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54. CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade

Author

Giavridis, Theodoros, van der Stegen, Sjoukje J. C., Eyquem, Justin, Hamieh, Mohamad, Piersigilli, Alessandra, and Sadelain, Michel

Subjects
Laboratory rats -- Models, Gene therapy -- Usage, Corticosteroid drugs -- Dosage and administration, Acute lymphocytic leukemia -- Drug therapy -- Prevention, T cells -- Research, Lymphocytic leukemia, Antigens, Cytokines, Nitrogen oxides, Cancer, Respiratory insufficiency, Preventive medicine, Tumors, Interleukins, Steroids (Organic compounds), Macrophages, Nitric oxide, Biological sciences, Health
Abstract

Chimeric antigen receptor (CAR) therapy targeting CD19 is an effective treatment for refractory B cell malignancies, especially acute lymphoblastic leukemia (ALL).sup.1. Although a majority of patients will achieve a complete response following a single infusion of CD19-targeted CAR-modified T cells (CD19 CAR T cells).sup.2-4, the broad applicability of this treatment is hampered by severe cytokine release syndrome (CRS), which is characterized by fever, hypotension and respiratory insufficiency associated with elevated serum cytokines, including interleukin-6 (IL-6).sup.2,5. CRS usually occurs within days of T cell infusion at the peak of CAR T cell expansion. In ALL, it is most frequent and more severe in patients with high tumor burden.sup.2-4. CRS may respond to IL-6 receptor blockade but can require further treatment with high dose corticosteroids to curb potentially lethal severity.sup.2-9. Improved therapeutic and preventive treatments require a better understanding of CRS physiopathology, which has so far remained elusive. Here we report a murine model of CRS that develops within 2-3 d of CAR T cell infusion and that is potentially lethal and responsive to IL-6 receptor blockade. We show that its severity is mediated not by CAR T cell-derived cytokines, but by IL-6, IL-1 and nitric oxide (NO) produced by recipient macrophages, which enables new therapeutic interventions. Blocking IL-1 and iNOS prevents CAR T cell-induced cytokine release syndrome., Author(s): Theodoros Giavridis [sup.1] , Sjoukje J. C. van der Stegen [sup.1] , Justin Eyquem [sup.1] , Mohamad Hamieh [sup.1] , Alessandra Piersigilli [sup.2] , Michel Sadelain [sup.1] Author Affiliations: [...]

Published
2018
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56. Data from 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

Author

Adusumilli, Prasad S., primary, Zauderer, Marjorie G., primary, Rivière, Isabelle, primary, Solomon, Stephen B., primary, Rusch, Valerie W., primary, O'Cearbhaill, Roisin E., primary, Zhu, Amy, primary, Cheema, Waseem, primary, Chintala, Navin K., primary, Halton, Elizabeth, primary, Pineda, John, primary, Perez-Johnston, Rocio, primary, Tan, Kay See, primary, Daly, Bobby, primary, Araujo Filho, Jose A., primary, Ngai, Daniel, primary, McGee, Erin, primary, Vincent, Alain, primary, Diamonte, Claudia, primary, Sauter, Jennifer L., primary, Modi, Shanu, primary, Sikder, Devanjan, primary, Senechal, Brigitte, primary, Wang, Xiuyan, primary, Travis, William D., primary, Gönen, Mithat, primary, Rudin, Charles M., primary, Brentjens, Renier J., primary, Jones, David R., primary, and Sadelain, Michel, primary

Published
2023
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58. Supplementary Figures from 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

Author

Adusumilli, Prasad S., primary, Zauderer, Marjorie G., primary, Rivière, Isabelle, primary, Solomon, Stephen B., primary, Rusch, Valerie W., primary, O'Cearbhaill, Roisin E., primary, Zhu, Amy, primary, Cheema, Waseem, primary, Chintala, Navin K., primary, Halton, Elizabeth, primary, Pineda, John, primary, Perez-Johnston, Rocio, primary, Tan, Kay See, primary, Daly, Bobby, primary, Araujo Filho, Jose A., primary, Ngai, Daniel, primary, McGee, Erin, primary, Vincent, Alain, primary, Diamonte, Claudia, primary, Sauter, Jennifer L., primary, Modi, Shanu, primary, Sikder, Devanjan, primary, Senechal, Brigitte, primary, Wang, Xiuyan, primary, Travis, William D., primary, Gönen, Mithat, primary, Rudin, Charles M., primary, Brentjens, Renier J., primary, Jones, David R., primary, and Sadelain, Michel, primary

