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Johannes L Zakrzewski, David Suh, John C Markley, Odette M Smith, Christopher King, Gabrielle L Goldberg, Robert Jenq, Amanda M Holland, Jeremy Grubin, Javier Cabrera-Perez, Renier J Brentjens, Sydney X Lu, Gabrielle Rizzuto, Derek B Sant'Angelo, Isabelle Riviere, Michel Sadelain, Glenn Heller, Juan Carlos Zúñiga-Pflücker, Chen Lu, Marcel R M van den Brink
No abstract text is available yet for this article.
March 26, 2024: Nature Biotechnology
#2
Onur Eskiocak, Saria Chowdhury, Vyom Shah, Emmanuella Nnuji-John, Charlie Chung, Jacob A Boyer, Alexander S Harris, Jill Habel, Michel Sadelain, Semir Beyaz, Corina Amor
Intestinal stem cells (ISCs) drive the rapid regeneration of the gut epithelium to maintain organismal homeostasis. Aging, however, significantly reduces intestinal regenerative capacity. While cellular senescence is a key feature of the aging process, little is known about the in vivo effects of senescent cells on intestinal fitness. Here, we identify the accumulation of senescent cells in the aging gut and, by harnessing senolytic CAR T cells to eliminate them, we uncover their detrimental impact on epithelial integrity and overall intestinal homeostasis in natural aging, injury and colitis...
March 22, 2024: bioRxiv
#3
JOURNAL ARTICLE
Anton Dobrin, Pieter L Lindenbergh, Yuzhe Shi, Karlo Perica, Hongyao Xie, Nayan Jain, Andrew Chow, Jedd D Wolchok, Taha Merghoub, Michel Sadelain, Mohamad Hamieh
Chimeric antigen receptor T cells have dramatically improved the treatment of hematologic malignancies. T cell antigen receptor (TCR)-based cell therapies are yet to achieve comparable outcomes. Importantly, chimeric antigen receptors not only target selected antigens but also reprogram T cell functions through the co-stimulatory pathways that they engage upon antigen recognition. We show here that a fusion receptor comprising the CD80 ectodomain and the 4-1BB cytoplasmic domain, termed 80BB, acts as both a ligand and a receptor to engage the CD28 and 4-1BB pathways, thereby increasing the antitumor potency of human leukocyte antigen-independent TCR (HIT) receptor- or TCR-engineered T cells and tumor-infiltrating lymphocytes...
March 19, 2024: Nature Cancer
#4
Fei Yi, Tal Cohen, Natalie Zimmerman, Friederike Dündar, Paul Zumbo, Razan Eltilib, Erica J Brophy, Hannah Arkin, Judith Feucht, Michael V Gormally, Christopher S Hackett, Korbinian N Kropp, Inaki Etxeberria, Smita S Chandran, Jae H Park, Katharine C Hsu, Michel Sadelain, Doron Betel, Christopher A Klebanoff
Chimeric antigen receptor (CAR)-engineered T and NK cells can cause durable remission of B-cell malignancies; however, limited persistence restrains the full potential of these therapies in many patients. The FAS ligand (FAS-L)/FAS pathway governs naturally-occurring lymphocyte homeostasis, yet knowledge of which cells express FAS-L in patients and whether these sources compromise CAR persistence remains incomplete. Here, we constructed a single-cell atlas of diverse cancer types to identify cellular subsets expressing FASLG , the gene encoding FAS-L...
March 1, 2024: bioRxiv
#5
Matthias T Stephan, Vladimir Ponomarev, Renier J Brentjens, Alex H Chang, Konstantin V Dobrenkov, Glenn Heller, Michel Sadelain
No abstract text is available yet for this article.
February 28, 2024: Nature Medicine
#6
Corina Amor, Judith Feucht, Josef Leibold, Yu-Jui Ho, Changyu Zhu, Direna Alonso-Curbelo, Jorge Mansilla-Soto, Jacob A Boyer, Xiang Li, Theodoros Giavridis, Amanda Kulick, Shauna Houlihan, Ellinor Peerschke, Scott L Friedman, Vladimir Ponomarev, Alessandra Piersigilli, Michel Sadelain, Scott W Lowe
No abstract text is available yet for this article.
