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1,467 results on '"Sadelain, Michel"'

3. Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction

Author

Amor, Corina, Fernández-Maestre, Inés, Chowdhury, Saria, Ho, Yu-Jui, Nadella, Sandeep, Graham, Courtenay, Carrasco, Sebastian E., Nnuji-John, Emmanuella, Feucht, Judith, Hinterleitner, Clemens, Barthet, Valentin J. A., Boyer, Jacob A., Mezzadra, Riccardo, Wereski, Matthew G., Tuveson, David A., Levine, Ross L., Jones, Lee W., Sadelain, Michel, and Lowe, Scott W.

Published
2024
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4. Generation of T-cell-receptor-negative CD8αβ-positive CAR T cells from T-cell-derived induced pluripotent stem cells.

Author

van der Stegen, Sjoukje, Lindenbergh, Pieter, Petrovic, Roseanna, Xie, Hongyao, Diop, Mame, Alexeeva, Vera, Shi, Yuzhe, Mansilla-Soto, Jorge, Hamieh, Mohamad, Eyquem, Justin, Cabriolu, Annalisa, Wang, Xiuyan, Abujarour, Ramzey, Lee, Tom, Clarke, Raedun, Valamehr, Bahram, Themeli, Maria, Riviere, Isabelle, and Sadelain, Michel

Subjects
Mice, Animals, Humans, T-Lymphocytes, Induced Pluripotent Stem Cells, Receptors, Antigen, T-Cell, CD8 Antigens, Receptors, Chimeric Antigen
Abstract

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. Delaying CAR expression and calibrating its signalling strength in TiPS enabled the generation of human TCR- CD8αβ+ CAR T cells that perform similarly to CD8αβ+ CAR T cells from peripheral blood, achieving effective tumour control on systemic administration in a mouse model of leukaemia and without causing graft-versus-host disease. Driving T-cell maturation in TiPS in the absence of a TCR by taking advantage of a CAR may facilitate the large-scale development of potent allogeneic CD8αβ+ T cells for a broad range of immunotherapies.

Published
2022

7. HLA-independent T cell receptors for targeting tumors with low antigen density.

Author

Mansilla-Soto, Jorge, Eyquem, Justin, Haubner, Sascha, Hamieh, Mohamad, Feucht, Judith, Paillon, Noémie, Zucchetti, Andrés, Li, Zhuoning, Sjöstrand, Maria, Lindenbergh, Pieter, Saetersmoen, Michelle, Dobrin, Anton, Maurin, Mathieu, Iyer, Archana, Garcia Angus, Andreina, Miele, Matthew, Zhao, Zeguo, Giavridis, Theodoros, van der Stegen, Sjoukje, Tamzalit, Fella, Rivière, Isabelle, Huse, Morgan, Hendrickson, Ronald, Hivroz, Claire, and Sadelain, Michel

Subjects
Animals, Antigens, CD19, Histocompatibility Antigens, Humans, Immunotherapy, Adoptive, Leukemia, Myeloid, Acute, Mice, Receptors, Antigen, T-Cell, Receptors, Chimeric Antigen, Xenograft Model Antitumor Assays
Abstract

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. We demonstrate that the functional persistence of HIT T cells can be augmented by constitutive coexpression of CD80 and 4-1BBL. Finally, we validate the increased antigen sensitivity afforded by HIT receptors in xenograft mouse models of B cell leukemia and acute myeloid leukemia, targeting CD19 and CD70, respectively. Overall, HIT receptors are well suited for targeting cell surface antigens of low abundance.

Published
2022

8. CD19 CAR T-cell therapy and prophylactic anakinra in relapsed or refractory lymphoma: phase 2 trial interim results

Author

Park, Jae H., Nath, Karthik, Devlin, Sean M., Sauter, Craig S., Palomba, M. Lia, Shah, Gunjan, Dahi, Parastoo, Lin, Richard J., Scordo, Michael, Perales, Miguel-Angel, Shouval, Roni, Tomas, Ana Alarcon, Cathcart, Elizabeth, Mead, Elena, Santomasso, Bianca, Holodny, Andrei, Brentjens, Renier J., Riviere, Isabelle, and Sadelain, Michel

