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1. B-cell–directed CAR T-cell therapy activates CD8+ cytotoxic CARneg bystander T cells in patients and nonhuman primates

Author

Kaminski, James, Fleming, Ryan A., Alvarez-Calderon, Francesca, Winschel, Marlana B., McGuckin, Connor, Ho, Emily E., Eng, Fay, Rui, Xianliang, Keskula, Paula, Cagnin, Lorenzo, Charles, Joanne, Zavistaski, Jillian, Margossian, Steven P., Kapadia, Malika A., Rottman, James B., Lane, Jennifer, Baumeister, Susanne H. C., Tkachev, Victor, Shalek, Alex K., Kean, Leslie S., and Gerdemann, Ulrike

Published
2024
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2. Alloengraftment without significant toxicity or GVHD in CD45 antibody-drug conjugate–conditioned Fanconi anemia mice

Author

Saha, Asim, Palchaudhuri, Rahul, Lanieri, Leanne, Hyzy, Sharon, Riddle, Megan J., Panthera, Jamie, Eide, Cindy R., Tolar, Jakub, Panoskaltsis-Mortari, Angela, Gorfinkel, Lev, Tkachev, Victor, Gerdemann, Ulrike, Alvarez-Calderon, Francesca, Palato, Elisa Rojas, MacMillan, Margaret L., Wagner, John E., Kean, Leslie S., Osborn, Mark J., Kiem, Hans-Peter, Scadden, David T., Olson, Lisa M., and Blazar, Bruce R.

Published
2024
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3. Pre-existing immunity does not impair the engraftment of CRISPR-Cas9-edited cells in rhesus macaques conditioned with busulfan or radiation

Author

Essawi, Khaled, Hakami, Waleed, Naeem Khan, Muhammad Behroz, Martin, Reid, Zeng, Jing, Chu, Rebecca, Uchida, Naoya, Bonifacino, Aylin C., Krouse, Allen E., Linde, Nathaniel S., Donahue, Robert E., Blobel, Gerd A., Gerdemann, Ulrike, Kean, Leslie S., Maitland, Stacy A., Wolfe, Scot A., Metais, Jean-Yves, Gottschalk, Stephen, Bauer, Daniel E., Tisdale, John F., and Demirci, Selami

Published
2023
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4. A pilot study of axicabtagene ciloleucel (axi-cel) for relapsed/refractory primary and secondary central nervous system lymphoma (PCNSL and SCNSL).

Author

Nayak, Lakshmi, primary, Chukwueke, Ugonma Nnenna, additional, Meehan, Christopher, additional, Redd, Robert, additional, Hogan, Sarah, additional, Lee, Eudocia Quant, additional, Kim, Austin Injae, additional, Arrillaga-Romany, Isabel, additional, McFaline Figueroa, J. Ricardo Ricardo, additional, Gonzalez Castro, Luis Nicolas, additional, Murakami, Mark Alan, additional, Huang, Raymond Yi-kun, additional, Gerdemann, Ulrike, additional, Kaminski, James, additional, Filosto, Simone, additional, Poddar, Soumya, additional, Mattie, Mike, additional, Armand, Philippe, additional, Kean, Leslie, additional, and Jacobson, Caron Alyce, additional

Published
2024
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6. Human OX40L–CAR-Tregs target activated antigen-presenting cells and control T cell alloreactivity.

Author

Rui, Xianliang, Alvarez Calderon, Francesca, Wobma, Holly, Gerdemann, Ulrike, Albanese, Alexandre, Cagnin, Lorenzo, McGuckin, Connor, Michaelis, Katherine A., Naqvi, Kisa, Blazar, Bruce R., Tkachev, Victor, and Kean, Leslie S.