February 21, 2024: Nature
#7
Sjoukje J C van der Stegen, Pieter L Lindenbergh, Roseanna M Petrovic, Hongyao Xie, Mame P Diop, Vera Alexeeva, Yuzhe Shi, Jorge Mansilla-Soto, Mohamad Hamieh, Justin Eyquem, Annalisa Cabriolu, Xiuyan Wang, Ramzey Abujarour, Tom Lee, Raedun Clarke, Bahram Valamehr, Maria Themeli, Isabelle Riviere, Michel Sadelain
No abstract text is available yet for this article.
February 12, 2024: Nature Biomedical Engineering
#8
JOURNAL ARTICLE
Corina Amor, Inés Fernández-Maestre, Saria Chowdhury, Yu-Jui Ho, Sandeep Nadella, Courtenay Graham, Sebastian E Carrasco, Emmanuella Nnuji-John, Judith Feucht, Clemens Hinterleitner, Valentin J A Barthet, Jacob A Boyer, Riccardo Mezzadra, Matthew G Wereski, David A Tuveson, Ross L Levine, Lee W Jones, Michel Sadelain, Scott W Lowe
Senescent cells, which accumulate in organisms over time, contribute to age-related tissue decline. Genetic ablation of senescent cells can ameliorate various age-related pathologies, including metabolic dysfunction and decreased physical fitness. While small-molecule drugs that eliminate senescent cells ('senolytics') partially replicate these phenotypes, they require continuous administration. We have developed a senolytic therapy based on chimeric antigen receptor (CAR) T cells targeting the senescence-associated protein urokinase plasminogen activator receptor (uPAR), and we previously showed these can safely eliminate senescent cells in young animals...
March 2024: Nature aging
#9
JOURNAL ARTICLE
Nayan Jain, Zeguo Zhao, Richard P Koche, Chenling Antelope, Yosi Gozlan, Antonino Montalbano, David Brocks, Michael Lopez, Anton Dobrin, Yuzhe Shi, Gertrude Gunset, Theodoros Giavridis, Michel Sadelain
Suboptimal functional persistence limits the efficacy of adoptive T cell therapies. CD28-based chimeric antigen receptors (CARs) impart potent effector function to T cells but with a limited lifespan. We show here that the genetic disruption of SUV39H1, which encodes a histone-3, lysine-9 methyl-transferase, enhances the early expansion, long-term persistence, and overall anti-tumor efficacy of human CAR T cells in leukemia and prostate cancer models. Persisting SUV39H1-edited CAR T cells demonstrate improved expansion and tumor rejection upon multiple rechallenges...
November 7, 2023: Cancer Discovery
#10
Quirin Hammer, Karlo Perica, Hanna van Ooijen, Rina Mbofung, Pouria Momayyezi, Erika Varady, Karen E Martin, Yijia Pan, Mark Jelcic, Brian Groff, Ramzey Abujarour, Silje Krokeide, Tom Lee, Alan Williams, Jode P Goodridge, Bahram Valamehr, Björn Önfelt, Michel Sadelain, Karl-Johan Malmberg
Allogeneic cell therapies hold promise for broad clinical implementation, but face limitations due to potential rejection by the recipient immune system. Silencing of beta-2-microglobulin ( B2M ) expression is commonly employed to evade T cell-mediated rejection, although absence of B2M triggers missing-self responses by recipient natural killer (NK) cells. Here, we demonstrate that deletion of the adhesion ligands CD54 and CD58 on targets cells robustly dampens NK cell reactivity across all sub-populations...