Published
2023
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9. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer

Author

Rojas, Luis A., Sethna, Zachary, Soares, Kevin C., Olcese, Cristina, Pang, Nan, Patterson, Erin, Lihm, Jayon, Ceglia, Nicholas, Guasp, Pablo, Chu, Alexander, Yu, Rebecca, Chandra, Adrienne Kaya, Waters, Theresa, Ruan, Jennifer, Amisaki, Masataka, Zebboudj, Abderezak, Odgerel, Zagaa, Payne, George, Derhovanessian, Evelyna, Müller, Felicitas, Rhee, Ina, Yadav, Mahesh, Dobrin, Anton, Sadelain, Michel, Łuksza, Marta, Cohen, Noah, Tang, Laura, Basturk, Olca, Gönen, Mithat, Katz, Seth, Do, Richard Kinh, Epstein, Andrew S., Momtaz, Parisa, Park, Wungki, Sugarman, Ryan, Varghese, Anna M., Won, Elizabeth, Desai, Avni, Wei, Alice C., D’Angelica, Michael I., Kingham, T. Peter, Mellman, Ira, Merghoub, Taha, Wolchok, Jedd D., Sahin, Ugur, Türeci, Özlem, Greenbaum, Benjamin D., Jarnagin, William R., Drebin, Jeffrey, O’Reilly, Eileen M., and Balachandran, Vinod P.

Published
2023
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10. Author Correction: Tumor immunotherapy across MHC barriers using allogeneic T-cell precursors

Author

Zakrzewski, Johannes L., Suh, David, Markley, John C., Smith, Odette M., King, Christopher, Goldberg, Gabrielle L., Jenq, Robert, Holland, Amanda M., Grubin, Jeremy, Cabrera-Perez, Javier, Brentjens, Renier J., Lu, Sydney X., Rizzuto, Gabrielle, Sant’Angelo, Derek B., Riviere, Isabelle, Sadelain, Michel, Heller, Glenn, Zúñiga-Pflücker, Juan Carlos, Lu, Chen, and van den Brink, Marcel R. M.

Published
2024
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14. Author Correction: Gut microbiome correlates of response and toxicity following anti-CD19 CAR T cell therapy

Author

Smith, Melody, Dai, Anqi, Ghilardi, Guido, Amelsberg, Kimberly V., Devlin, Sean M., Pajarillo, Raymone, Slingerland, John B., Beghi, Silvia, Herrera, Pamela S., Giardina, Paul, Clurman, Annelie, Dwomoh, Emmanuel, Armijo, Gabriel, Gomes, Antonio L. C., Littmann, Eric R., Schluter, Jonas, Fontana, Emily, Taur, Ying, Park, Jae H., Palomba, Maria Lia, Halton, Elizabeth, Ruiz, Josel, Jain, Tania, Pennisi, Martina, Afuye, Aishat Olaide, Perales, Miguel-Angel, Freyer, Craig W., Garfall, Alfred, Gier, Shannon, Nasta, Sunita, Landsburg, Daniel, Gerson, James, Svoboda, Jakub, Cross, Justin, Chong, Elise A., Giralt, Sergio, Gill, Saar I., Riviere, Isabelle, Porter, David L., Schuster, Stephen J., Sadelain, Michel, Frey, Noelle, Brentjens, Renier J., June, Carl H., Pamer, Eric G., Peled, Jonathan U., Facciabene, Andrea, van den Brink, Marcel R. M., and Ruella, Marco

Published
2023
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16. Clinical utilization of Chimeric Antigen Receptor T-cells (CAR-T) in B-cell acute lymphoblastic leukemia (ALL)–an expert opinion from the European Society for Blood and Marrow Transplantation (EBMT) and the American Society for Blood and Marrow Transplantation (ASBMT)

