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7. Diagnostic biomarkers to differentiate sepsis from cytokine release syndrome in critically ill children

Author

Diorio, Caroline, Shaw, Pamela A., Pequignot, Edward, Orlenko, Alena, Chen, Fang, Aplenc, Richard, Barrett, David M., Bassiri, Hamid, Behrens, Edward, DiNofia, Amanda M., Gonzalez, Vanessa, Koterba, Natalka, Levine, Bruce L., Maude, Shannon L., Meyer, Nuala J., Moore, Jason H., Paessler, Michele, Porter, David L., Bush, Jenny L., Siegel, Don L., Davis, Megan M., Zhang, Donglan, June, Carl H., Grupp, Stephan A., Melenhorst, J. Joseph, Lacey, Simon F., Weiss, Scott L., and Teachey, David T.

Published
2020
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8. Red cell exchange for rapid leukoreduction in adults with hyperleukocytosis and leukostasis

Author

Mack, Ethan Andrew, primary, Dougher, Meaghan C., additional, Ginda, Ashley, additional, Cahill, Caitlin Q, additional, Murter, Melissa, additional, Schell, Kevin, additional, Tanhehco, Yvette C, additional, Bhoj, Vijay, additional, Fesnak, Andrew D, additional, Siegel, Don L, additional, Kambayashi, Taku, additional, Aqui, Nicole, additional, and O'Doherty, Una, additional

Published
2023
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9. Development and pharmacokinetic assessment of a fully canine anti-PD-1 monoclonal antibody for comparative translational research in dogs with spontaneous tumors

Author

Yoshimoto, Sho, primary, Chester, Nicholas, additional, Xiong, Ailian, additional, Radaelli, Enrico, additional, Wang, Hong, additional, Brillantes, Marc, additional, Gulendran, Gayathri, additional, Glassman, Patrick, additional, Siegel, Don L., additional, and Mason, Nicola J., additional

Published
2023
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11. B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma

Author

Cohen, Adam D., Garfall, Alfred L., Stadtmauer, Edward A., Melenhorst, J. Joseph, Lacey, Simon F., Lancaster, Eric, Vogl, Dan T., Weiss, Brendan M., Dengel, Karen, Nelson, Annemarie, Plesa, Gabriela, Chen, Fang, Davis, Megan M., Hwang, Wei-Ting, Young, Regina M., Brogdon, Jennifer L., Isaacs, Randi, Pruteanu-Malinici, Iulian, Siegel, Don L., Levine, Bruce L., June, Carl H., and Milone, Michael C.

Subjects
United States. National Cancer Institute, Novartis AG, Antigens, Cyclophosphamide, Chemotherapy, Pharmaceutical industry, T cells, Toxicity, Encephalopathy, Health care industry
Abstract

BACKGROUND. CAR T cells are a promising therapy for hematologic malignancies. B cell maturation antigen (BCMA) is a rational target in multiple myeloma (MM). METHODS. We conducted a phase I study of autologous T cells lentivirally transduced with a fully human, BCMA-specific CAR containing CD3[zeta] and 4-1BB signaling domains (CART-BCMA), in subjects with relapsed/refractory MM. Twenty-five subjects were treated in 3 cohorts as follows: cohort 1, 1 x [10.sup.8] to 5 x [10.sup.8] CART-BCMA cells alone; cohort 2, cyclophosphamide (Cy) 1.5 g/ [m.sup.2] plus 1 x [10.sup.7] to 5 x [10.sup.7] CART-BCMA cells; cohort 3, Cy 1.5 g/[m.sup.2] plus 1 x [10.sup.8] to 5 x [10.sup.8] CART-BCMA cells. No prespecified BCMA expression level was required. RESULTS. CART-BCMA cells were manufactured and expanded in all subjects. Toxicities included cytokine release syndrome and neurotoxicity, which were grade 3-4 in 8 (32%) and 3 (12%) subjects, respectively, and reversible. One subject died at day 24 from candidemia and progressive myeloma, following treatment for severe cytokine release syndrome and encephalopathy. Responses (based on treated subjects) were seen in 4 of 9 (44%) in cohort 1, 1 of 5 (20%) in cohort 2, and 7 of 11 (64%) in cohort 3, including 5 partial, 5 very good partial, and 2 complete responses, 3 of which were ongoing at 11, 14, and 32 months. Decreased BCMA expression on residual MM cells was noted in responders; expression increased at progression in most. Responses and CART-BCMA expansion were associated with CD4/CD8 T cell ratio and frequency of [CD45RO.sup.-] [CD27.sup.+][CD8.sup.+] T cells in the premanufacturing leukapheresis product. CONCLUSION. CART-BCMA infusions with or without lymphodepleting chemotherapy are clinically active in heavily pretreated patients with MM. TRIAL REGISTRATION. NCT02546167. FUNDING. University of Pennsylvania-Novartis Alliance and NIH., Introduction Despite advances in multiple myeloma (MM) therapy, the disease remains incurable in most patients, and novel approaches are needed. B cell maturation antigen (BCMA) is a cell surface receptor [...]