Published
2023
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60. Data from Clinical and Biological Correlates of Neurotoxicity Associated with CAR T-cell Therapy in Patients with B-cell Acute Lymphoblastic Leukemia

Author

Santomasso, Bianca D., primary, Park, Jae H., primary, Salloum, Darin, primary, Riviere, Isabelle, primary, Flynn, Jessica, primary, Mead, Elena, primary, Halton, Elizabeth, primary, Wang, Xiuyan, primary, Senechal, Brigitte, primary, Purdon, Terence, primary, Cross, Justin R., primary, Liu, Hui, primary, Vachha, Behroze, primary, Chen, Xi, primary, DeAngelis, Lisa M., primary, Li, Daniel, primary, Bernal, Yvette, primary, Gonen, Mithat, primary, Wendel, Hans-Guido, primary, Sadelain, Michel, primary, and Brentjens, Renier J., primary

Published
2023
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61. Figure S1, Figure S2, Figure S3, Figure S4 from Clinical and Biological Correlates of Neurotoxicity Associated with CAR T-cell Therapy in Patients with B-cell Acute Lymphoblastic Leukemia

Author

Santomasso, Bianca D., primary, Park, Jae H., primary, Salloum, Darin, primary, Riviere, Isabelle, primary, Flynn, Jessica, primary, Mead, Elena, primary, Halton, Elizabeth, primary, Wang, Xiuyan, primary, Senechal, Brigitte, primary, Purdon, Terence, primary, Cross, Justin R., primary, Liu, Hui, primary, Vachha, Behroze, primary, Chen, Xi, primary, DeAngelis, Lisa M., primary, Li, Daniel, primary, Bernal, Yvette, primary, Gonen, Mithat, primary, Wendel, Hans-Guido, primary, Sadelain, Michel, primary, and Brentjens, Renier J., primary

Published
2023
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62. Supplementary Material from 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

Author

Adusumilli, Prasad S., primary, Zauderer, Marjorie G., primary, Rivière, Isabelle, primary, Solomon, Stephen B., primary, Rusch, Valerie W., primary, O'Cearbhaill, Roisin E., primary, Zhu, Amy, primary, Cheema, Waseem, primary, Chintala, Navin K., primary, Halton, Elizabeth, primary, Pineda, John, primary, Perez-Johnston, Rocio, primary, Tan, Kay See, primary, Daly, Bobby, primary, Araujo Filho, Jose A., primary, Ngai, Daniel, primary, McGee, Erin, primary, Vincent, Alain, primary, Diamonte, Claudia, primary, Sauter, Jennifer L., primary, Modi, Shanu, primary, Sikder, Devanjan, primary, Senechal, Brigitte, primary, Wang, Xiuyan, primary, Travis, William D., primary, Gönen, Mithat, primary, Rudin, Charles M., primary, Brentjens, Renier J., primary, Jones, David R., primary, and Sadelain, Michel, primary

Published
2023
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63. Supplementary Tables from 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

Author

Adusumilli, Prasad S., primary, Zauderer, Marjorie G., primary, Rivière, Isabelle, primary, Solomon, Stephen B., primary, Rusch, Valerie W., primary, O'Cearbhaill, Roisin E., primary, Zhu, Amy, primary, Cheema, Waseem, primary, Chintala, Navin K., primary, Halton, Elizabeth, primary, Pineda, John, primary, Perez-Johnston, Rocio, primary, Tan, Kay See, primary, Daly, Bobby, primary, Araujo Filho, Jose A., primary, Ngai, Daniel, primary, McGee, Erin, primary, Vincent, Alain, primary, Diamonte, Claudia, primary, Sauter, Jennifer L., primary, Modi, Shanu, primary, Sikder, Devanjan, primary, Senechal, Brigitte, primary, Wang, Xiuyan, primary, Travis, William D., primary, Gönen, Mithat, primary, Rudin, Charles M., primary, Brentjens, Renier J., primary, Jones, David R., primary, and Sadelain, Michel, primary

Published
2023
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66. Table S1, Table S2, Table S3, Table S4 from Clinical and Biological Correlates of Neurotoxicity Associated with CAR T-cell Therapy in Patients with B-cell Acute Lymphoblastic Leukemia