Subjects
REGULATORY T cells, GRAFT versus host disease, TRANSCRIPTION factors, T cells, SYSTEMIC lupus erythematosus, AUTOIMMUNE diseases
Abstract

Regulatory T cells (Tregs) make major contributions to immune homeostasis. Because Treg dysfunction can lead to both allo- and autoimmunity, there is interest in correcting these disorders through Treg adoptive transfer. Two of the central challenges in clinically deploying Treg cellular therapies are ensuring phenotypic stability and maximizing potency. Here, we describe an approach to address both issues through the creation of OX40 ligand (OX40L)–specific chimeric antigen receptor (CAR)–Tregs under the control of a synthetic forkhead box P3 (FOXP3) promoter. The creation of these CAR-Tregs enabled selective Treg stimulation by engagement of OX40L, a key activation antigen in alloimmunity, including both graft-versus-host disease and solid organ transplant rejection, and autoimmunity, including rheumatoid arthritis, systemic sclerosis, and systemic lupus erythematosus. We demonstrated that OX40L–CAR-Tregs were robustly activated in the presence of OX40L-expressing cells, leading to up-regulation of Treg suppressive proteins without induction of proinflammatory cytokine production. Compared with control Tregs, OX40L–CAR-Tregs more potently suppressed alloreactive T cell proliferation in vitro and were directly inhibitory toward activated monocyte-derived dendritic cells (DCs). We identified trogocytosis as one of the central mechanisms by which these CAR-Tregs effectively decrease extracellular display of OX40L, resulting in decreased DC stimulatory capacity. OX40L–CAR-Tregs demonstrated an enhanced ability to control xenogeneic graft-versus-host disease compared with control Tregs without abolishing the graft-versus-leukemia effect. These results suggest that OX40L–CAR-Tregs may have wide applicability as a potent cellular therapy to control both allo- and autoimmune diseases. Editor's summary: Regulatory T cell (Treg) therapies have emerged as a promising approach for diseases ranging from autoimmunity to transplantation, but delivery of a mixed pool of Tregs has not proven consistently successful. To make an improved Treg-based therapy, Rui et al. developed OX40L–CAR-Tregs, where expression of an OX40 ligand (OX40L)–specific chimeric antigen receptor (CAR) is expressed only in Tregs that have turned on the master Treg transcription factor FoxP3. The authors showed that OX40L–CAR-Tregs outperformed control, standard Tregs in their ability to suppress effector T cells, in part through their ability to strip OX40L from the surface of antigen-presenting cells. In vivo, OX40L–CAR-Tregs were able to suppress development of graft-versus-host disease without an obvious detrimental effect on the antileukemia response, supporting further development of this potent cellular therapy. —Courtney Malo [ABSTRACT FROM AUTHOR]

Published
2024
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7. Reshaping of Local Alloimmunity By Organ-Specific Microenvironments during Acute Gvhd.

Author

Omdahl, Kayleigh Ingersoll, primary, Bermea, Rene S., additional, Fleming, Ryan, additional, Kimler, Kyle, additional, Hariri, Lida P., additional, Ly, Amy, additional, Rui, Xianliang, additional, Lane, Jennifer, additional, Kaminski, James, additional, Gerdemann, Ulrike, additional, Blazar, Bruce R., additional, Kean, Leslie S., additional, and Tkachev, Victor, additional

Published
2024
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9. The epigenetic landscape of T cell exhaustion

Author

Sen, Debattama R, Kaminski, James, Barnitz, R Anthony, Kurachi, Makoto, Gerdemann, Ulrike, Yates, Kathleen B, Tsao, Hsiao-Wei, Godec, Jernej, LaFleur, Martin W, Brown, Flavian D, Tonnerre, Pierre, Chung, Raymond T, Tully, Damien C, Allen, Todd M, Frahm, Nicole, Lauer, Georg M, Wherry, E John, Yosef, Nir, and Haining, W Nicholas