Published
2019
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13. Data from Anti-BCMA/CD19 CAR T Cells with Early Immunomodulatory Maintenance for Multiple Myeloma Responding to Initial or Later-Line Therapy

Author

Garfall, Alfred L., primary, Cohen, Adam D., primary, Susanibar-Adaniya, Sandra P., primary, Hwang, Wei-Ting, primary, Vogl, Dan T., primary, Waxman, Adam J., primary, Lacey, Simon F., primary, Gonzalez, Vanessa E., primary, Fraietta, Joseph A., primary, Gupta, Minnal, primary, Kulikovskaya, Irina, primary, Tian, Lifeng, primary, Chen, Fang, primary, Koterba, Natalka, primary, Bartoszek, Robert L., primary, Patchin, Margaret, primary, Xu, Rong, primary, Plesa, Gabriela, primary, Siegel, Don L., primary, Brennan, Andrea, primary, Nelson, Anne Marie, primary, Ferthio, Regina, primary, Cosey, Angela, primary, Shea, Kim-Marie, primary, Leskowitz, Rachel, primary, Four, Megan, primary, Wilson, Wesley V., primary, Miao, Fei, primary, Lancaster, Eric, primary, Carreno, Beatriz M., primary, Linette, Gerald P., primary, Hexner, Elizabeth O., primary, Young, Regina M., primary, Bu, Dexiu, primary, Mansfield, Keith G., primary, Brogdon, Jennifer L., primary, June, Carl H., primary, Milone, Michael C., primary, and Stadtmauer, Edward A., primary

Published
2023
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14. Supplementary Tables and Figures from Anti-BCMA/CD19 CAR T Cells with Early Immunomodulatory Maintenance for Multiple Myeloma Responding to Initial or Later-Line Therapy

Author

Garfall, Alfred L., primary, Cohen, Adam D., primary, Susanibar-Adaniya, Sandra P., primary, Hwang, Wei-Ting, primary, Vogl, Dan T., primary, Waxman, Adam J., primary, Lacey, Simon F., primary, Gonzalez, Vanessa E., primary, Fraietta, Joseph A., primary, Gupta, Minnal, primary, Kulikovskaya, Irina, primary, Tian, Lifeng, primary, Chen, Fang, primary, Koterba, Natalka, primary, Bartoszek, Robert L., primary, Patchin, Margaret, primary, Xu, Rong, primary, Plesa, Gabriela, primary, Siegel, Don L., primary, Brennan, Andrea, primary, Nelson, Anne Marie, primary, Ferthio, Regina, primary, Cosey, Angela, primary, Shea, Kim-Marie, primary, Leskowitz, Rachel, primary, Four, Megan, primary, Wilson, Wesley V., primary, Miao, Fei, primary, Lancaster, Eric, primary, Carreno, Beatriz M., primary, Linette, Gerald P., primary, Hexner, Elizabeth O., primary, Young, Regina M., primary, Bu, Dexiu, primary, Mansfield, Keith G., primary, Brogdon, Jennifer L., primary, June, Carl H., primary, Milone, Michael C., primary, and Stadtmauer, Edward A., primary

Published
2023
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15. CCR5-edited [CD4.sup.+] T cells augment HIV-specific immunity to enable post-rebound control of HIV replication

Author

Tebas, Pablo, Jadlowsky, Julie K., Shaw, Pamela A., Tian, Lifeng, Esparza, Erin, Brennan, Andrea L., Kim, Sukyung, Naing, Soe Yu, Richardson, Max W., Vogel, Ashley N., Maldini, Colby R., Kong, Hong, Liu, Xiaojun, Lacey, Simon F., Bauer, Anya M., Mampe, Felicity, Richman, Lee P., Lee, Gary, Ando, Dale, Levine, Bruce L., Porter, David L., Zhao, Yangbing, Siegel, Don L., Bar, Katharine J., June, Carl H., and Riley, James L.