Author

Santomasso, Bianca D., primary, Park, Jae H., primary, Salloum, Darin, primary, Riviere, Isabelle, primary, Flynn, Jessica, primary, Mead, Elena, primary, Halton, Elizabeth, primary, Wang, Xiuyan, primary, Senechal, Brigitte, primary, Purdon, Terence, primary, Cross, Justin R., primary, Liu, Hui, primary, Vachha, Behroze, primary, Chen, Xi, primary, DeAngelis, Lisa M., primary, Li, Daniel, primary, Bernal, Yvette, primary, Gonen, Mithat, primary, Wendel, Hans-Guido, primary, Sadelain, Michel, primary, and Brentjens, Renier J., primary

Published
2023
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68. Supplementary Data from Combined CD28 and 4-1BB Costimulation Potentiates Affinity-tuned Chimeric Antigen Receptor–engineered T Cells

Author

Drent, Esther, primary, Poels, Renée, primary, Ruiter, Ruud, primary, van de Donk, Niels W.C.J., primary, Zweegman, Sonja, primary, Yuan, Huipin, primary, de Bruijn, Joost, primary, Sadelain, Michel, primary, Lokhorst, Henk M., primary, Groen, Richard W.J., primary, Mutis, Tuna, primary, and Themeli, Maria, primary

Published
2023
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69. Supplementary Figure 3 from Mesothelin Overexpression Is a Marker of Tumor Aggressiveness and Is Associated with Reduced Recurrence-Free and Overall Survival in Early-Stage Lung Adenocarcinoma

Author

Kachala, Stefan S., primary, Bograd, Adam J., primary, Villena-Vargas, Jonathan, primary, Suzuki, Kei, primary, Servais, Elliot L., primary, Kadota, Kyuichi, primary, Chou, Joanne, primary, Sima, Camelia S., primary, Vertes, Eva, primary, Rusch, Valerie W., primary, Travis, William D., primary, Sadelain, Michel, primary, and Adusumilli, Prasad S., primary

Published
2023
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70. Supplementary Figure Legend from Mesothelin Overexpression Is a Marker of Tumor Aggressiveness and Is Associated with Reduced Recurrence-Free and Overall Survival in Early-Stage Lung Adenocarcinoma

Author

Kachala, Stefan S., primary, Bograd, Adam J., primary, Villena-Vargas, Jonathan, primary, Suzuki, Kei, primary, Servais, Elliot L., primary, Kadota, Kyuichi, primary, Chou, Joanne, primary, Sima, Camelia S., primary, Vertes, Eva, primary, Rusch, Valerie W., primary, Travis, William D., primary, Sadelain, Michel, primary, and Adusumilli, Prasad S., primary

Published
2023
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72. Supplementary Figure 2 from Mesothelin Overexpression Is a Marker of Tumor Aggressiveness and Is Associated with Reduced Recurrence-Free and Overall Survival in Early-Stage Lung Adenocarcinoma

Author

Kachala, Stefan S., primary, Bograd, Adam J., primary, Villena-Vargas, Jonathan, primary, Suzuki, Kei, primary, Servais, Elliot L., primary, Kadota, Kyuichi, primary, Chou, Joanne, primary, Sima, Camelia S., primary, Vertes, Eva, primary, Rusch, Valerie W., primary, Travis, William D., primary, Sadelain, Michel, primary, and Adusumilli, Prasad S., primary

Published
2023
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74. Supplementary Figure 1 from Mesothelin Overexpression Is a Marker of Tumor Aggressiveness and Is Associated with Reduced Recurrence-Free and Overall Survival in Early-Stage Lung Adenocarcinoma

Author

Kachala, Stefan S., primary, Bograd, Adam J., primary, Villena-Vargas, Jonathan, primary, Suzuki, Kei, primary, Servais, Elliot L., primary, Kadota, Kyuichi, primary, Chou, Joanne, primary, Sima, Camelia S., primary, Vertes, Eva, primary, Rusch, Valerie W., primary, Travis, William D., primary, Sadelain, Michel, primary, and Adusumilli, Prasad S., primary

Published
2023
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75. Supplementary Figure Legends 1-2 from Mesothelin Overexpression Promotes Mesothelioma Cell Invasion and MMP-9 Secretion in an Orthotopic Mouse Model and in Epithelioid Pleural Mesothelioma Patients

Author

Servais, Elliot L., primary, Colovos, Christos, primary, Rodriguez, Luis, primary, Bograd, Adam J., primary, Nitadori, Jun-ichi, primary, Sima, Camelia, primary, Rusch, Valerie W., primary, Sadelain, Michel, primary, and Adusumilli, Prasad S., primary