October 9, 2023: bioRxiv
#11
Corina Amor, Inés Fernández-Maestre, Saria Chowdhury, Yu-Jui Ho, Sandeep Nadella, Courtenay Graham, Sebastian E Carrasco, Emmanuella Nnuji-John, Judith Feucht, Clemens Hinterleitner, Valentin J A Barthet, Jacob A Boyer, Riccardo Mezzadra, Matthew G Wereski, David A Tuveson, Ross L Levine, Lee W Jones, Michel Sadelain, Scott W Lowe
Senescent cells accumulate in organisms over time because of tissue damage and impaired immune surveillance and contribute to age-related tissue decline 1,2 . In agreement, genetic ablation studies reveal that elimination of senescent cells from aged tissues can ameliorate various age-related pathologies, including metabolic dysfunction and decreased physical fitness 3-7 . While small-molecule drugs capable of eliminating senescent cells (known as 'senolytics') partially replicate these phenotypes, many have undefined mechanisms of action and all require continuous administration to be effective...
September 26, 2023: Research Square
#12
JOURNAL ARTICLE
Sascha Haubner, Jorge Mansilla-Soto, Sarah Nataraj, Friederike Kogel, Qing Chang, Elisa de Stanchina, Michael Lopez, Mei Rosa Ng, Kathryn Fraser, Marion Subklewe, Jae H Park, Xiuyan Wang, Isabelle Rivière, Michel Sadelain
Acute myeloid leukemia (AML) poses a singular challenge for chimeric antigen receptor (CAR) therapy owing to its phenotypic heterogeneity and similarity to normal hematopoietic stem/progenitor cells (HSPCs). Here we expound a CAR strategy intended to efficiently target AML while minimizing HSPC toxicity. Quantification of target expression in relapsed/refractory patient samples and normal HSPCs reveals a therapeutic window for gated co-targeting of ADGRE2 and CLEC12A: We combine an attenuated ADGRE2-CAR with a CLEC12A-chimeric costimulatory receptor (ADCLEC...
November 13, 2023: Cancer Cell
#13
JOURNAL ARTICLE
Jae H Park, Karthik Nath, Sean M Devlin, Craig S Sauter, M Lia Palomba, Gunjan Shah, Parastoo Dahi, Richard J Lin, Michael Scordo, Miguel-Angel Perales, Roni Shouval, Ana Alarcon Tomas, Elizabeth Cathcart, Elena Mead, Bianca Santomasso, Andrei Holodny, Renier J Brentjens, Isabelle Riviere, Michel Sadelain
In preclinical models, anakinra, an IL-1 receptor antagonist (IL-1Ra), reduced immune effector cell-associated neurotoxicity syndrome (ICANS) without compromising anti-CD19 chimeric antigen receptor (CAR) T-cell efficacy. We initiated a phase 2 clinical trial of anakinra in patients with relapsed/refractory large B-cell lymphoma and mantle cell lymphoma treated with commercial anti-CD19 CAR T-cell therapy. Here we report a non-prespecified interim analysis reporting the final results from cohort 1 in which patients received subcutaneous anakinra from day 2 until at least day 10 post-CAR T-cell infusion...
July 3, 2023: Nature Medicine
#14
JOURNAL ARTICLE
Maria E Arcila, Utsav Patel, Amir Momeni-Boroujeni, JinJuan Yao, Roger Chan, Joe Chan, Ivelise Rijo, Wayne Yu, Nelio Chaves, Hina Patel, Srushti Kakadiya, Sean Lachhander, Brigitte Senechal, Isabelle C Riviere, Xiuyan Wang, Michel Sadelain, Khedoudja Nafa, Paulo Salazar, Lia Palomba, Kevin J Curran, Jae H Park, Anthony Daniyan, Laetitia Borsu
Although in-vivo engraftment, expansion, and persistence of CAR T cells are pivotal components of treatment efficacy, quantitative monitoring has not been implemented in routine clinical practice. We describe the development and analytical validation of a digital-PCR (dPCR) assay for ultra-sensitive detection of CAR constructs post-treatment, circumventing known technical limitations of low partitioning platforms. Primers and probes, designed for detection of axicabtagene, brexucabtagene and MSK CAR constructs, were employed to validate testing on the Bio-Rad dPCR low-partitioning platform; results were compared to Raindrop, a high-partitioning system, as reference method...