Subjects
T cells -- Genetic aspects -- Health aspects, Gene expression -- Health aspects, Cellular proteins -- Health aspects, HIV infection -- Genetic aspects -- Development and progression -- Care and treatment, Health care industry
Abstract

BACKGROUND. We conducted a phase I clinical trial that infused CCR5 gene-edited [CD4.sup.+] T cells to determine how these T cells can better enable HIV cure strategies. METHODS. The aim of trial was to develop RNA-based approaches to deliver zinc finger nuclease (ZFN), evaluate the effect of CCR5 gene-edited [CD4.sup.+] T cells on the HIV-specific T cell response, test the ability of infused CCR5 gene- edited T cells to delay viral rebound during analytical treatment interruption, and determine whether individuals heterozygous for CCR5 [DELTA]32 preferentially benefit. We enrolled 14 individuals living with HIV whose viral load was well controlled by antiretroviral therapy (ART). We measured the time to viral rebound after ART withdrawal, the persistence of CCR5-edited [CD4.sup.+] T cells, and whether infusion of 10 billion CCR5-edited [CD4.sup.+] T cells augmented the HIV-specific immune response. RESULTS. Infusion of the [CD4.sup.+] T cells was well tolerated, with no serious adverse events. We observed a modest delay in the time to viral rebound relative to historical controls; however, 3 of the 14 individuals, 2 of whom were heterozygous for CCR5 [DELTA]32, showed post-viral rebound control of viremia, before ultimately losing control of viral replication. Interestingly, only these individuals had substantial restoration of HIV-specific [CD8.sup.+] T cell responses. We observed immune escape for 1 of these reinvigorated responses at viral recrudescence, illustrating a direct link between viral control and enhanced [CD8.sup.+] T cell responses. CONCLUSION. These findings demonstrate how CCR5 gene-edited [CD4.sup.+] T cell infusion could aid HIV cure strategies by augmenting preexisting HIV-specific immune responses. REGISTRATION. ClinicalTrials.gov NCT02388594. FUNDING. NIH funding (R01AI104400, UM1AI126620, U19AI149680, T32AI007632) was provided by the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), and the National Institute of Neurological Disorders and Stroke (NINDS). Sangamo Therapeutics also provided funding for these studies., Introduction Prolonged HIV-1 infection results in massive [CD4.sup.+] T cell loss and profound immunodeficiency (1). Even with effective antiretroviral therapy (ART), the resident [CD4.sup.+] T cell response does not fully [...]

Published
2021
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16. Anti-BCMA/CD19 CAR T Cells with Early Immunomodulatory Maintenance for Multiple Myeloma Responding to Initial or Later-Line Therapy

Author

Garfall, Alfred L., primary, Cohen, Adam D., additional, Susanibar-Adaniya, Sandra P., additional, Hwang, Wei-Ting, additional, Vogl, Dan T., additional, Waxman, Adam J., additional, Lacey, Simon F., additional, Gonzalez, Vanessa E., additional, Fraietta, Joseph A., additional, Gupta, Minnal, additional, Kulikovskaya, Irina, additional, Tian, Lifeng, additional, Chen, Fang, additional, Koterba, Natalka, additional, Bartoszek, Robert L., additional, Patchin, Margaret, additional, Xu, Rong, additional, Plesa, Gabriela, additional, Siegel, Don L., additional, Brennan, Andrea, additional, Nelson, Anne Marie, additional, Ferthio, Regina, additional, Cosey, Angela, additional, Shea, Kim-Marie, additional, Leskowitz, Rachel, additional, Four, Megan, additional, Wilson, Wesley V., additional, Miao, Fei, additional, Lancaster, Eric, additional, Carreno, Beatriz M., additional, Linette, Gerald P., additional, Hexner, Elizabeth O., additional, Young, Regina M., additional, Bu, Dexiu, additional, Mansfield, Keith G., additional, Brogdon, Jennifer L., additional, June, Carl H., additional, Milone, Michael C., additional, and Stadtmauer, Edward A., additional

Published
2023
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22. Targeted In Vivo Loading of Red Blood Cells Markedly Prolongs Nanocarrier Circulation

Author

Glassman, Patrick M., primary, Villa, Carlos H., additional, Marcos-Contreras, Oscar A., additional, Hood, Elizabeth D., additional, Walsh, Landis R., additional, Greineder, Colin F., additional, Myerson, Jacob W., additional, Shuvaeva, Tea, additional, Puentes, Laura, additional, Brenner, Jacob S., additional, Siegel, Don L., additional, and Muzykantov, Vladimir R., additional

Published
2022
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23. NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma

Author

Rapoport, Aaron P., Stadtmauer, Edward A., Binder-Scholl, Gwendolyn K., Goloubeva, Olga, Vogl, Dan T., Lacey, Simon F., Badros, Ashraf Z., Garfall, Alfred, Weiss, Brendan, Finklestein, Jeffrey, Kulikovskaya, Irina, Sinha, Sanjoy K., Kronsberg, Shari, Gupta, Minnal, Bond, Sarah, Melchiori, Luca, Brewer, Joanna E., Bennett, Alan D., Gerry, Andrew B., Pumphrey, Nicholas J., Williams, Daniel, Tayton-Martin, Helen K., Ribeiro, Lilliam, Holdich, Tom, Yanovich, Saul, Hardy, Nancy, Yared, Jean, Kerr, Naseem, Philip, Sunita, Westphal, Sandra, Siegel, Don L., Levine, Bruce L., Jakobsen, Bent K., Kalos, Michael, and June, Carl H.