Author

Kansagra, Ankit J, Frey, Noelle V, Bar, Merav, Laetsch, Theodore W, Carpenter, Paul A, Savani, Bipin N, Heslop, Helen E, Bollard, Catherine M, Komanduri, Krishna V, Gastineau, Dennis A, Chabannon, Christian, Perales, Miguel A, Hudecek, Michael, Aljurf, Mahmoud, Andritsos, Leslie, Barrett, John A, Bachanova, Veronika, Bonini, Chiara, Ghobadi, Armin, Gill, Saar I, Hill, Joshua A, Kenderian, Saad, Kebriaei, Partow, Nagler, Arnon, Maloney, David, Liu, Hien D, Shah, Nirali N, Kharfan-Dabaja, Mohamed A, Shpall, Elizabeth J, Mufti, Ghulam J, Johnston, Laura, Jacoby, Elad, Bazarbachi, Ali, DiPersio, John F, Pavletic, Steven Z, Porter, David L, Grupp, Stephan A, Sadelain, Michel, Litzow, Mark R, Mohty, Mohamad, and Hashmi, Shahrukh K

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Cancer, Pediatric, Childhood Leukemia, Immunization, Genetics, Transplantation, Biotechnology, Gene Therapy, Pediatric Cancer, Pediatric Research Initiative, Hematology, Orphan Drug, Rare Diseases, Development of treatments and therapeutic interventions, 5.2 Cellular and gene therapies, Good Health and Well Being, Clinical Sciences, Cardiovascular medicine and haematology, Oncology and carcinogenesis
Abstract

On August 30, 2017, the U.S. Food and Drug Administration (US-FDA) approved tisagenlecleucel (KYMRIAH, Novartis, Basel, Switzerland), a synthetic bioimmune product of anti-CD19 chimeric antigen receptor-T cells (CAR-T), for the treatment of children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). With this new era of personalized cancer immunotherapy, multiple challenges are present ranging from implementation of a CAR-T program to safe delivery of the drug, long-term toxicity monitoring and disease assessments. To address these issues, experts representing the American Society for Blood and Marrow Transplant (ASBMT), the European Group for Blood and Marrow Transplantation (EBMT), the International Society of Cell and Gene Therapy (ISCT), and the Foundation for the Accreditation of Cellular Therapy (FACT), formed a global CAR-T task force to identify and address key questions pertinent for hematologists and transplant physicians regarding the clinical use of anti CD19 CAR-T therapy in patients with B-ALL. This article presents an initial roadmap for navigating common clinical practice scenarios that will become more prevalent now that the first commercially available CAR-T product for B-ALL has been approved.

Published
2019

18. Neoantigen quality predicts immunoediting in survivors of pancreatic cancer

Author

Łuksza, Marta, Sethna, Zachary M., Rojas, Luis A., Lihm, Jayon, Bravi, Barbara, Elhanati, Yuval, Soares, Kevin, Amisaki, Masataka, Dobrin, Anton, Hoyos, David, Guasp, Pablo, Zebboudj, Abderezak, Yu, Rebecca, Chandra, Adrienne Kaya, Waters, Theresa, Odgerel, Zagaa, Leung, Joanne, Kappagantula, Rajya, Makohon-Moore, Alvin, Johns, Amber, Gill, Anthony, Gigoux, Mathieu, Wolchok, Jedd, Merghoub, Taha, Sadelain, Michel, Patterson, Erin, Monasson, Remi, Mora, Thierry, Walczak, Aleksandra M., Cocco, Simona, Iacobuzio-Donahue, Christine, Greenbaum, Benjamin D., and Balachandran, Vinod P.

Published
2022
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19. CAR T cell trogocytosis and cooperative killing regulate tumour antigen escape.

Author

Hamieh, Mohamad, Dobrin, Anton, Cabriolu, Annalisa, van der Stegen, Sjoukje, Giavridis, Theodoros, Mansilla-Soto, Jorge, Eyquem, Justin, Zhao, Zeguo, Whitlock, Benjamin, Miele, Matthew, Li, Zhuoning, Cunanan, Kristen, Huse, Morgan, Hendrickson, Ronald, Wang, Xiuyan, Rivière, Isabelle, and Sadelain, Michel

Subjects
4-1BB Ligand, Animals, Antigens, Neoplasm, CD28 Antigens, Cytotoxicity, Immunologic, Female, Immunotherapy, Adoptive, Leukemia, Male, Mice, Mice, Inbred NOD, Neoplasm Recurrence, Local, Receptors, Chimeric Antigen, T-Lymphocytes, Tumor Escape
Abstract