Subjects
Genetics, Infectious Diseases, Prevention, Human Genome, 1.1 Normal biological development and functioning, Underpinning research, Infection, Animals, B7-H1 Antigen, CD8-Positive T-Lymphocytes, Cell Lineage, Chromatin, Chronic Disease, Disease Models, Animal, Enhancer Elements, Genetic, Epigenesis, Genetic, Gene Editing, HIV Infections, Hepatitis C, Chronic, Humans, Immunologic Memory, Immunotherapy, Lymphocytic Choriomeningitis, Mice, Mice, Inbred C57BL, SOXB1 Transcription Factors, T-Box Domain Proteins, Transcription, Genetic, General Science & Technology
Abstract

Exhausted T cells in cancer and chronic viral infection express distinctive patterns of genes, including sustained expression of programmed cell death protein 1 (PD-1). However, the regulation of gene expression in exhausted T cells is poorly understood. Here, we define the accessible chromatin landscape in exhausted CD8+ T cells and show that it is distinct from functional memory CD8+ T cells. Exhausted CD8+ T cells in humans and a mouse model of chronic viral infection acquire a state-specific epigenetic landscape organized into functional modules of enhancers. Genome editing shows that PD-1 expression is regulated in part by an exhaustion-specific enhancer that contains essential RAR, T-bet, and Sox3 motifs. Functional enhancer maps may offer targets for genome editing that alter gene expression preferentially in exhausted CD8+ T cells.

Published
2016

11. CTIM-37. A PILOT STUDY OF AXICABTAGENE CILOLEUCEL (AXI-CEL) FOR THE TREATMENT OF RELAPSED/REFRACTORY PRIMARY AND SECONDARY CENTRAL NERVOUS SYSTEM LYMPHOMA (PCNSL AND SCNSL)

Author

Nayak, Lakshmi, primary, Falvey, Caroline, additional, Bouvier, Riemke, additional, Chukwueke, Ugonma, additional, Hogan, Sarah, additional, Kendricken, Elizabeth, additional, Meehan, Christopher, additional, Redd, Robert, additional, Fisher, Jennifer, additional, Torres, Alexandra, additional, Jones, Julia, additional, Lee, Eudocia, additional, Kim, Austin, additional, Castro, Luis Nicolas Gonzalez, additional, McFaline-Figueroa, Jose Ricardo, additional, Aquilanti, Elisa, additional, Youssef, Gilbert, additional, Arrillaga-Romany, Isabel, additional, Murakami, Mark, additional, Sholl, Lynette, additional, Meredith, David, additional, Huang, Raymond Y, additional, Ramsdell, Linda, additional, Gerdemann, Ulrike, additional, Keskula, Paula, additional, Kaminski, Jim, additional, Albanese, Alexandre, additional, Bi, Wenya Linda, additional, Arnaout, Omar, additional, Reardon, David, additional, Wen, Patrick, additional, Poddar, Soumya, additional, Mao, Daqin, additional, Mattie, Mike, additional, Davis, Madison, additional, Filosto, Simone, additional, Kean, Leslie, additional, Armand, Philippe, additional, and Jacobson, Caron, additional

Published
2023
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12. B cell directed CAR-T cell therapy results in activation of CD8+ cytotoxic CAR-negative bystander T cells in both non-human primates and patients

Author

Kaminski, James, primary, Fleming, Ryan A, additional, Alvarez-Calderon, Francesca, additional, McGuckin, Connor, additional, Ho, Emily E., additional, Eng, Fay, additional, Rui, Xianliang, additional, Keskula, Paula, additional, Cagnin, Lorenzo, additional, Charles, Joanne, additional, Zavistaski, Jillian, additional, Margossian, Steven P., additional, Kapadia, Malika A., additional, Rottman, James B., additional, Lane, Jennifer, additional, Baumeister, Susanne H.C., additional, Tkachev, Victor, additional, Shalek, Alex K., additional, Kean, Leslie S., additional, and Gerdemann, Ulrike, additional

Published
2023
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13. Pre-existing immunity does not impair the engraftment of electroporation-mediated RNP CRISPR-Cas9-edited cells in rhesus macaques conditioned with busulfan or radiation