Subjects
Cytokines -- Health aspects, T cells -- Research, Multiple myeloma -- Care and treatment, Biological sciences, Health
Abstract

Despite recent therapeutic advances, multiple myeloma (MM) remains largely incurable. Here we report results of a phase I/II trial to evaluate the safety and activity of autologous T cells engineered to express an affinity-enhanced T cell receptor (TCR) recognizing a naturally processed peptide shared by the cancer-testis antigens NY-ESO-1 and LAGE-1. Twenty patients with antigen-positive MM received an average 2.4 x [10.sup.9] engineered T cells 2 d after autologous stem cell transplant. Infusions were well tolerated without clinically apparent cytokine-release syndrome, despite high IL-6 levels. Engineered T cells expanded, persisted, trafficked to marrow and exhibited a cytotoxic phenotype. Persistence of engineered T cells in blood was inversely associated with NY-ESO-1 levels in the marrow. Disease progression was associated with loss of T cell persistence or antigen escape, in accordance with the expected mechanism of action of the transferred T cells. Encouraging clinical responses were observed in 16 of 20 patients (80%) with advanced disease, with a median progression-free survival of 19.1 months. NY-ESO-1-LAGE-1 TCR-engineered T cells were safe, trafficked to marrow and showed extended persistence that correlated with clinical activity against antigen- positive myeloma., Allogeneic stem cell transplants can eradicate myeloma through the T cell-mediated 'graft-versus-myeloma' (GVM) effect, but their success is limited by morbidity and mortality from infections and organ toxicity. Autologous stem [...]

Published
2015
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26. Decade-Long Remissions of Leukemia Sustained By the Persistence of Activated CD4+ CAR T-Cells

Author

Melenhorst, J. Joseph, primary, Chen, Gregory M, additional, Wang, Meng, additional, Porter, David L., additional, Gao, Peng, additional, Bandyopadhyay, Shovik, additional, Pruteanu-Malinici, Iulian, additional, Nobles, Christopher L, additional, Maji, Sayantan, additional, Frey, Noelle V, additional, Gill, Saar, additional, Tian, Lifeng, additional, Kulikovskaya, Irina, additional, Davis, Megan M, additional, Fraietta, Joseph A, additional, Brogdon, Jennifer L, additional, Young, Regina, additional, Ambrose, David E, additional, Chew, Anne, additional, Levine, Bruce L, additional, Siegel, Don L., additional, Alanio, Cécile, additional, Wherry, E. John, additional, Bushman, Frederic D., additional, Lacey, Simon F, additional, Tan, Kai, additional, and June, Carl H, additional

Published
2021
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30. Contributors

