keyword
https://read.qxmd.com/read/36745870/novel-extragenic-genomic-safe-harbors-for-precise-therapeutic-t-cell-engineering
#21
JOURNAL ARTICLE
Ashlesha Odak, Han Yuan, Judith Feucht, Vito Adrian Cantu, Jorge Mansilla-Soto, Friederike Kogel, Justin Eyquem, John K Everett, Frederic D Bushman, Christina Leslie, Michel Sadelain
Cell therapies that rely on engineered immune cells can be enhanced by achieving uniform and controlled transgene expression in order to maximize T cell function and achieve predictable patient responses. Although effective, current genetic engineering strategies that utilize g-retroviral, lentiviral and transposon-based vectors to integrate transgenes, unavoidably produce variegated transgene expression in addition to posing a risk of insertional mutagenesis. In the setting of chimeric antigen receptor (CAR) therapy, inconsistent and random CAR expression may result in tonic signaling, T cell exhaustion and variable T cell persistence...
February 6, 2023: Blood
https://read.qxmd.com/read/36574773/the-ectonucleotidase-cd39-identifies-tumor-reactive-cd8-t%C3%A2-cells-predictive-of-immune-checkpoint-blockade-efficacy-in-human-lung-cancer
#22
JOURNAL ARTICLE
Andrew Chow, Fathema Z Uddin, Michael Liu, Anton Dobrin, Barzin Y Nabet, Levi Mangarin, Yonit Lavin, Hira Rizvi, Sam E Tischfield, Alvaro Quintanal-Villalonga, Joseph M Chan, Nisargbhai Shah, Viola Allaj, Parvathy Manoj, Marissa Mattar, Maximiliano Meneses, Rebecca Landau, Mariana Ward, Amanda Kulick, Charlene Kwong, Matthew Wierzbicki, Jessica Yavner, Jacklynn Egger, Shweta S Chavan, Abigail Farillas, Aliya Holland, Harsha Sridhar, Metamia Ciampricotti, Daniel Hirschhorn, Xiangnan Guan, Allison L Richards, Glenn Heller, Jorge Mansilla-Soto, Michel Sadelain, Christopher A Klebanoff, Matthew D Hellmann, Triparna Sen, Elisa de Stanchina, Jedd D Wolchok, Taha Merghoub, Charles M Rudin
Improved identification of anti-tumor T cells is needed to advance cancer immunotherapies. CD39 expression is a promising surrogate of tumor-reactive CD8+ T cells. Here, we comprehensively profiled CD39 expression in human lung cancer. CD39 expression enriched for CD8+ T cells with features of exhaustion, tumor reactivity, and clonal expansion. Flow cytometry of 440 lung cancer biospecimens revealed weak association between CD39+ CD8+ T cells and tumoral features, such as programmed death-ligand 1 (PD-L1), tumor mutation burden, and driver mutations...
January 10, 2023: Immunity
https://read.qxmd.com/read/36253610/author-correction-gut-microbiome-correlates-of-response-and-toxicity-following-anti-cd19-car-t-cell-therapy
#23
Melody Smith, Anqi Dai, Guido Ghilardi, Kimberly V Amelsberg, Sean M Devlin, Raymone Pajarillo, John B Slingerland, Silvia Beghi, Pamela S Herrera, Paul Giardina, Annelie Clurman, Emmanuel Dwomoh, Gabriel Armijo, Antonio L C Gomes, Eric R Littmann, Jonas Schluter, Emily Fontana, Ying Taur, Jae H Park, Maria Lia Palomba, Elizabeth Halton, Josel Ruiz, Tania Jain, Martina Pennisi, Aishat Olaide Afuye, Miguel-Angel Perales, Craig W Freyer, Alfred Garfall, Shannon Gier, Sunita Nasta, Daniel Landsburg, James Gerson, Jakub Svoboda, Justin Cross, Elise A Chong, Sergio Giralt, Saar I Gill, Isabelle Riviere, David L Porter, Stephen J Schuster, Michel Sadelain, Noelle Frey, Renier J Brentjens, Carl H June, Eric G Pamer, Jonathan U Peled, Andrea Facciabene, Marcel R M van den Brink, Marco Ruella
No abstract text is available yet for this article.