Chimeric antigen receptors (CARs) are synthetic antigen receptors that reprogram T cell specificity, function and persistence1. 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

20. Clinical Utilization of Chimeric Antigen Receptor T Cells in B Cell Acute Lymphoblastic Leukemia: An Expert Opinion from the European Society for Blood and Marrow Transplantation and the American Society for Transplantation and Cellular Therapy

Author

Kansagra, Ankit J, Frey, Noelle V, Bar, Merav, Laetsch, Theodore W, Carpenter, Paul A, Savani, Bipin N, Heslop, Helen E, Bollard, Catherine M, Komanduri, Krishna V, Gastineau, Dennis A, Chabannon, Christian, Perales, Miguel A, Hudecek, Michael, Aljurf, Mahmoud, Andritsos, Leslie, Barrett, John A, Bachanova, Veronika, Bonini, Chiara, Ghobadi, Armin, Gill, Saar I, Hill, Joshua, Kenderian, Saad, Kebriaei, Partow, Nagler, Arnon, Maloney, David, Liu, Hien D, Shah, Nirali N, Kharfan-Dabaja, Mohamed A, Shpall, Elizabeth J, Mufti, Ghulam J, Johnston, Laura, Jacoby, Elad, Bazarbachi, Ali, DiPersio, John F, Pavletic, Steven Z, Porter, David L, Grupp, Stephan A, Sadelain, Michel, Litzow, Mark R, Mohty, Mohamad, and Hashmi, Shahrukh K

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Transplantation, Childhood Leukemia, Pediatric Cancer, Pediatric, Biotechnology, Orphan Drug, Genetics, Pediatric Research Initiative, Cancer, Rare Diseases, Gene Therapy, Immunization, Hematology, Development of treatments and therapeutic interventions, 5.2 Cellular and gene therapies, Good Health and Well Being, Antigens, CD19, Child, Critical Pathways, Drug Approval, Expert Testimony, Humans, Immunotherapy, Adoptive, Practice Patterns, Physicians', Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Receptors, Antigen, T-Cell, Societies, Medical, United States, Young Adult, Chimeric antigen receptor, Leukemia, T cell, Clinical Sciences, Cardiovascular medicine and haematology
Abstract

On August 30, 2017 the US Food and Drug Administration approved tisagenlecleucel (Kymriah; Novartis, Basel, Switzerland), a synthetic bioimmune product of anti-CD19 chimeric antigen receptor T cells (CAR-T), for the treatment of children and young adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL). With this new era of personalized cancer immunotherapy, multiple challenges are present, ranging from implementation of a CAR-T program to safe delivery of the drug, long-term toxicity monitoring, and disease assessments. To address these issues experts representing the American Society for Blood and Marrow Transplant, the European Society for Blood and Marrow Transplantation, the International Society of Cell and Gene Therapy, and the Foundation for the Accreditation of Cellular Therapy formed a global CAR-T task force to identify and address key questions pertinent for hematologists and transplant physicians regarding the clinical use of anti CD19 CAR-T therapy in patients with B-ALL. This article presents an initial roadmap for navigating common clinical practice scenarios that will become more prevalent now that the first commercially available CAR-T product for B-ALL has been approved.

Published
2019

21. Antibody with Infinite Affinity for In Vivo Tracking of Genetically Engineered Lymphocytes.

Author

Krebs, Simone, Ahad, Afruja, Carter, Lukas, Eyquem, Justin, Brand, Christian, Bell, Meghan, Ponomarev, Vladimir, Reiner, Thomas, Meares, Claude, Gottschalk, Stephen, Sadelain, Michel, Larson, Steven, and Weber, Wolfgang

Subjects
CAR T cells, DOTA antibody reporter gene, PET imaging, lymphocytes, Animals, Cell Line, Tumor, Cell Tracking, Genes, Reporter, Heterocyclic Compounds, 1-Ring, Humans, Immunoglobulin Fragments, Immunotherapy, Adoptive, Lutetium, Male, Mice, Mice, Inbred ICR, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Positron Emission Tomography Computed Tomography, Radiation Dosage, Radioisotopes, Radiopharmaceuticals, Receptors, Chimeric Antigen, Single Photon Emission Computed Tomography Computed Tomography, T-Lymphocytes, Tissue Distribution, Xenograft Model Antitumor Assays, Yttrium Radioisotopes
Abstract