Author

Abella, Benjamin S., primary, Aberra, Faten N., additional, Adeseun, Gbemisola A., additional, Ahmad, Nuzhat A., additional, Allen, Steven R., additional, Ali, Zarina S., additional, Atluri, Pavan, additional, Ball, Amanda M., additional, Balu, Ramani, additional, Banerjee, Audreesh, additional, Becker, Danielle A., additional, Bellamy, Cassandra J., additional, Berns, Jeffrey S., additional, Bird, Shawn J., additional, Blaya, Marcelo, additional, Bleicher, Melissa B., additional, Bowens, Nina M., additional, Brainard, Jason C., additional, Braslow, Benjamin, additional, Callans, David, additional, Carr-Lettieri, Megan E., additional, Cereda, Maurizio, additional, Chatterjee, Pia, additional, Chen, H. Isaac, additional, Cohen, Debbie L., additional, Cohen, Jeffrey E., additional, Criner, Gerald J., additional, Deitz, Joel, additional, DeLisser, Horace M., additional, Deutschman, Clifford S., additional, Diamond, Joshua, additional, Dibble, Christopher T., additional, Dolan, Jennifer M., additional, Dostal, Courtney L., additional, Ely, E. Wesley, additional, Faigel, Douglas O., additional, Ferrari, Victor A., additional, Fields, Barry, additional, Fishman, Neil, additional, Frank, Ian, additional, Frazer, Michael J., additional, Freese, Andrew, additional, Fried, David A., additional, Fuchs, Barry D., additional, Fuhrman, Steven A., additional, Gazourian, Lee, additional, Glickman, Joel D., additional, Gluckman, Stephen J., additional, Goldberg, Andrew N., additional, Goldberg, Lee R., additional, Goldfarb, Stanley, additional, Goodman, Diane, additional, Gottlieb, Jonathan E., additional, Gracias, Vicente H., additional, Grippi, Michael A., additional, Gurubhagavatula, Indira, additional, Haas, Andrew R., additional, Hamilton, Keith, additional, William Hansen, C., additional, Hermann, Robin, additional, Hess, John R., additional, Hoff, Kolin, additional, Hoke, Linda, additional, Holena, Daniel N., additional, Hudock, Kristin, additional, Isakow, Warren, additional, Janz, David R., additional, Jassar, Arminder, additional, Judy, Kevin D., additional, Kahn, Marc J., additional, Kadakia, Mitul B., additional, Kapa, Suraj, additional, Kasner, Scott E., additional, Kayser, Joshua B., additional, Keeney, Scott A., additional, Kim, Patrick K., additional, Kim, Stephen, additional, King, Rhonda S., additional, Kirkwood, Melissa L., additional, Kobrin, Sidney M., additional, Kohl, Benjamin A., additional, Kolansky, Daniel M., additional, Kotapka, Mark J., additional, Kovach, Stephen J., additional, Kreider, Maryl, additional, Krok, Karen L., additional, Kruse-Jarres, Rebecca, additional, Kucharczuk, John C., additional, Landsburg, Daniel J., additional, Lane-Fall, Meghan B., additional, Lanken, Paul N., additional, Leary, Marion, additional, Levine, David N., additional, Levine, Joshua M., additional, Levine, Lisa D., additional, Lichtenstein, Gary R., additional, Lilly, Craig M., additional, Lilly, Scott M., additional, Loren, Alison W., additional, Low, David W., additional, Maguire, Cheryl, additional, Maki, Junsuke, additional, Malloy, Kelly M., additional, Malone, Daniel, additional, Malosky, Stephen A., additional, Manaker, Scott, additional, Mannes, Andrew, additional, Marchlinski, Francis E., additional, Marcotte, Paul, additional, Masangkay, Neil M., additional, Mascitti, Kara B., additional, McCarthy, Fenton, additional, McGarvey, Michael L., additional, Mechem, C. Crawford, additional, Mehta, Samir, additional, Menard-Katcher, Paul, additional, Meyer, Nuala J., additional, Mikkelsen, Mark E., additional, Milas, Bonnie L., additional, Mirza, Natasha, additional, Moon, Edmund K., additional, Myers, Jennifer S., additional, Netzer, Giora, additional, Nold, Christopher, additional, O’Doherty, Una, additional, Oxman, David A., additional, Paget-Brown, Alix O., additional, Palevsky, Harold I., additional, Panettieri, Reynold A., additional, Parry, Samuel, additional, Pascual, Jose L., additional, Patel, Nirav P., additional, Pechet, Taine T.V., additional, Perrone, Jeanmarie, additional, Phillips, Matthew F., additional, Polk, Travis M., additional, Preston, Ave Maria, additional, Reed, Amy J., additional, Reilly, Eugene F., additional, Reilly, James B., additional, Reilly, John P., additional, Reilly, Patrick M., additional, Ries, Michael, additional, Rosen, Ilene M., additional, Rosenbach, Misha, additional, Rudnick, Michael R., additional, Samadani, Uzma, additional, Sarani, Babak, additional, Sareli, Aharon, additional, Satti, Aditi, additional, Schwab, Richard J., additional, Schweickert, William, additional, Scott, Benjamin K., additional, Segal, Miriam, additional, Shafi, Bilal, additional, Shah, Chirag V., additional, Shah, Siddharth P., additional, Shashaty, Michael G., additional, Shiroff, Adam M., additional, Siegel, Don L., additional, Silvestry, Frank E., additional, Simonian, Melissa A., additional, Sims, Carrie A., additional, Sims, Michael W., additional, Sinkin, Robert A., additional, Soisson, Michael J., additional, Souder, Jeremy, additional, Sunwoo, Bernie, additional, Supple, Gregory E., additional, Takach, Patricia, additional, Talati, Naasha, additional, Tariq, Nabil, additional, Thaler, Erica R., additional, Theodore, Arthur C., additional, Tobias, Mitchell D., additional, Townsend, Raymond R., additional, Turowski, Jason B., additional, Uritsky, Tanya J., additional, Vorovich, Esther, additional, Wade, Alisha N., additional, Washington, Alexander W., additional, Wasserstein, Alan G., additional, Weinhouse, Gerald L., additional, Wilck, Marissa B., additional, Williams, Noel N., additional, Wilson, F. Perry, additional, Wilson, Kevin C., additional, Wolfe, Laura, additional, Woo, Edward Y., additional, Zager, Eric L., additional, and Zhou, Ting, additional