October 17, 2022: Nature Medicine
https://read.qxmd.com/read/36164217/ct-329-cd19-directed-chimeric-antigen-receptor-t-cell-therapy-in-waldenstr%C3%A3-m-macroglobulinemia-initial-experience-in-two-clinical-trials
#24
JOURNAL ARTICLE
David Qualls, Sebastien Monette, Shenon Sethi, Ahmet Dogan, Mikhail Roshal, Brigitte Senechal, Xiuyan Wang, Isabelle Riviere, Michel Sadelain, Renier Brentjens, Jae Park, Eric Smith, M Lia Palomba
CONTEXT: Waldenström macroglobulinemia (WM) is a treatable but incurable disease that can cause significant morbidity or mortality when refractory to available therapies. Chimeric antigen receptor (CAR) T cell therapy directed against the CD19 antigen has demonstrated efficacy in relapsed or refractory B lymphoid malignancies but has not been evaluated in WM. DESIGN: We included patients with relapsed/refractory (R/R) WM in two clinical trials evaluating the safety and activity of autologous CD19-directed CAR T therapy for lymphoid malignancies...
October 2022: Clinical Lymphoma, Myeloma & Leukemia
https://read.qxmd.com/read/35941192/generation-of-t-cell-receptor-negative-cd8%C3%AE-%C3%AE-positive-car-t-cells-from-t-cell-derived-induced-pluripotent-stem-cells
#25
JOURNAL ARTICLE
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
The production of autologous T cells expressing a chimaeric antigen receptor (CAR) is time-consuming, costly and occasionally unsuccessful. T-cell-derived induced pluripotent stem cells (TiPS) are a promising source for the generation of 'off-the-shelf' CAR T cells, but the in vitro differentiation of TiPS often yields T cells with suboptimal features. Here we show that the premature expression of the T-cell receptor (TCR) or a constitutively expressed CAR in TiPS promotes the acquisition of an innate phenotype, which can be averted by disabling the TCR and relying on the CAR to drive differentiation...
August 8, 2022: Nature Biomedical Engineering
https://read.qxmd.com/read/35589842/neoantigen-quality-predicts-immunoediting-in-survivors-of-pancreatic-cancer
#26
JOURNAL ARTICLE
Marta Łuksza, Zachary M Sethna, Luis A Rojas, Jayon Lihm, Barbara Bravi, Yuval Elhanati, Kevin Soares, Masataka Amisaki, Anton Dobrin, David Hoyos, Pablo Guasp, Abderezak Zebboudj, Rebecca Yu, Adrienne Kaya Chandra, Theresa Waters, Zagaa Odgerel, Joanne Leung, Rajya Kappagantula, Alvin Makohon-Moore, Amber Johns, Anthony Gill, Mathieu Gigoux, Jedd Wolchok, Taha Merghoub, Michel Sadelain, Erin Patterson, Remi Monasson, Thierry Mora, Aleksandra M Walczak, Simona Cocco, Christine Iacobuzio-Donahue, Benjamin D Greenbaum, Vinod P Balachandran
Cancer immunoediting1 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)...
June 2022: Nature
https://read.qxmd.com/read/35027758/hla-independent-t-cell-receptors-for-targeting-tumors-with-low-antigen-density
#27
JOURNAL ARTICLE
Jorge Mansilla-Soto, Justin Eyquem, Sascha Haubner, Mohamad Hamieh, Judith Feucht, Noémie Paillon, Andrés Ernesto Zucchetti, Zhuoning Li, Maria Sjöstrand, Pieter L Lindenbergh, Michelle Saetersmoen, Anton Dobrin, Mathieu Maurin, Archana Iyer, Andreina Garcia Angus, Matthew M Miele, Zeguo Zhao, Theodoros Giavridis, Sjoukje J C van der Stegen, Fella Tamzalit, Isabelle Rivière, Morgan Huse, Ronald C Hendrickson, Claire Hivroz, Michel Sadelain
Chimeric antigen receptors (CARs) are receptors for antigen that direct potent immune responses. Tumor escape associated with low target antigen expression is emerging as one potential limitation of their efficacy. Here we edit the TRAC locus in human peripheral blood T cells to engage cell-surface targets through their T cell receptor-CD3 complex reconfigured to utilize the same immunoglobulin heavy and light chains as a matched CAR. We demonstrate that these HLA-independent T cell receptors (HIT receptors) consistently afford high antigen sensitivity and mediate tumor recognition beyond what CD28-based CARs, the most sensitive design to date, can provide...