Author

Essawi, Khaled, primary, Hakami, Waleed, additional, Naeem Khan, Muhammad Behroz, additional, Martin, Reid, additional, Zeng, Jing, additional, Chu, Rebecca, additional, Uchida, Naoya, additional, Bonifacino, Aylin C., additional, Krouse, Allen E., additional, Linde, Nathaniel S., additional, Donahue, Robert E., additional, Blobel, Gerd A., additional, Gerdemann, Ulrike, additional, Kean, Leslie S., additional, Maitland, Stacy A., additional, Wolfe, Scot A., additional, Metais, Jean-Yves, additional, Gottschalk, Stephen, additional, Bauer, Daniel E., additional, Tisdale, John F., additional, and Demirci, Selami, additional

Published
2023
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15. Supplementary Figures 1-4 from Improving T-cell Therapy for Relapsed EBV-Negative Hodgkin Lymphoma by Targeting Upregulated MAGE-A4

Author

Cruz, Conrad R., primary, Gerdemann, Ulrike, primary, Leen, Ann M., primary, Shafer, Jessica A., primary, Ku, Stephanie, primary, Tzou, Benjamin, primary, Horton, Terzah M., primary, Sheehan, Andrea, primary, Copeland, Amanda, primary, Younes, Anas, primary, Rooney, Cliona M., primary, Heslop, Helen E., primary, and Bollard, Catherine M., primary

Published
2023
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17. Supplementary Table 1 from Oncolytic Immunotherapy of Advanced Solid Tumors with a CD40L-Expressing Replicating Adenovirus: Assessment of Safety and Immunologic Responses in Patients

Author

Pesonen, Sari, primary, Diaconu, Iulia, primary, Kangasniemi, Lotta, primary, Ranki, Tuuli, primary, Kanerva, Anna, primary, Pesonen, Saila K., primary, Gerdemann, Ulrike, primary, Leen, Ann M., primary, Kairemo, Kalevi, primary, Oksanen, Minna, primary, Haavisto, Elina, primary, Holm, Sirkka-Liisa, primary, Karioja-Kallio, Aila, primary, Kauppinen, Satu, primary, Partanen, Kaarina P. L., primary, Laasonen, Leena, primary, Joensuu, Tima, primary, Alanko, Tuomo, primary, Cerullo, Vincenzo, primary, and Hemminki, Akseli, primary

Published
2023
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18. Supplementary Table 3 from Oncolytic Immunotherapy of Advanced Solid Tumors with a CD40L-Expressing Replicating Adenovirus: Assessment of Safety and Immunologic Responses in Patients

Author

Pesonen, Sari, primary, Diaconu, Iulia, primary, Kangasniemi, Lotta, primary, Ranki, Tuuli, primary, Kanerva, Anna, primary, Pesonen, Saila K., primary, Gerdemann, Ulrike, primary, Leen, Ann M., primary, Kairemo, Kalevi, primary, Oksanen, Minna, primary, Haavisto, Elina, primary, Holm, Sirkka-Liisa, primary, Karioja-Kallio, Aila, primary, Kauppinen, Satu, primary, Partanen, Kaarina P. L., primary, Laasonen, Leena, primary, Joensuu, Tima, primary, Alanko, Tuomo, primary, Cerullo, Vincenzo, primary, and Hemminki, Akseli, primary

Published
2023
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19. Supplementary Figure 2 from Oncolytic Immunotherapy of Advanced Solid Tumors with a CD40L-Expressing Replicating Adenovirus: Assessment of Safety and Immunologic Responses in Patients