Published
2014
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32. CCR5-edited CD4+ T cells augment HIV-specific immunity to enable post-rebound control of HIV replication

Author

Klinische infectiologie en microb. lab., Tebas, Pablo, Jadlowsky, Julie K., Shaw, Pamela A., Tian, Lifeng, Esparza, Erin, Brennan, Andrea L., Kim, Sukyung, Naing, Soe Yu, Richardson, Max W., Vogel, Ashley N., Maldini, Colby R., Kong, Hong, Liu, Xiaojun, Lacey, Simon F., Bauer, Anya M., Mampe, Felicity, Richman, Lee P., Lee, Gary, Ando, Dale, Levine, Bruce L., Porter, David L., Zhao, Yangbing, Siegel, Don L., Bar, Katharine J., June, Carl H., Riley, James L., Klinische infectiologie en microb. lab., Tebas, Pablo, Jadlowsky, Julie K., Shaw, Pamela A., Tian, Lifeng, Esparza, Erin, Brennan, Andrea L., Kim, Sukyung, Naing, Soe Yu, Richardson, Max W., Vogel, Ashley N., Maldini, Colby R., Kong, Hong, Liu, Xiaojun, Lacey, Simon F., Bauer, Anya M., Mampe, Felicity, Richman, Lee P., Lee, Gary, Ando, Dale, Levine, Bruce L., Porter, David L., Zhao, Yangbing, Siegel, Don L., Bar, Katharine J., June, Carl H., and Riley, James L.

Published
2021

33. Hypogammaglobulinemia and Infection Risk in Chronic Lymphocytic Leukemia (CLL) Patients Treated with CD19-Directed Chimeric Antigen Receptor T (CAR-T) Cells

Author

Uy, Natalie F., Pequignot, Edward, Frey, Noelle V., Davis, Megan, Hexner, Elizabeth O., Schuster, Stephen J., Gill, Saar, Loren, Alison W., Grupp, Stephan A, Melenhorst, J. Joseph, Lacey, Simon F, Fraietta, Joseph A, Gilmore, Joan, Lledo, Lester, Hwang, Wei-Ting, Siegel, Don L., Levine, Bruce L, June, Carl H, and Porter, David L.

Published
2020
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34. Homologous regions of autoantibody heavy chain complementarity-determining region 3 (H-CDR3) in patients with prmphigus cause pathogenicity

Author

Yamagami, Jun, Payne, Aimee S., Kacir, Stephen, Ishii, Ken, Siegel, Don L., and Stanley, John R.

Subjects
Autoantibodies -- Physiological aspects -- Genetic aspects, Cell adhesion molecules -- Physiological aspects -- Genetic aspects -- Research, Autoimmune diseases -- Development and progression -- Genetic aspects -- Research, Health care industry
Abstract

Pemphigus is a life-threatening autoimmune disease in which antibodies specific for desmogleins (Dsgs) cause loss of keratinocyte cell adhesion and blisters. In order to understand how antibodies cause pathogenicity and whether there are commonalities among antibodies in different patients that could ultimately be used to target specific therapy against these antibodies, we characterized Dsg-specific mAbs cloned by phage display from 3 patients with pemphigus vulgaris and 2 with pemphigus foliaceus. Variable heavy chain gene usage was restricted, but similar genes were used for both pathogenic and nonpathogenic mAbs. However, the heavy chain complementarity-determining region 3 (H-CDR3) of most pathogenic, but not nonpathogenic, mAbs shared an amino acid consensus sequence. Randomization of the H-CDR3 and sitedirected mutagenesis indicated that changes in this sequence could block pathogenicity but not necessarily binding. In addition, for 2 antibodies with longer H-CDR3s, a tryptophan was critical for pathogenicity but not binding, a result that is consistent with blocking the tryptophan acceptor site that is thought to be necessary for Dsg-mediated adhesion. These studies indicate that H-CDR3 is critical for pathogenicity of a human autoantibody, that a small region (even 1 amino acid) can mediate pathogenicity, and that pathogenicity can be uncoupled from binding in these antibodies., Introduction Pemphigus is a tissue-specific autoimmune disease in which autoantibodies against the keratinocyte cell surface cause skin blisters due to loss of cell-cell adhesion (1). These autoantibodies are directed against [...]