February 2022: Nature Medicine
https://read.qxmd.com/read/34980909/lentiviral-globin-gene-therapy-with-reduced-intensity-conditioning-in-adults-with-%C3%AE-thalassemia-a-phase-1-trial
#28
JOURNAL ARTICLE
Farid Boulad, Aurelio Maggio, Xiuyan Wang, Paolo Moi, Santina Acuto, Friederike Kogel, Chayamon Takpradit, Susan Prockop, Jorge Mansilla-Soto, Annalisa Cabriolu, Ashlesha Odak, Jinrong Qu, Keyur Thummar, Fang Du, Lingbo Shen, Simona Raso, Rita Barone, Rosario Di Maggio, Lorella Pitrolo, Antonino Giambona, Maura Mingoia, John K Everett, Pascha Hokama, Aoife M Roche, Vito Adrian Cantu, Hriju Adhikari, Shantan Reddy, Eric Bouhassira, Narla Mohandas, Frederic D Bushman, Isabelle Rivière, Michel Sadelain
β-Thalassemias are inherited anemias that are caused by the absent or insufficient production of the β chain of hemoglobin. Here we report 6-8-year follow-up of four adult patients with transfusion-dependent β-thalassemia who were infused with autologous CD34+ cells transduced with the TNS9.3.55 lentiviral globin vector after reduced-intensity conditioning (RIC) in a phase 1 clinical trial ( NCT01639690) . Patients were monitored for insertional mutagenesis and the generation of a replication-competent lentivirus (safety and tolerability of the infusion product after RIC-primary endpoint) and engraftment of genetically modified autologous CD34+ cells, expression of the transduced β-globin gene and post-transplant transfusion requirements (efficacy-secondary endpoint)...
January 2022: Nature Medicine
https://read.qxmd.com/read/34927998/cas9-cleavage-sequences-in-size-reduced-plasmids-enhance-nonviral-genome-targeting-of-cars-in-primary-human-t-cells
#29
JOURNAL ARTICLE
Ruirui Jing, Peng Jiao, Jiangqing Chen, Xianhui Meng, Xiaoyan Wu, Yanting Duan, Kai Shang, Liling Qian, Yanjie Huang, Junwei Liu, Tao Huang, Jin Jin, Wei Chen, Xun Zeng, Weiwei Yin, Xiaofei Gao, Chun Zhou, Michel Sadelain, Jie Sun
T cell genome editing holds great promise to advance a range of immunotherapies but is encumbered by the dependence on difficult-to-produce and expensive viral vectors. Here, small double-stranded plasmid DNA modified to mediate high-efficiency homologous recombination is designed. The resulting chimeric antigen receptor (CAR)-T cells display a similar phenotype, transcriptional profile, and in vivo potency to CAR-T cells generated using adeno-associated viral vector. This method should simplify and accelerate the use of precision engineering to produce edited T cells for research and clinical purposes...
July 2021: Small Methods
https://read.qxmd.com/read/34878825/combining-a-car-and-a-chimeric-costimulatory-receptor-enhances-t-cell-sensitivity-to-low-antigen-density-and-promotes-persistence
#30
JOURNAL ARTICLE
Afroditi Katsarou, Maria Sjöstrand, Jyoti Naik, Jorge Mansilla-Soto, Dionysia Kefala, Georgios Kladis, Alexandros Nianias, Ruud Ruiter, Renée Poels, Irene Sarkar, Yash R Patankar, Elena Merino, Rogier M Reijmers, Kristine A Frerichs, Huipin Yuan, Joost de Bruijn, Dina Stroopinsky, David Avigan, Niels W C J van de Donk, Sonja Zweegman, Tuna Mutis, Michel Sadelain, Richard W J Groen, Maria Themeli
Despite the high remission rates achieved using T cells bearing a chimeric antigen receptor (CAR) against hematogical malignancies, there is still a considerable proportion of patients who eventually experience tumor relapse. Clinical studies have established that mechanisms of treatment failure include the down-regulation of target antigen expression and the limited persistence of effective CAR T cells. We hypothesized that dual targeting mediated by a CAR and a chimeric costimulatory receptor (CCR) could simultaneously enhance T cell cytotoxicity and improve durability...