Author

Pesonen, Sari, primary, Diaconu, Iulia, primary, Kangasniemi, Lotta, primary, Ranki, Tuuli, primary, Kanerva, Anna, primary, Pesonen, Saila K., primary, Gerdemann, Ulrike, primary, Leen, Ann M., primary, Kairemo, Kalevi, primary, Oksanen, Minna, primary, Haavisto, Elina, primary, Holm, Sirkka-Liisa, primary, Karioja-Kallio, Aila, primary, Kauppinen, Satu, primary, Partanen, Kaarina P. L., primary, Laasonen, Leena, primary, Joensuu, Tima, primary, Alanko, Tuomo, primary, Cerullo, Vincenzo, primary, and Hemminki, Akseli, primary

Published
2023
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20. Data from Oncolytic Immunotherapy of Advanced Solid Tumors with a CD40L-Expressing Replicating Adenovirus: Assessment of Safety and Immunologic Responses in Patients

Author

Pesonen, Sari, primary, Diaconu, Iulia, primary, Kangasniemi, Lotta, primary, Ranki, Tuuli, primary, Kanerva, Anna, primary, Pesonen, Saila K., primary, Gerdemann, Ulrike, primary, Leen, Ann M., primary, Kairemo, Kalevi, primary, Oksanen, Minna, primary, Haavisto, Elina, primary, Holm, Sirkka-Liisa, primary, Karioja-Kallio, Aila, primary, Kauppinen, Satu, primary, Partanen, Kaarina P. L., primary, Laasonen, Leena, primary, Joensuu, Tima, primary, Alanko, Tuomo, primary, Cerullo, Vincenzo, primary, and Hemminki, Akseli, primary

Published
2023
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21. Supplementary Table 5 from Oncolytic Immunotherapy of Advanced Solid Tumors with a CD40L-Expressing Replicating Adenovirus: Assessment of Safety and Immunologic Responses in Patients

Author

Pesonen, Sari, primary, Diaconu, Iulia, primary, Kangasniemi, Lotta, primary, Ranki, Tuuli, primary, Kanerva, Anna, primary, Pesonen, Saila K., primary, Gerdemann, Ulrike, primary, Leen, Ann M., primary, Kairemo, Kalevi, primary, Oksanen, Minna, primary, Haavisto, Elina, primary, Holm, Sirkka-Liisa, primary, Karioja-Kallio, Aila, primary, Kauppinen, Satu, primary, Partanen, Kaarina P. L., primary, Laasonen, Leena, primary, Joensuu, Tima, primary, Alanko, Tuomo, primary, Cerullo, Vincenzo, primary, and Hemminki, Akseli, primary

Published
2023
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22. Supplementary Table 4 from Oncolytic Immunotherapy of Advanced Solid Tumors with a CD40L-Expressing Replicating Adenovirus: Assessment of Safety and Immunologic Responses in Patients

Author

Pesonen, Sari, primary, Diaconu, Iulia, primary, Kangasniemi, Lotta, primary, Ranki, Tuuli, primary, Kanerva, Anna, primary, Pesonen, Saila K., primary, Gerdemann, Ulrike, primary, Leen, Ann M., primary, Kairemo, Kalevi, primary, Oksanen, Minna, primary, Haavisto, Elina, primary, Holm, Sirkka-Liisa, primary, Karioja-Kallio, Aila, primary, Kauppinen, Satu, primary, Partanen, Kaarina P. L., primary, Laasonen, Leena, primary, Joensuu, Tima, primary, Alanko, Tuomo, primary, Cerullo, Vincenzo, primary, and Hemminki, Akseli, primary

Published
2023
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23. Supplementary Figure 3 from Oncolytic Immunotherapy of Advanced Solid Tumors with a CD40L-Expressing Replicating Adenovirus: Assessment of Safety and Immunologic Responses in Patients

Author

Pesonen, Sari, primary, Diaconu, Iulia, primary, Kangasniemi, Lotta, primary, Ranki, Tuuli, primary, Kanerva, Anna, primary, Pesonen, Saila K., primary, Gerdemann, Ulrike, primary, Leen, Ann M., primary, Kairemo, Kalevi, primary, Oksanen, Minna, primary, Haavisto, Elina, primary, Holm, Sirkka-Liisa, primary, Karioja-Kallio, Aila, primary, Kauppinen, Satu, primary, Partanen, Kaarina P. L., primary, Laasonen, Leena, primary, Joensuu, Tima, primary, Alanko, Tuomo, primary, Cerullo, Vincenzo, primary, and Hemminki, Akseli, primary