Published
2010
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36. Adoptive T cell immunotherapy for medullary thyroid carcinoma targeting GDNF family receptor alpha 4

Author

Bhoj, Vijay G., primary, Li, Lucy, additional, Parvathaneni, Kalpana, additional, Zhang, Zheng, additional, Kacir, Stephen, additional, Arhontoulis, Dimitrios, additional, Zhou, Kenneth, additional, McGettigan-Croce, Bevin, additional, Nunez-Cruz, Selene, additional, Gulendran, Gayathri, additional, Boesteanu, Alina C., additional, Johnson, Laura, additional, Feldman, Michael D., additional, Radaelli, Enrico, additional, Mansfield, Keith, additional, Nasrallah, MacLean, additional, Goydel, Rebecca S., additional, Peng, Haiyong, additional, Rader, Christoph, additional, Milone, Michael C., additional, and Siegel, Don L., additional

Published
2021
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37. CCR5-edited CD4+ T cells augment HIV-specific immunity to enable post-rebound control of HIV replication

Author

Tebas, Pablo, Jadlowsky, Julie K., Shaw, Pamela A., Tian, Lifeng, Esparza, Erin, Brennan, Andrea L., Kim, Sukyung, Naing, Soe Yu, Richardson, Max W., Vogel, Ashley N., Maldini, Colby R., Kong, Hong, Liu, Xiaojun, Lacey, Simon F., Bauer, Anya M., Mampe, Felicity, Richman, Lee P., Lee, Gary, Ando, Dale, Levine, Bruce L., Porter, David L., Zhao, Yangbing, Siegel, Don L., Bar, Katharine J., June, Carl H., Riley, James L., Klinische infectiologie en microb. lab., and Klinische infectiologie en microb. lab.

Subjects
0301 basic medicine, Adult, CD4-Positive T-Lymphocytes, Male, Receptors, CCR5, Genetic enhancement, T cell, viruses, Viremia, HIV Infections, CD8-Positive T-Lymphocytes, Virus Replication, 03 medical and health sciences, 0302 clinical medicine, Immune system, Medicine, Humans, Adverse effect, Medicine(all), Gene Editing, business.industry, virus diseases, General Medicine, Middle Aged, Viral Load, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Viral replication, Anti-Retroviral Agents, 030220 oncology & carcinogenesis, Lymphocyte Transfusion, Immunology, HIV-1, Female, Clinical Medicine, business, Viral load, CD8
Abstract

BACKGROUND: We conducted a phase I clinical trial that infused CCR5 gene–edited CD4(+) T cells to determine how these T cells can better enable HIV cure strategies. METHODS: The aim of trial was to develop RNA-based approaches to deliver zinc finger nuclease (ZFN), evaluate the effect of CCR5 gene–edited CD4(+) T cells on the HIV-specific T cell response, test the ability of infused CCR5 gene–edited T cells to delay viral rebound during analytical treatment interruption, and determine whether individuals heterozygous for CCR5 Δ32 preferentially benefit. We enrolled 14 individuals living with HIV whose viral load was well controlled by antiretroviral therapy (ART). We measured the time to viral rebound after ART withdrawal, the persistence of CCR5-edited CD4(+) T cells, and whether infusion of 10 billion CCR5-edited CD4(+) T cells augmented the HIV-specific immune response. RESULTS: Infusion of the CD4(+) T cells was well tolerated, with no serious adverse events. We observed a modest delay in the time to viral rebound relative to historical controls; however, 3 of the 14 individuals, 2 of whom were heterozygous for CCR5 Δ32, showed post-viral rebound control of viremia, before ultimately losing control of viral replication. Interestingly, only these individuals had substantial restoration of HIV-specific CD8(+) T cell responses. We observed immune escape for 1 of these reinvigorated responses at viral recrudescence, illustrating a direct link between viral control and enhanced CD8(+) T cell responses. CONCLUSION: These findings demonstrate how CCR5 gene–edited CD4(+) T cell infusion could aid HIV cure strategies by augmenting preexisting HIV-specific immune responses. REGISTRATION: ClinicalTrials.gov NCT02388594. FUNDING: NIH funding (R01AI104400, UM1AI126620, U19AI149680, T32AI007632) was provided by the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), and the National Institute of Neurological Disorders and Stroke (NINDS). Sangamo Therapeutics also provided funding for these studies.

Published
2020

43. Synthetic nucleic acid antibody prophylaxis confers rapid and durable protective immunity against Zika virus challenge

Author

Choi, Hyeree, primary, Kudchodkar, Sagar B., additional, Reuschel, Emma L., additional, Asija, Kanika, additional, Borole, Piyush, additional, Agarwal, Sangya, additional, Van Gorder, Lucas, additional, Reed, Charles C., additional, Gulendran, Gayathri, additional, Ramos, Stephanie, additional, Broderick, Kate E., additional, Kim, J Joseph, additional, Ugen, Kenneth E., additional, Kobinger, Gary, additional, Siegel, Don L., additional, Weiner, David B., additional, and Muthumani, Kar, additional

Published
2019
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44. Response to Anti-Bcma CAR T Cell Therapy Correlates with T Cell Exhaustion and Activation Status in T Cells at Baseline in Myeloma