There remains an urgent need for the noninvasive tracking of transfused chimeric antigen receptor (CAR) T cells to determine their biodistribution, viability, expansion, and antitumor functionality. DOTA antibody reporter 1 (DAbR1) comprises a single-chain fragment of the antilanthanoid-DOTA antibody 2D12.5/G54C fused to the human CD4-transmembrane domain and binds irreversibly to lanthanoid (S)-2-(4-acrylamidobenzyl)-DOTA (AABD). The aim of this study was to investigate whether DAbR1 can be expressed on lymphocytes and used as a reporter gene as well as a suicide gene for therapy of immune-related adverse effects. Methods: DAbR1 was subcloned together with green fluorescent protein into an SFG-retroviral vector and used to transduce CD3/CD28-activated primary human T cells and second-generation 1928z (CAR) T cells. Cell surface expression of DAbR1 was confirmed by cell uptake studies with radiolabeled AABD. In addition, the feasibility of imaging of DAbR1-positive T cells in vivo after intravenous injection of 86Y/177Lu-AABD was studied and radiation doses determined. Results: A panel of DAbR1-expressing T cells and CAR T cells exhibited greater than 8-fold increased uptake of 86Y-AABD in vitro when compared with nontransduced cells. Imaging studies showed 86Y-AABD was retained by DAbR1-positive T cells while it continuously cleared from normal tissues, allowing for in vivo tracking of intravenously administered CAR T cells. Normal-organ dose estimates were favorable for repeated PET/CT studies. Selective T cell ablation in vivo with 177Lu-AABD seems feasible for clustered T-cell populations. Conclusion: We have demonstrated for the first time that T cells can be modified with DAbR1, enabling their in vivo tracking via PET and SPECT. The favorable biodistribution and high image contrast observed warrant further studies of this new reporter gene.

Published
2018

22. Low-Dose Radiation Conditioning Enables CAR T Cells to Mitigate Antigen Escape.

Author

DeSelm, Carl, Palomba, M, Yahalom, Joachim, Hamieh, Mohamad, Eyquem, Justin, Rajasekhar, Vinagolu, and Sadelain, Michel

Subjects
CAR T cell, antigen escape, pancreatic cancer, radiation, sialyl Lewis-A, Animals, Antigens, CD19, Antigens, Neoplasm, CA-19-9 Antigen, Combined Modality Therapy, Disease Models, Animal, Humans, Immunotherapy, Adoptive, Insulin-Secreting Cells, Mice, Oligosaccharides, Pancreatic Neoplasms, Radiation, Radiation Dosage, Receptors, Chimeric Antigen, Sequence Analysis, RNA, TNF-Related Apoptosis-Inducing Ligand
Abstract

CD19 chimeric antigen receptors (CARs) have demonstrated great efficacy against a range of B cell malignancies. However, antigen escape and, more generally, heterogeneous antigen expression pose a challenge to applying CAR therapy to a wide range of cancers. We find that low-dose radiation sensitizes tumor cells to immune rejection by locally activated CAR T cells. In a model of pancreatic adenocarcinoma heterogeneously expressing sialyl Lewis-A (sLeA), we show that not only sLeA+ but also sLeA- tumor cells exposed to low-dose radiation become susceptible to CAR therapy, reducing antigen-negative tumor relapse. RNA sequencing analysis of low-dose radiation-exposed tumors reveals the transcriptional signature of cells highly sensitive to TRAIL-mediated death. We find that sLeA-targeted CAR T cells produce TRAIL upon engaging sLeA+ tumor cells, and eliminate sLeA- tumor cells previously exposed to systemic or local low-dose radiation in a TRAIL-dependent manner. These findings enhance the prospects for successfully applying CAR therapy to heterogeneous solid tumors. Local radiation is integral to many tumors standard of care and can be easily implemented as a CAR conditioning regimen.