Published
2023
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24. Supplementary Table 2 from Oncolytic Immunotherapy of Advanced Solid Tumors with a CD40L-Expressing Replicating Adenovirus: Assessment of Safety and Immunologic Responses in Patients

Author

Pesonen, Sari, primary, Diaconu, Iulia, primary, Kangasniemi, Lotta, primary, Ranki, Tuuli, primary, Kanerva, Anna, primary, Pesonen, Saila K., primary, Gerdemann, Ulrike, primary, Leen, Ann M., primary, Kairemo, Kalevi, primary, Oksanen, Minna, primary, Haavisto, Elina, primary, Holm, Sirkka-Liisa, primary, Karioja-Kallio, Aila, primary, Kauppinen, Satu, primary, Partanen, Kaarina P. L., primary, Laasonen, Leena, primary, Joensuu, Tima, primary, Alanko, Tuomo, primary, Cerullo, Vincenzo, primary, and Hemminki, Akseli, primary

Published
2023
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25. Supplementary Figure 1 from Oncolytic Immunotherapy of Advanced Solid Tumors with a CD40L-Expressing Replicating Adenovirus: Assessment of Safety and Immunologic Responses in Patients

Author

Pesonen, Sari, primary, Diaconu, Iulia, primary, Kangasniemi, Lotta, primary, Ranki, Tuuli, primary, Kanerva, Anna, primary, Pesonen, Saila K., primary, Gerdemann, Ulrike, primary, Leen, Ann M., primary, Kairemo, Kalevi, primary, Oksanen, Minna, primary, Haavisto, Elina, primary, Holm, Sirkka-Liisa, primary, Karioja-Kallio, Aila, primary, Kauppinen, Satu, primary, Partanen, Kaarina P. L., primary, Laasonen, Leena, primary, Joensuu, Tima, primary, Alanko, Tuomo, primary, Cerullo, Vincenzo, primary, and Hemminki, Akseli, primary

Published
2023
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26. Supplementary Figure 4 from Oncolytic Immunotherapy of Advanced Solid Tumors with a CD40L-Expressing Replicating Adenovirus: Assessment of Safety and Immunologic Responses in Patients

Author

Pesonen, Sari, primary, Diaconu, Iulia, primary, Kangasniemi, Lotta, primary, Ranki, Tuuli, primary, Kanerva, Anna, primary, Pesonen, Saila K., primary, Gerdemann, Ulrike, primary, Leen, Ann M., primary, Kairemo, Kalevi, primary, Oksanen, Minna, primary, Haavisto, Elina, primary, Holm, Sirkka-Liisa, primary, Karioja-Kallio, Aila, primary, Kauppinen, Satu, primary, Partanen, Kaarina P. L., primary, Laasonen, Leena, primary, Joensuu, Tima, primary, Alanko, Tuomo, primary, Cerullo, Vincenzo, primary, and Hemminki, Akseli, primary

Published
2023
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28. CAR-T Cell Infusion Results in Activation of CD160+/NKG2D+/CCL5+ Non-CAR CD8+ Cytotoxic 'Bystander' T Cells in Both Non-Human Primates (NHP) and Patients Receiving B-Cell-Directed CAR-Ts

Author

Gerdemann, Ulrike, primary, Kaminski, James, additional, Fleming, Ryan A, additional, Tkachev, Victor, additional, Alvarez Calderon, Francesca, additional, McGuckin, Connor, additional, Rui, Xianliang, additional, Lane, Jennifer, additional, Shalek, Alex K., additional, and Kean, Leslie, additional