Author

Wang, Meng, primary, Pruteanu, Iulian, additional, Cohen, Adam D., additional, Garfall, Alfred L., additional, Tian, Lifeng, additional, Lacey, Simon F, additional, Fraietta, Joseph A, additional, Brogdon, Jennifer, additional, Davis, Megan, additional, Gonzalez, Vanessa E., additional, Levine, Bruce L, additional, Siegel, Don L., additional, Milone, Michael C., additional, Stadtmauer, Edward A., additional, June, Carl H, additional, and Melenhorst, J. Joseph, additional

Published
2019
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45. First-in-Human Assessment of Feasibility and Safety of Multiplexed Genetic Engineering of Autologous T Cells Expressing NY-ESO -1 TCR and CRISPR/Cas9 Gene Edited to Eliminate Endogenous TCR and PD-1 (NYCE T cells) in Advanced Multiple Myeloma (MM) and Sarcoma

Author

Stadtmauer, Edward A., primary, Cohen, Adam D., primary, Weber, Kristy, primary, Lacey, Simon F, primary, Gonzalez, Vanessa E., primary, Melenhorst, J. Joseph, primary, Fraietta, Joseph A, primary, Plesa, Gabriela, primary, Shea, Joanne, primary, Matlawski, Tina, primary, Cervini, Amanda, primary, Mangan, Patricia, primary, Gaymon, Avery, primary, Desjardins, Stephanie, primary, Lancaster, Eric, primary, Salas-Mckee, January, primary, Suhoski, Megan M., primary, Fesnak, Andrew, primary, O'Rourke, Matthew, primary, Lamontagne, Anne, primary, Siegel, Don L., primary, Young, Regina M, primary, Chew, Anne, primary, Nobles, Christopher L, primary, Bushman, Frederic D., primary, Chang, Howard Y., primary, Satpathy, Ansuman T., primary, Zhao, Yangbing, primary, Hwang, Wei-Ting, primary, Hexner, Elizabeth O., primary, and June, Carl H, primary

Published
2019
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46. Combination Anti-Bcma and Anti-CD19 CAR T Cells As Consolidation of Response to Prior Therapy in Multiple Myeloma

Author

Garfall, Alfred L., primary, Cohen, Adam D., additional, Lacey, Simon F, additional, Tian, Lifeng, additional, Hwang, Wei-Ting, additional, Vogl, Dan T., additional, Waxman, Adam, additional, Lancaster, Eric, additional, Nelson, Anne Marie, additional, Ferthio, Regina, additional, Fesnak, Andrew, additional, Lamontagne, Anne, additional, Brennan, Andrea, additional, Guilliams, Jamie, additional, Gladney, Whitney Lynn, additional, Melenhorst, J. Joseph, additional, Young, Regina M, additional, Siegel, Don L., additional, Levine, Bruce L, additional, Brogdon, Jennifer, additional, Isaacs, Randi E., additional, June, Carl H, additional, Milone, Michael C., additional, and Stadtmauer, Edward A., additional

Published
2019
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47. Identification and Validation of Predictive Biomarkers to CD19- and BCMA-Specific CAR T-Cell Responses in CAR T-Cell Precursors

Author

Wang, Meng, primary, Pruteanu, Iulian, primary, Cohen, Adam D., primary, Garfall, Alfred L, primary, Milone, Michael C., primary, Tian, Lifeng, primary, Gonzalez, Vanessa E., primary, Gill, Saar, primary, Frey, Noelle V., primary, Barrett, David M., primary, Ruella, Marco, primary, Lacey, Simon F, primary, Svoboda, Jakub, primary, Chong, Elise A., primary, Fraietta, Joseph A, primary, Davis, Megan, primary, Nasta, Sunita D, primary, Levine, Bruce L, primary, Siegel, Don L., primary, Maude, Shannon L., primary, Schuster, Stephen J., primary, Stadtmauer, Edward A., primary, Grupp, Stephan, primary, Porter, David L., primary, June, Carl H, primary, and Melenhorst, J. Joseph, primary

Published
2019
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48. Outcomes in Aggressive B-Cell Non-Hodgkin Lymphomas with Anti-CD19 CAR T-Cell (CTL019) Products Not Meeting Commercial Release Specifications

Author

Chong, Elise A., primary, Gerson, James N., primary, Landsburg, Daniel J., primary, Dwivedy Nasta, Sunita, primary, Svoboda, Jakub, primary, Porter, David L., primary, Dengel, Karen, primary, Siegel, Don L., primary, Gilmore, Joan, primary, Barta, Stefan K., primary, Levine, Bruce L, primary, June, Carl H, primary, and Schuster, Stephen J., primary

Published
2019
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