December 8, 2021: Science Translational Medicine
https://read.qxmd.com/read/34524864/ectopic-activation-of-the-mir-200c-epcam-axis-enhances-antitumor-t-cell-responses-in-models-of-adoptive-cell-therapy
#31
JOURNAL ARTICLE
Minggang Zhang, Zeguo Zhao, Yuri Pritykin, Margaret Hannum, Andrew C Scott, Fengshen Kuo, Viraj Sanghvi, Timothy A Chan, Venkatraman Seshan, Hans-Guido Wendel, Andrea Schietinger, Michel Sadelain, Morgan Huse
Adoptive T cell therapy (ACT) is a promising strategy for treating cancer, but it often fails because of cell intrinsic regulatory programs that limit the degree or duration of T cell function. In this study, we found that ectopic expression of microRNA-200c (miR-200c) markedly enhanced the antitumor activity of CD8+ cytotoxic T lymphocytes (CTLs) during ACT in multiple mouse models. CTLs transduced with miR-200c exhibited reduced apoptosis during engraftment and enhanced in vivo persistence, accompanied by up-regulation of the transcriptional regulator T cell factor 1 (TCF1) and the inflammatory cytokine tumor necrosis factor (TNF)...
September 15, 2021: Science Translational Medicine
https://read.qxmd.com/read/34266984/a-phase-i-trial-of-regional-mesothelin-targeted-car-t-cell-therapy-in-patients-with-malignant-pleural-disease-in-combination-with-the-anti-pd-1-agent-pembrolizumab
#32
JOURNAL ARTICLE
Prasad S Adusumilli, Marjorie G Zauderer, Isabelle Rivière, Stephen B Solomon, Valerie W Rusch, Roisin E O'Cearbhaill, Amy Zhu, Waseem Cheema, Navin K Chintala, Elizabeth Halton, John Pineda, Rocio Perez-Johnston, Kay See Tan, Bobby Daly, Jose A Araujo Filho, Daniel Ngai, Erin McGee, Alain Vincent, Claudia Diamonte, Jennifer L Sauter, Shanu Modi, Devanjan Sikder, Brigitte Senechal, Xiuyan Wang, William D Travis, Mithat Gönen, Charles M Rudin, Renier J Brentjens, David R Jones, Michel Sadelain
Malignant pleural diseases, comprising metastatic lung and breast cancers and malignant pleural mesothelioma (MPM), are aggressive solid tumors with poor therapeutic response. We developed and conducted a first-in-human, phase I study of regionally delivered, autologous, mesothelin-targeted chimeric antigen receptor (CAR) T-cell therapy. Intrapleural administration of 0.3M to 60M CAR T cells/kg in 27 patients (25 with MPM) was safe and well tolerated. CAR T cells were detected in peripheral blood for >100 days in 39% of patients...
November 2021: Cancer Discovery
https://read.qxmd.com/read/34196410/car-t-cells-building-on-the-cd19-paradigm
#33
REVIEW
Anat Globerson Levin, Isabelle Rivière, Zelig Eshhar, Michel Sadelain
Spearheaded by the therapeutic use of chimeric antigen receptors (CARs) targeting CD19, synthetic immunology has entered the clinical arena. CARs are recombinant receptors for antigen that engage cell surface molecules through the variable region of an antibody and signal through arrayed T-cell activating and costimulatory domains. CARs allow redirection of T-cell cytotoxicity against any antigen of choice, independent of MHC expression. Patient T cells engineered to express CARs specific for CD19 have yielded remarkable outcomes in subjects with relapsed/refractory B- cell malignancies, setting off unprecedented interest in T-cell engineering and cell-based cancer immunotherapy...
September 2021: European Journal of Immunology
https://read.qxmd.com/read/34166998/evidence-for-continued-dose-escalation-of-plerixafor-for-hematopoietic-progenitor-cell-collections-in-sickle-cell-disease
#34
JOURNAL ARTICLE
Farid Boulad, Jiahao Zhang, Karina Yazdanbakhsh, Michel Sadelain, Patricia A Shi
We present data from our study of plerixafor mobilization (NCT02193191) relevant to the question of whether further dose escalation of plerixafor can address inconsistent adequacy of CD34+ mobilization for gene therapy of sickle cell disease (SCD). We found that, in the same patient, higher plerixafor dosing was associated with higher fold increases in PB CD34+ count, but not necessarily higher absolute CD34+ counts. Variation in pre-apheresis absolute CD34+ counts was related to intra-individual variation in baseline PB CD34+ counts and inter-individual variation in responsiveness to plerixafor...