Published
2023
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78. Data from PLZF Confers Effector Functions to Donor T Cells That Preserve Graft-versus-Tumor Effects while Attenuating GVHD

Author

Ghosh, Arnab, primary, Holland, Amanda M., primary, Dogan, Yildirim, primary, Yim, Nury L., primary, Rao, Uttam K., primary, Young, Lauren F., primary, West, Mallory L., primary, Singer, Natalie V., primary, Lee, Hae, primary, Na, Il-Kang, primary, Tsai, Jennifer J., primary, Jenq, Robert R., primary, Penack, Olaf, primary, Hanash, Alan M., primary, Lezcano, Cecilia, primary, Murphy, George F., primary, Liu, Chen, primary, Sadelain, Michel, primary, Sauer, Martin G., primary, Sant'Angelo, Derek, primary, and van den Brink, Marcel R.M., primary

Published
2023
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79. Supplementary Figure 2 from Targeted Elimination of Prostate Cancer by Genetically Directed Human T Lymphocytes

Author

Gade, Terence P.F., primary, Hassen, Waleed, primary, Santos, Elmer, primary, Gunset, Gertrude, primary, Saudemont, Aurore, primary, Gong, Michael C., primary, Brentjens, Renier, primary, Zhong, Xiao-Song, primary, Stephan, Matthias, primary, Stefanski, Jolanta, primary, Lyddane, Clay, primary, Osborne, Joseph R., primary, Buchanan, Ian M., primary, Hall, Simon J., primary, Heston, Warren D., primary, Rivière, Isabelle, primary, Larson, Steven M., primary, Koutcher, Jason A., primary, and Sadelain, Michel, primary

Published
2023
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80. Supplementary Figure 1 from Targeted Elimination of Prostate Cancer by Genetically Directed Human T Lymphocytes

Author

Gade, Terence P.F., primary, Hassen, Waleed, primary, Santos, Elmer, primary, Gunset, Gertrude, primary, Saudemont, Aurore, primary, Gong, Michael C., primary, Brentjens, Renier, primary, Zhong, Xiao-Song, primary, Stephan, Matthias, primary, Stefanski, Jolanta, primary, Lyddane, Clay, primary, Osborne, Joseph R., primary, Buchanan, Ian M., primary, Hall, Simon J., primary, Heston, Warren D., primary, Rivière, Isabelle, primary, Larson, Steven M., primary, Koutcher, Jason A., primary, and Sadelain, Michel, primary

Published
2023
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81. Supplementary Figures 1-3 from PLZF Confers Effector Functions to Donor T Cells That Preserve Graft-versus-Tumor Effects while Attenuating GVHD

Author

Ghosh, Arnab, primary, Holland, Amanda M., primary, Dogan, Yildirim, primary, Yim, Nury L., primary, Rao, Uttam K., primary, Young, Lauren F., primary, West, Mallory L., primary, Singer, Natalie V., primary, Lee, Hae, primary, Na, Il-Kang, primary, Tsai, Jennifer J., primary, Jenq, Robert R., primary, Penack, Olaf, primary, Hanash, Alan M., primary, Lezcano, Cecilia, primary, Murphy, George F., primary, Liu, Chen, primary, Sadelain, Michel, primary, Sauer, Martin G., primary, Sant'Angelo, Derek, primary, and van den Brink, Marcel R.M., primary

Published
2023
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83. CD19 CAR antigen engagement mechanisms and affinity tuning

Author

He, Changhao, primary, Mansilla-Soto, Jorge, additional, Khanra, Nandish, additional, Hamieh, Mohamad, additional, Bustos, Victor, additional, Paquette, Alice J., additional, Garcia Angus, Andreina, additional, Shore, Derek M., additional, Rice, William J., additional, Khelashvili, George, additional, Sadelain, Michel, additional, and Meyerson, Joel R., additional

Published
2023
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87. The ectonucleotidase CD39 identifies tumor-reactive CD8+ T cells predictive of immune checkpoint blockade efficacy in human lung cancer