Published
2018

23. Gut microbiome correlates of response and toxicity following anti-CD19 CAR T cell therapy

Author

Smith, Melody, Dai, Anqi, Ghilardi, Guido, Amelsberg, Kimberly V., Devlin, Sean M., Pajarillo, Raymone, Slingerland, John B., Beghi, Silvia, Herrera, Pamela S., Giardina, Paul, Clurman, Annelie, Dwomoh, Emmanuel, Armijo, Gabriel, Gomes, Antonio L. C., Littmann, Eric R., Schluter, Jonas, Fontana, Emily, Taur, Ying, Park, Jae H., Palomba, Maria Lia, Halton, Elizabeth, Ruiz, Josel, Jain, Tania, Pennisi, Martina, Afuye, Aishat Olaide, Perales, Miguel-Angel, Freyer, Craig W., Garfall, Alfred, Gier, Shannon, Nasta, Sunita, Landsburg, Daniel, Gerson, James, Svoboda, Jakub, Cross, Justin, Chong, Elise A., Giralt, Sergio, Gill, Saar I., Riviere, Isabelle, Porter, David L., Schuster, Stephen J., Sadelain, Michel, Frey, Noelle, Brentjens, Renier J., June, Carl H., Pamer, Eric G., Peled, Jonathan U., Facciabene, Andrea, van den Brink, Marcel R. M., and Ruella, Marco

Published
2022
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25. Lentiviral globin gene therapy with reduced-intensity conditioning in adults with β-thalassemia: a phase 1 trial

Author

Boulad, Farid, Maggio, Aurelio, Wang, Xiuyan, Moi, Paolo, Acuto, Santina, Kogel, Friederike, Takpradit, Chayamon, Prockop, Susan, Mansilla-Soto, Jorge, Cabriolu, Annalisa, Odak, Ashlesha, Qu, Jinrong, Thummar, Keyur, Du, Fang, Shen, Lingbo, Raso, Simona, Barone, Rita, Di Maggio, Rosario, Pitrolo, Lorella, Giambona, Antonino, Mingoia, Maura, Everett, John K., Hokama, Pascha, Roche, Aoife M., Cantu, Vito Adrian, Adhikari, Hriju, Reddy, Shantan, Bouhassira, Eric, Mohandas, Narla, Bushman, Frederic D., Rivière, Isabelle, and Sadelain, Michel

Published
2022
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27. Mechanogenetics for the remote and noninvasive control of cancer immunotherapy

Author

Pan, Yijia, Yoon, Sangpil, Sun, Jie, Huang, Ziliang, Lee, Changyang, Allen, Molly, Wu, Yiqian, Chang, Ya-Ju, Sadelain, Michel, Shung, K Kirk, Chien, Shu, and Wang, Yingxiao

Subjects
Biotechnology, Genetics, Cancer, Immunization, Rare Diseases, Vaccine Related, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Good Health and Well Being, Animals, Biomechanical Phenomena, Calcium Signaling, Genes, Synthetic, Genetic Engineering, Genetic Techniques, HEK293 Cells, Humans, Immunotherapy, Ion Channels, Jurkat Cells, Mechanotransduction, Cellular, NFATC Transcription Factors, Neoplasms, Synthetic Biology, T-Lymphocytes, Ultrasonics, ultrasound, mechanogenetics, remote control, cancer immunotherapy, synthetic biology
Abstract

While cell-based immunotherapy, especially chimeric antigen receptor (CAR)-expressing T cells, is becoming a paradigm-shifting therapeutic approach for cancer treatment, there is a lack of general methods to remotely and noninvasively regulate genetics in live mammalian cells and animals for cancer immunotherapy within confined local tissue space. To address this limitation, we have identified a mechanically sensitive Piezo1 ion channel (mechanosensor) that is activatable by ultrasound stimulation and integrated it with engineered genetic circuits (genetic transducer) in live HEK293T cells to convert the ultrasound-activated Piezo1 into transcriptional activities. We have further engineered the Jurkat T-cell line and primary T cells (peripheral blood mononuclear cells) to remotely sense the ultrasound wave and transduce it into transcriptional activation for the CAR expression to recognize and eradicate target tumor cells. This approach is modular and can be extended for remote-controlled activation of different cell types with high spatiotemporal precision for therapeutic applications.