Published
2022
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30. Targeting CNS Lymphoma with Intravenous Axicabtagene Ciloleucel: Evidence for Transcriptional Evolution Towards a Prominent Interferon Signature in CAR-T Cells Trafficking to the Tumor Site

Author

Gerdemann, Ulrike, primary, Kaminski, James, additional, Albanese, Alexandre, additional, Keskula, Paula, additional, Cagnin, Lorenzo, additional, Betz, Kayla, additional, Zavistaski, Jillian, additional, Fleming, Ryan A, additional, Falvey, Caroline, additional, Bouvier, Riemke, additional, Jones, Julia, additional, Poddar, Soumya, additional, Mattie, Mike, additional, Chukwueke, Ugonma, additional, Torres, Alexandra, additional, Jacobson, Caron A., additional, Nayak, Lakshmi, additional, and Kean, Leslie S., additional

Published
2022
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32. A Pilot Study of Axicabtagene Ciloleucel (axi-cel) for the Treatment of Relapsed/Refractory Primary and Secondary Central Nervous System Lymphoma (CNSL)

Author

Jacobson, Caron A., primary, Falvey, Caroline, additional, Bouvier, Riemke, additional, Hogan, Sarah, additional, Kendricken, Elizabeth, additional, Jones, Julia, additional, Grimm, Elizabeth, additional, Redd, Robert A., additional, Lee, Eudocia Q, additional, Gonzalez Castro, Luis, additional, Chukwueke, Ugonma, additional, McFaline Figueroa, Jose, additional, Kim, Austin I., additional, Torres, Alexandra, additional, Ramsdell, Linda, additional, Kean, Leslie S., additional, Gerdemann, Ulrike, additional, Albanese, Alexandre, additional, Keskula, Paula, additional, Meredith, David, additional, Sholl, Lynette, additional, Poddar, Soumya, additional, Davis, Madison, additional, Mao, Daquin, additional, Filosto, Simone, additional, Mattie, Mike, additional, Armand, Philippe, additional, and Nayak, Lakshmi, additional

Published
2022
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33. Safety and clinical efficacy of rapidly-generated trivirus-directed T cells as treatment for adenovirus, EBV, and CMV infections after allogeneic hematopoietic stem cell transplant

Author

Gerdemann, Ulrike, Katari, Usha L, Papadopoulou, Anastasia, Keirnan, Jacqueline M, Craddock, John A, Liu, Hao, Martinez, Caridad A, Kennedy-Nasser, Alana, Leung, Kathryn S, Gottschalk, Stephen M, Krance, Robert A, Brenner, Malcolm K, Rooney, Cliona M, Heslop, Helen E, and Leen, Ann M

Published
2013
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35. Notch signaling drives intestinal graft-versus-host disease in mice and nonhuman primates.

Author

Tkachev, Victor, Vanderbeck, Ashley, Perkey, Eric, Furlan, Scott N., McGuckin, Connor, Gómez Atria, Daniela, Gerdemann, Ulrike, Rui, Xianliang, Lane, Jennifer, Hunt, Daniel J., Zheng, Hengqi, Colonna, Lucrezia, Hoffman, Michelle, Yu, Alison, Outen, Riley, Kelly, Samantha, Allman, Anneka, Koch, Ute, Radtke, Freddy, and Ludewig, Burkhard