Author

Chow, Andrew, primary, Uddin, Fathema Z., additional, Liu, Michael, additional, Dobrin, Anton, additional, Nabet, Barzin Y., additional, Mangarin, Levi, additional, Lavin, Yonit, additional, Rizvi, Hira, additional, Tischfield, Sam E., additional, Quintanal-Villalonga, Alvaro, additional, Chan, Joseph M., additional, Shah, Nisargbhai, additional, Allaj, Viola, additional, Manoj, Parvathy, additional, Mattar, Marissa, additional, Meneses, Maximiliano, additional, Landau, Rebecca, additional, Ward, Mariana, additional, Kulick, Amanda, additional, Kwong, Charlene, additional, Wierzbicki, Matthew, additional, Yavner, Jessica, additional, Egger, Jacklynn, additional, Chavan, Shweta S., additional, Farillas, Abigail, additional, Holland, Aliya, additional, Sridhar, Harsha, additional, Ciampricotti, Metamia, additional, Hirschhorn, Daniel, additional, Guan, Xiangnan, additional, Richards, Allison L., additional, Heller, Glenn, additional, Mansilla-Soto, Jorge, additional, Sadelain, Michel, additional, Klebanoff, Christopher A., additional, Hellmann, Matthew D., additional, Sen, Triparna, additional, de Stanchina, Elisa, additional, Wolchok, Jedd D., additional, Merghoub, Taha, additional, and Rudin, Charles M., additional

Published
2023
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88. A Phase I Study of CD19-Targeted 19(T2)28z1xx CAR T Cells in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Author

Park, Jae H, primary, Palomba, M. Lia, additional, Rivière, Isabelle, additional, Sikder, Devanjan S., additional, Senechal, Brigitte, additional, Wang, Xiuyan, additional, Bermudez, Vladimir P., additional, Cathcart, Elizabeth R., additional, Liotta, Kelly, additional, Joseph, Jannakie, additional, Li, Jia, additional, Zhao, Yunqi, additional, Liu, Rachael, additional, Chen, Sharon, additional, Sellner, Leopold, additional, and Sadelain, Michel, additional

Published
2022
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89. The Development of Allogeneic Tips-Derived TCR- CAR+ CD8αβ T Cells

Author

van der Stegen, Sjoukje J.C., primary, Petrovic, Roseanna M., additional, Lindenbergh, Pieter L., additional, Diop, Mame P., additional, Alexeeva, Vera, additional, Xie, Hongyao, additional, Clarke, Raedun, additional, Valamehr, Bahram, additional, Rivière, Isabelle, additional, and Sadelain, Michel, additional

Published
2022
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92. Combined Genetic Ablation of CD54 and CD58 in CAR Engineered Cytotoxic Lymphocytes Effectively Averts Allogeneic Immune Cell Rejection

Author

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

Published
2022
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93. Therapeutic T cell engineering

Author

Sadelain, Michel, Rivire, Isabelle, and Riddell, Stanley

Subjects
Genetic engineering -- Methods, T cells -- Health aspects -- Usage -- Genetic aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
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., Author(s): Michel Sadelain (corresponding author) [1]; Isabelle Rivire [1]; Stanley Riddell [2] T lymphocytes develop in the thymus [1], where they acquire their antigen receptor, known as the T cell [...]

Published
2017
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94. Donor CD19 CAR T cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity

Author

Ghosh, Arnab, Smith, Melody, James, Scott E, Davila, Marco L, Velardi, Enrico, Argyropoulos, Kimon V, Gunset, Gertrude, Perna, Fabiana, Kreines, Fabiana M, Levy, Emily R, Lieberman, Sophie, Jay, Hillary V, Tuckett, Andrea Z, Zakrzewski, Johannes L, Tan, Lisa, Young, Lauren F, Takvorian, Kate, Dudakov, Jarrod A, Jenq, Robert R, Hanash, Alan M, Motta, Ana Carolina F, Murphy, George F, Liu, Chen, Schietinger, Andrea, Sadelain, Michel, and van den Brink, Marcel R M

Subjects
Cell receptors -- Health aspects, Graft vs. host disease -- Genetic aspects -- Risk factors, Cellular signal transduction -- Genetic aspects -- Health aspects, Biological sciences, Health
Abstract

Author(s): Arnab Ghosh [1]; Melody Smith [1]; Scott E James [1, 2]; Marco L Davila [2]; Enrico Velardi [1]; Kimon V Argyropoulos [1]; Gertrude Gunset [2]; Fabiana Perna [2]; Fabiana [...]