Published
2018

28. CAR-engineered lymphocyte persistence is governed by a FAS ligand/FAS auto-regulatory circuit

Author

Yi, Fei, primary, Cohen, Tal, additional, Zimmerman, Natalie, additional, Dündar, Friederike, additional, Zumbo, Paul, additional, Eltilib, Razan, additional, Brophy, Erica J., additional, Arkin, Hannah, additional, Feucht, Judith, additional, Gormally, Michael V., additional, Hackett, Christopher S., additional, Kropp, Korbinian N., additional, Etxeberria, Inaki, additional, Chandran, Smita S., additional, Park, Jae H., additional, Hsu, Katharine C., additional, Sadelain, Michel, additional, Betel, Doron, additional, and Klebanoff, Christopher A., additional

Published
2024
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29. Integrating Proteomics and Transcriptomics for Systematic Combinatorial Chimeric Antigen Receptor Therapy of AML.

Author

Perna, Fabiana, Berman, Samuel, Soni, Rajesh, Mansilla-Soto, Jorge, Eyquem, Justin, Hamieh, Mohamad, Hendrickson, Ronald, Brennan, Cameron, and Sadelain, Michel

Subjects
CAR T cell, acute myeloid leukemia (AML), algorithm, combinatorial strategies, high-throughput annotation, immunotherapy, leukemia, proteomics, surfaceome, target discovery, Antigens, CD19, Cell Line, Tumor, Gene Expression Profiling, Humans, Immunotherapy, Leukemia, Myeloid, Acute, Proteomics, Receptors, Antigen, T-Cell, Recombinant Fusion Proteins, T-Lymphocytes
Abstract

Chimeric antigen receptor (CAR) therapy targeting CD19 has yielded remarkable outcomes in patients with acute lymphoblastic leukemia. To identify potential CAR targets in acute myeloid leukemia (AML), we probed the AML surfaceome for overexpressed molecules with tolerable systemic expression. We integrated large transcriptomics and proteomics datasets from malignant and normal tissues, and developed an algorithm to identify potential targets expressed in leukemia stem cells, but not in normal CD34+CD38- hematopoietic cells, T cells, or vital tissues. As these investigations did not uncover candidate targets with a profile as favorable as CD19, we developed a generalizable combinatorial targeting strategy fulfilling stringent efficacy and safety criteria. Our findings indicate that several target pairings hold great promise for CAR therapy of AML.

Published
2017

31. Disruption of SUV39H1-mediated H3K9 methylation sustains CAR T cell function

Author

Jain, Nayan, primary, Zhao, Zeguo, additional, Koche, Richard P., additional, Antelope, Chenling, additional, Gozlan, Yosi, additional, Montalbano, Antonino, additional, Brocks, David, additional, Lopez, Michael, additional, Dobrin, Anton, additional, Shi, Yuzhe, additional, Gunset, Gertrude, additional, Giavridis, Theodoros, additional, and Sadelain, Michel, additional

Published
2023
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32. Toxicity and response after CD19-specific CAR T-cell therapy in pediatric/young adult relapsed/refractory B-ALL

Author

Curran, Kevin J., Margossian, Steven P., Kernan, Nancy A., Silverman, Lewis B., Williams, David A., Shukla, Neerav, Kobos, Rachel, Forlenza, Christopher J., Steinherz, Peter, Prockop, Susan, Boulad, Farid, Spitzer, Barbara, Cancio, Maria I., Boelens, Jaap Jan, Kung, Andrew L., Khakoo, Yasmin, Szenes, Victoria, Park, Jae H., Sauter, Craig S., Heller, Glenn, Wang, Xiuyan, Senechal, Brigitte, O'Reilly, Richard J., Riviere, Isabelle, Sadelain, Michel, and Brentjens, Renier J.

Published
2019
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33. Senolytic CAR T cells reverse senescence-associated pathologies

Author

Amor, Corina, Feucht, Judith, Leibold, Josef, Ho, Yu-Jui, Zhu, Changyu, Alonso-Curbelo, Direna, Mansilla-Soto, Jorge, Boyer, Jacob A., Li, Xiang, Giavridis, Theodoros, Kulick, Amanda, Houlihan, Shauna, Peerschke, Ellinor, Friedman, Scott L., Ponomarev, Vladimir, Piersigilli, Alessandra, Sadelain, Michel, and Lowe, Scott W.