September 2021: Blood Cells, Molecules & Diseases
https://read.qxmd.com/read/34160085/process-and-procedural-adjustments-to-improve-cd34-collection-efficiency-of-hematopoietic-progenitor-cell-collections-in-sickle-cell-disease
#35
JOURNAL ARTICLE
Scott T Avecilla, Farid Boulad, Karina Yazdanbakhsh, Michel Sadelain, Patricia A Shi
BACKGROUND: Adequate CD34+ collection efficiency (CE) is critical to achieve target CD34+ cell doses in hematopoietic progenitor cell (HPC) collections. Autologous HPC collection in sickle cell disease (SCD) is associated with unstable collection interfaces and low CD34+ CEs. We hypothesized that variables specific to SCD, activation of blood cells and elevated viscosity, might contribute to these issues and made adjustments to the collection process and procedure to address our hypothesis...
September 2021: Transfusion
https://read.qxmd.com/read/34002066/cytokine-release-syndrome-and-associated-neurotoxicity-in-cancer-immunotherapy
#36
REVIEW
Emma C Morris, Sattva S Neelapu, Theodoros Giavridis, Michel Sadelain
A paradigm shift has recently occurred in the field of cancer therapeutics. Traditional anticancer agents, such as chemotherapy, radiotherapy and small-molecule drugs targeting specific signalling pathways, have been joined by cellular immunotherapies based on T cell engineering. The rapid adoption of novel, patient-specific cellular therapies builds on scientific developments in tumour immunology, genetic engineering and cell manufacturing, best illustrated by the curative potential of chimeric antigen receptor (CAR) T cell therapy targeting CD19-expressing malignancies...
February 2022: Nature Reviews. Immunology
https://read.qxmd.com/read/33851211/interventions-and-outcomes-of-adult-patients-with-b-all-progressing-after-cd19-chimeric-antigen-receptor-t-cell-therapy
#37
JOURNAL ARTICLE
Kitsada Wudhikarn, Jessica R Flynn, Isabelle Rivière, Mithat Gönen, Xiuyan Wang, Brigitte Senechal, Kevin J Curran, Mikhail Roshal, Peter G Maslak, Mark B Geyer, Elizabeth F Halton, Claudia Diamonte, Marco L Davila, Michel Sadelain, Renier J Brentjens, Jae H Park
CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has become a breakthrough treatment of patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, despite the high initial response rate, the majority of adult patients with B-ALL progress after CD19 CAR T-cell therapy. Data on the natural history, management, and outcome of adult B-ALL progressing after CD19 CAR T cells have not been described in detail. Herein, we report comprehensive data of 38 adult patients with B-ALL who progressed after CD19 CAR T therapy at our institution...
August 19, 2021: Blood
https://read.qxmd.com/read/33686196/impact-of-bridging-chemotherapy-on-clinical-outcome-of-cd19-car-t-therapy-in-adult-acute-lymphoblastic-leukemia
#38
JOURNAL ARTICLE
Karlo Perica, Jessica Flynn, Kevin J Curran, Isabelle Rivere, Xiuyan Wang, Brigitte Senechal, Elizabeth Halton, Claudia Diamonte, John Pineda, Yvette Bernal, Mithat Gonen, Michel Sadelain, Renier J Brentjens, Jae H Park
No abstract text is available yet for this article.
November 2021: Leukemia
https://read.qxmd.com/read/32817291/severe-delayed-hemolytic-transfusion-reaction-due-to-anti-fy3-in-a-patient-with-sickle-cell-disease-undergoing-red-cell-exchange-prior-to-hematopoietic-progenitor-cell-collection-for-gene-therapy
#39
Elizabeth F Stone, Scott T Avecilla, David L Wuest, Christine Lomas-Francis, Connie M Westhoff, David L Diuguid, Michel Sadelain, Farid Boulad, Patricia A Shi
No abstract text is available yet for this article.
January 1, 2021: Haematologica
https://read.qxmd.com/read/32555459/senolytic-car-t-cells-reverse-senescence-associated-pathologies
#40
JOURNAL ARTICLE
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
Cellular senescence is characterized by stable cell-cycle arrest and a secretory program that modulates the tissue microenvironment1,2 . 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 ...
July 2020: Nature
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