June 15, 2023: Journal of Molecular Diagnostics: JMD
#15
JOURNAL ARTICLE
Zeguo Zhao, Michel Sadelain
No abstract text is available yet for this article.
May 23, 2023: Cell Research
#16
JOURNAL ARTICLE
Luis A Rojas, Zachary Sethna, Kevin C Soares, Cristina Olcese, Nan Pang, Erin Patterson, Jayon Lihm, Nicholas Ceglia, Pablo Guasp, Alexander Chu, Rebecca Yu, Adrienne Kaya Chandra, Theresa Waters, Jennifer Ruan, Masataka Amisaki, Abderezak Zebboudj, Zagaa Odgerel, George Payne, Evelyna Derhovanessian, Felicitas Müller, Ina Rhee, Mahesh Yadav, Anton Dobrin, Michel Sadelain, Marta Łuksza, Noah Cohen, Laura Tang, Olca Basturk, Mithat Gönen, Seth Katz, Richard Kinh Do, Andrew S Epstein, Parisa Momtaz, Wungki Park, Ryan Sugarman, Anna M Varghese, Elizabeth Won, Avni Desai, Alice C Wei, Michael I D'Angelica, T Peter Kingham, Ira Mellman, Taha Merghoub, Jedd D Wolchok, Ugur Sahin, Özlem Türeci, Benjamin D Greenbaum, William R Jarnagin, Jeffrey Drebin, Eileen M O'Reilly, Vinod P Balachandran
Pancreatic ductal adenocarcinoma (PDAC) is lethal in 88% of patients1 , yet harbours mutation-derived T cell neoantigens that are suitable for vaccines 2,3 . 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)...
June 2023: Nature
#17
JOURNAL ARTICLE
Mohamad Hamieh, Jorge Mansilla-Soto, Isabelle Rivière, Michel Sadelain
UNLABELLED: The success of chimeric antigen receptor (CAR) T cells targeting B-cell malignancies propelled the field of synthetic immunology and raised hopes to treat solid tumors in a similar fashion. Antigen escape and the paucity of tumor-restricted CAR targets are recognized challenges to fulfilling this prospect. Recent advances in CAR T cell engineering extend the toolbox of chimeric receptors available to calibrate antigen sensitivity and combine receptors to create adapted tumor-sensing T cells...
March 24, 2023: Cancer Discovery
#18
JOURNAL ARTICLE
Changhao He, Jorge Mansilla-Soto, Nandish Khanra, Mohamad Hamieh, Victor Bustos, Alice J Paquette, Andreina Garcia Angus, Derek M Shore, William J Rice, George Khelashvili, Michel Sadelain, Joel R Meyerson
Chimeric antigen receptor (CAR) T cell therapy relies on T cells that are guided by synthetic receptors to target and lyse cancer cells. CARs bind to cell surface antigens through an scFv (binder), the affinity of which is central to determining CAR T cell function and therapeutic success. CAR T cells targeting CD19 were the first to achieve marked clinical responses in patients with relapsed/refractory B cell malignancies and to be approved by the U.S. Food and Drug Administration (FDA). We report cryo-EM structures of CD19 antigen with the binder FMC63, which is used in four FDA-approved CAR T cell therapies (Kymriah, Yescarta, Tecartus, and Breyanzi), and the binder SJ25C1, which has also been used extensively in multiple clinical trials...
March 10, 2023: Science Immunology
#19
JOURNAL ARTICLE
Maria Sjöstrand, Michel Sadelain
Not available.
February 16, 2023: Haematologica
#20
JOURNAL ARTICLE
Nayan Jain, Zeguo Zhao, Judith Feucht, Richard Koche, Archana Iyer, Anton Dobrin, Jorge Mansilla-Soto, Julie Yang, Yingqian Zhan, Michael Lopez, Gertrude Gunset, Michel Sadelain
Further advances in cell engineering are needed to increase the efficacy of chimeric antigen receptor (CAR) and other T cell-based therapies1-5 . 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 ...
February 8, 2023: Nature
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