens, Neoplasm immunology, Antigens, Neoplasm metabolism, Leukemia immunology, Receptors, Chimeric Antigen immunology, T-Lymphocytes immunology, T-Lymphocytes metabolism, Tumor Escape immunology
- Abstract
Chimeric antigen receptors (CARs) are synthetic antigen receptors that reprogram T cell specificity, function and persistence
1 . Patient-derived CAR T cells have demonstrated remarkable efficacy against a range of B-cell malignancies1-3 , and the results of early clinical trials suggest activity in multiple myeloma4 . Despite high complete response rates, relapses occur in a large fraction of patients; some of these are antigen-negative and others are antigen-low1,2,4-9 . Unlike the mechanisms that result in complete and permanent antigen loss6,8,9 , those that lead to escape of antigen-low tumours remain unclear. Here, using mouse models of leukaemia, we show that CARs provoke reversible antigen loss through trogocytosis, an active process in which the target antigen is transferred to T cells, thereby decreasing target density on tumour cells and abating T cell activity by promoting fratricide T cell killing and T cell exhaustion. These mechanisms affect both CD28- and 4-1BB-based CARs, albeit differentially, depending on antigen density. These dynamic features can be offset by cooperative killing and combinatorial targeting to augment tumour responses to immunotherapy.- Published
- 2019
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7. Therapeutic T cell engineering.
- Author
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Sadelain M, Rivière I, and Riddell S
- Subjects
- Animals, Antigens, CD19 immunology, Antigens, CD19 metabolism, Autoimmune Diseases immunology, Autoimmune Diseases pathology, Autoimmune Diseases therapy, Humans, Infections immunology, Infections pathology, Infections therapy, Neoplasms pathology, Receptors, Antigen, T-Cell immunology, Receptors, Antigen, T-Cell metabolism, Recombinant Fusion Proteins immunology, Recombinant Fusion Proteins metabolism, T-Lymphocytes immunology, Tumor Microenvironment, Cell Engineering methods, Neoplasms immunology, Neoplasms therapy, T-Lymphocytes metabolism, T-Lymphocytes transplantation
- Abstract
Genetically engineered T cells are powerful new medicines, offering hope for curative responses in patients with cancer. Chimaeric antigen receptors (CARs) are a class of synthetic receptors that reprogram lymphocyte specificity and function. CARs targeting CD19 have demonstrated remarkable potency in B cell malignancies. Engineered T cells are applicable in principle to many cancers, pending further progress to identify suitable target antigens, overcome immunosuppressive tumour microenvironments, reduce toxicities, and prevent antigen escape. Advances in the selection of optimal T cells, genetic engineering, and cell manufacturing are poised to broaden T-cell-based therapies and foster new applications in infectious diseases and autoimmunity.
- Published
- 2017
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8. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection.
- Author
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Eyquem J, Mansilla-Soto J, Giavridis T, van der Stegen SJ, Hamieh M, Cunanan KM, Odak A, Gönen M, and Sadelain M
- Subjects
- Animals, Antigens, CD19 immunology, Cell Differentiation genetics, Cell Differentiation immunology, Disease Models, Animal, Gene Expression Regulation, Genetic Loci genetics, Humans, Lymphocyte Activation, Male, Mice, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Promoter Regions, Genetic genetics, Receptors, Antigen, T-Cell, alpha-beta genetics, Receptors, Antigen, T-Cell, alpha-beta immunology, T-Lymphocytes cytology, T-Lymphocytes metabolism, Translational Research, Biomedical, CRISPR-Cas Systems, Gene Editing, Immunotherapy methods, Precursor Cell Lymphoblastic Leukemia-Lymphoma immunology, Receptors, Antigen, T-Cell genetics, Receptors, Antigen, T-Cell immunology, T-Lymphocytes immunology
- Abstract
Chimeric antigen receptors (CARs) are synthetic receptors that redirect and reprogram T cells to mediate tumour rejection. The most successful CARs used to date are those targeting CD19 (ref. 2), which offer the prospect of complete remission in patients with chemorefractory or relapsed B-cell malignancies. CARs are typically transduced into the T cells of a patient using γ-retroviral vectors or other randomly integrating vectors, which may result in clonal expansion, oncogenic transformation, variegated transgene expression and transcriptional silencing. Recent advances in genome editing enable efficient sequence-specific interventions in human cells, including targeted gene delivery to the CCR5 and AAVS1 loci. Here we show that directing a CD19-specific CAR to the T-cell receptor α constant (TRAC) locus not only results in uniform CAR expression in human peripheral blood T cells, but also enhances T-cell potency, with edited cells vastly outperforming conventionally generated CAR T cells in a mouse model of acute lymphoblastic leukaemia. We further demonstrate that targeting the CAR to the TRAC locus averts tonic CAR signalling and establishes effective internalization and re-expression of the CAR following single or repeated exposure to antigen, delaying effector T-cell differentiation and exhaustion. These findings uncover facets of CAR immunobiology and underscore the potential of CRISPR/Cas9 genome editing to advance immunotherapies.