Published
2020
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35. CD19 CAR T cells following autologous transplantation in poor-risk relapsed and refractory B-cell non-Hodgkin lymphoma

Author

Sauter, Craig S., Senechal, Brigitte, Rivière, Isabelle, Ni, Ai, Bernal, Yvette, Wang, Xiuyan, Purdon, Terence, Hall, Malloury, Singh, Ashvin N., Szenes, Victoria Z., Yoo, Sarah, Dogan, Ahmet, Wang, Yongzeng, Moskowitz, Craig H., Giralt, Sergio, Matasar, Matthew J., Perales, Miguel-Angel, Curran, Kevin J., Park, Jae, Sadelain, Michel, and Brentjens, Renier J.

Published
2019
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37. Genetic ablation of adhesion ligands averts rejection of allogeneic immune cells

Author

Hammer, Quirin, primary, Perica, Karlo, additional, van Ooijen, Hanna, additional, Mbofung, Rina, additional, Momayyezi, Pouria, additional, Varady, Erika, additional, Martin, Karen E, additional, Pan, Yijia, additional, Jelcic, Mark, additional, Groff, Brian, additional, Abujarour, Ramzey, additional, Krokeide, Silje, additional, Lee, Tom, additional, Williams, Alan, additional, Goodridge, Jode P, additional, Valamehr, Bahram, additional, Onfelt, Bjorn, additional, Sadelain, Michel, additional, and Malmberg, Karl-Johan, additional

Published
2023
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38. Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction

Author

Amor, Corina, primary, Fernández-Maestre, Inés, additional, Chowdhury, Saria, additional, Ho, Yu-Jui, additional, Nadella, Sandeep, additional, Graham, Courtenay, additional, E.Carrasco, Sebastian, additional, Nnuji-John, Emmanuella, additional, Feucht, Judith, additional, Hinterleitner, Clemens, additional, J.A.Barthet, Valentin, additional, A.Boyer, Jacob, additional, Mezzadra, Riccardo, additional, G.Wereski, Matthew, additional, A.Tuveson, David, additional, L.Levine, Ross, additional, W.Jones, Lee, additional, Sadelain, Michel, additional, and Lowe, Scott W, additional

Published
2023
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39. Validation of a High-Sensitivity Assay for Detection of Chimeric Antigen Receptor T-Cell Vectors Using Low-Partition Digital PCR Technology

Author

Arcila, Maria E., primary, Patel, Utsav, additional, Momeni-Boroujeni, Amir, additional, Yao, JinJuan, additional, Chan, Roger, additional, Chan, Joe, additional, Rijo, Ivelise, additional, Yu, Wayne, additional, Chaves, Nelio, additional, Patel, Hina, additional, Kakadiya, Srushti, additional, Lachhander, Sean, additional, Senechal, Brigitte, additional, Riviere, Isabelle C., additional, Wang, Xiuyan, additional, Sadelain, Michel, additional, Nafa, Khedoudja, additional, Salazar, Paulo, additional, Palomba, Lia, additional, Curran, Kevin J., additional, Park, Jae H., additional, Daniyan, Anthony, additional, and Borsu, Laetitia, additional

Published
2023
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40. S104: DIFFERENTIAL TARGET PROFILES AND EFFICACY OF ADCLEC.SYN1 AND CD33-CARS IN HUMANIZED AML MODELS

Author

Haubner, Sascha, primary, Mansilla-Soto, Jorge, additional, Nataraj, Sarah, additional, Kogel, Friederike, additional, Chang, Qing, additional, de Stanchina, Elisa, additional, Lopez, Michael, additional, Fraser, Kathryn, additional, Park, Jae, additional, Wang, Xiuyan, additional, Rivière, Isabelle, additional, and Sadelain, Michel, additional

Published
2023
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42. Gene therapy comes of age

Author

Dunbar, Cynthia E., High, Katherine A., Joung, J. Keith, Kohn, Donald B., Ozawa, Keiya, and Sadelain, Michel

Published
2018

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