Published
2017
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95. Targeted antibody-mediated depletion of murine CD19 CAR T cells permanently reverses B cell aplasia

Author

Paszkiewicz, Paulina J., Frassle, Simon P., Srivastava, Shivani, Sommermeyer, Daniel, Hudecek, Michael, Drexler, Ingo, Sadelain, Michel, Liu, Lingfeng, Jensen, Michael C., Riddell, Stanley R., and Busch, Dirk H.

Subjects
T cells -- Analysis, B cells -- Analysis, Cancer -- Care and treatment, Health care industry
Abstract

The adoptive transfer of T cells that have been genetically modified to express a CD19-specific chimeric antigen receptor (CAR) is effective for treating human B cell malignancies. However, the persistence of functional CD19 CAR T cells causes sustained depletion of endogenous CD19+ B cells and hypogammaglobulinemia. Thus, there is a need for a mechanism to ablate transferred T cells after tumor eradication is complete to allow recovery of normal B cells. Previously, we developed a truncated version of the epidermal growth factor receptor (EGFRt) that is coexpressed with the CAR on the T cell surface. Here, we show that targeting EGFRt with the IgG1 monoclonal antibody cetuximab eliminates CD19 CAR T cells both early and late after adoptive transfer in mice, resulting in complete and permanent recovery of normal functional B cells, without tumor relapse. EGFRt can be incorporated into many clinical applications to regulate the survival of gene-engineered cells. These results support the concept that EGFRt represents a promising approach to improve safety of cell-based therapies., Introduction Adoptive transfer of genetically engineered T cells is a rapidly emerging area in cell-based cancer therapy. The most advanced application is the use of CD19 chimeric antigen receptor (CAR) [...]

Published
2016
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96. Author Correction: Gut microbiome correlates of response and toxicity following anti-CD19 CAR T cell therapy

Author

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

Published
2022
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97. Poster: CT-329 CD19-Directed Chimeric Antigen Receptor T Cell Therapy in Waldenström Macroglobulinemia: Initial Experience in Two Clinical Trials

Author

Qualls, David, primary, Monette, Sebastien, additional, Sethi, Shenon, additional, Dogan, Ahmet, additional, Roshal, Mikhail, additional, Senechal, Brigitte, additional, Wang, Xiuyan, additional, Riviere, Isabelle, additional, Sadelain, Michel, additional, Brentjens, Renier, additional, Park, Jae, additional, Smith, Eric, additional, and Palomba, M. Lia, additional

Published
2022
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99. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition

Author

Cherkassky, Leonid, Morello, Aurore, Villena-Vargas, Jonathan, Feng, Yang, Dimitrov, Dimiter S., Jones, David R., Sadelain, Michel, and Adusumilli, Prasad S.

Subjects
Cell death -- Health aspects, T cells -- Health aspects, Cellular therapy -- Innovations, Health care industry
Abstract

Following immune attack, solid tumors upregulate coinhibitory ligands that bind to inhibitory receptors on T cells. This adaptive resistance compromises the efficacy of chimeric antigen receptor (CAR) T cell therapies, which redirect T cells to solid tumors. Here, we investigated whether programmed death-1-mediated (PD-1-mediated) T cell exhaustion affects mesothelin- targeted CAR T cells and explored cell-intrinsic strategies to overcome inhibition of CAR T cells. Using an orthotopic mouse model of pleural mesothelioma, we determined that relatively high doses of both CD28- and 4-1BB-based second-generation CAR T cells achieved tumor eradication. CAR-mediated CD28 and 4-1BB costimulation resulted in similar levels of T cell persistence in animals treated with low T cell doses; however, PD-1 upregulation within the tumor microenvironment inhibited T cell function. At lower doses, 4-1BB CAR T cells retained their cytotoxic and cytokine secretion functions longer than CD28 CAR T cells. The prolonged function of 4-1BB CAR T cells correlated with improved survival. PD-1/PD-1 ligand [PD-L1] pathway interference, through PD-1 antibody checkpoint blockade, cell-intrinsic PD-1 shRNA blockade, or a PD-1 dominant negative receptor, restored the effector function of CD28 CAR T cells. These findings provide mechanistic insights into human CAR T cell exhaustion in solid tumors and suggest that PD-1/PD-L1 blockade may be an effective strategy for improving the potency of CAR T cell therapies., Introduction Chimeric antigen receptors (CARs) are synthetic receptors that retarget T cells to tumor surface antigens (1, 2). First-generation receptors typically link an antibody-derived tumor-binding element to either CD3θ or [...]

Published
2016
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