- Published
- 2017
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9. Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs.
- Author
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Lee G, Papapetrou EP, Kim H, Chambers SM, Tomishima MJ, Fasano CA, Ganat YM, Menon J, Shimizu F, Viale A, Tabar V, Sadelain M, and Studer L
- Subjects
- Adolescent, Alternative Splicing drug effects, Alternative Splicing genetics, Animals, Carrier Proteins genetics, Cell Dedifferentiation, Cell Differentiation, Cell Lineage, Cell Movement, Cells, Cultured, Child, Dysautonomia, Familial drug therapy, Dysautonomia, Familial genetics, Female, Fibroblasts cytology, Fibroblasts metabolism, Gene Expression Profiling, Humans, Kinetin pharmacology, Kinetin therapeutic use, Male, Mice, Neural Crest cytology, Neural Crest drug effects, Organ Specificity, Phenotype, Pluripotent Stem Cells cytology, Pluripotent Stem Cells drug effects, Transcriptional Elongation Factors, Dysautonomia, Familial pathology, Dysautonomia, Familial therapy, Models, Biological, Pluripotent Stem Cells metabolism, Pluripotent Stem Cells transplantation
- Abstract
The isolation of human induced pluripotent stem cells (iPSCs) offers a new strategy for modelling human disease. Recent studies have reported the derivation and differentiation of disease-specific human iPSCs. However, a key challenge in the field is the demonstration of disease-related phenotypes and the ability to model pathogenesis and treatment of disease in iPSCs. Familial dysautonomia (FD) is a rare but fatal peripheral neuropathy, caused by a point mutation in the IKBKAP gene involved in transcriptional elongation. The disease is characterized by the depletion of autonomic and sensory neurons. The specificity to the peripheral nervous system and the mechanism of neuron loss in FD are poorly understood owing to the lack of an appropriate model system. Here we report the derivation of patient-specific FD-iPSCs and the directed differentiation into cells of all three germ layers including peripheral neurons. Gene expression analysis in purified FD-iPSC-derived lineages demonstrates tissue-specific mis-splicing of IKBKAP in vitro. Patient-specific neural crest precursors express particularly low levels of normal IKBKAP transcript, suggesting a mechanism for disease specificity. FD pathogenesis is further characterized by transcriptome analysis and cell-based assays revealing marked defects in neurogenic differentiation and migration behaviour. Furthermore, we use FD-iPSCs for validating the potency of candidate drugs in reversing aberrant splicing and ameliorating neuronal differentiation and migration. Our study illustrates the promise of iPSC technology for gaining new insights into human disease pathogenesis and treatment.
- Published
- 2009
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10. Therapeutic haemoglobin synthesis in beta-thalassaemic mice expressing lentivirus-encoded human beta-globin.
- Author
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May C, Rivella S, Callegari J, Heller G, Gaensler KM, Luzzatto L, and Sadelain M
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- Animals, Bone Marrow Transplantation, Cell Line, Female, Gene Transfer Techniques, Genetic Vectors, Globins biosynthesis, HIV-1 genetics, Humans, Male, Mice, Recombinant Proteins genetics, Recombinant Proteins pharmacology, Transduction, Genetic, beta-Thalassemia metabolism, Genetic Therapy, Globins genetics, Hemoglobins biosynthesis, Lentivirus genetics, beta-Thalassemia therapy
- Abstract
The stable introduction of a functional beta-globin gene in haematopoietic stem cells could be a powerful approach to treat beta-thalassaemia and sickle-cell disease. Genetic approaches aiming to increase normal beta-globin expression in the progeny of autologous haematopoietic stem cells might circumvent the limitations and risks of allogeneic cell transplants. However, low-level expression, position effects and transcriptional silencing hampered the effectiveness of viral transduction of the human beta-globin gene when it was linked to minimal regulatory sequences. Here we show that the use of recombinant lentiviruses enables efficient transfer and faithful integration of the human beta-globin gene together with large segments of its locus control region. In long-term recipients of unselected transduced bone marrow cells, tetramers of two murine alpha-globin and two human betaA-globin molecules account for up to 13% of total haemoglobin in mature red cells of normal mice. In beta-thalassaemic heterozygous mice higher percentages are obtained (17% to 24%), which are sufficient to ameliorate anaemia and red cell morphology. Such levels should be of therapeutic benefit in patients with severe defects in haemoglobin production.
- Published
- 2000
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