Abstract

Notch signaling promotes T cell pathogenicity and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT) in mice, with a dominant role for the Delta-like Notch ligand DLL4. To assess whether Notch's effects are evolutionarily conserved and to identify the mechanisms of Notch signaling inhibition, we studied antibody-mediated DLL4 blockade in a nonhuman primate (NHP) model similar to human allo-HCT. Short-term DLL4 blockade improved posttransplant survival with durable protection from gastrointestinal GVHD in particular. Unlike prior immunosuppressive strategies tested in the NHP GVHD model, anti-DLL4 interfered with a T cell transcriptional program associated with intestinal infiltration. In cross-species investigations, Notch inhibition decreased surface abundance of the gut-homing integrin α4β7 in conventional T cells while preserving α4β7 in regulatory T cells, with findings suggesting increased β1 competition for α4 binding in conventional T cells. Secondary lymphoid organ fibroblastic reticular cells emerged as the critical cellular source of Delta-like Notch ligands for Notch-mediated up-regulation of α4β7 integrin in T cells after allo-HCT. Together, DLL4-Notch blockade decreased effector T cell infiltration into the gut, with increased regulatory to conventional T cell ratios early after allo-HCT. Our results identify a conserved, biologically unique, and targetable role of DLL4-Notch signaling in intestinal GVHD. Editor's summary: Acute graft-versus-host disease (aGVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation, and additional treatment strategies are urgently needed. Here, Tkachev et al. moved one candidate treatment, blockade of the Delta-like Notch ligand DLL4, closer to the clinic. DLL4 blockade has previously been shown to control aGVHD in mice, and here the authors found that that efficacy translated into nonhuman primate models. The authors also identified the mechanism by which the treatment may specifically control intestinal aGVHD; DLL4 blockade decreased effector T cell infiltration into the gut, thereby increasing the relative frequency of regulatory T cells. These studies highlight the clinical potential for targeting DLL4-Notch signaling for patients with aGVHD. —Courtney Malo [ABSTRACT FROM AUTHOR]

Published
2023
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38. Identification and Tracking of Alloreactive T Cell Clones in Rhesus Macaques Through the RM-scTCR-Seq Platform

Author

Massachusetts Institute of Technology. Department of Chemistry, Massachusetts Institute of Technology. Institute for Medical Engineering & Science, Koch Institute for Integrative Cancer Research at MIT, Ragon Institute of MGH, MIT and Harvard, Gerdemann, Ulrike, Fleming, Ryan A, Kaminski, James, McGuckin, Connor, Rui, Xianliang, Lane, Jennifer F, Keskula, Paula, Cagnin, Lorenzo, Shalek, Alex K, Tkachev, Victor, Kean, Leslie S, Massachusetts Institute of Technology. Department of Chemistry, Massachusetts Institute of Technology. Institute for Medical Engineering & Science, Koch Institute for Integrative Cancer Research at MIT, Ragon Institute of MGH, MIT and Harvard, Gerdemann, Ulrike, Fleming, Ryan A, Kaminski, James, McGuckin, Connor, Rui, Xianliang, Lane, Jennifer F, Keskula, Paula, Cagnin, Lorenzo, Shalek, Alex K, Tkachev, Victor, and Kean, Leslie S

Abstract

T cell receptor (TCR) clonotype tracking is a powerful tool for interrogating T cell mediated immune processes. New methods to pair a single cell’s transcriptional program with its TCR identity allow monitoring of T cell clonotype-specific transcriptional dynamics. While these technologies have been available for human and mouse T cells studies, they have not been developed for Rhesus Macaques (RM), a critical translational organism for autoimmune diseases, vaccine development and transplantation. We describe a new pipeline, ‘RM-scTCR-Seq’, which, for the first time, enables RM specific single cell TCR amplification, reconstruction and pairing of RM TCR’s with their transcriptional profiles. We apply this method to a RM model of GVHD, and identify and track in vitro detected alloreactive clonotypes in GVHD target organs and explore their GVHD driven cytotoxic T cell signature. This novel, state-of-the-art platform fundamentally advances the utility of RM to study protective and pathogenic T cell responses.

Published
2022

40. Evolutionarily conserved effects of Notch signaling drive intestinal graft-versus-host disease in mice and non-human primates

Author

Tkachev, Victor, primary, Vanderbeck, Ashley, additional, Perkey, Eric, additional, Furlan, Scott N., additional, McGuckin, Connor, additional, Atria, Daniela Gómez, additional, Gerdemann, Ulrike, additional, Rui, Xianliang, additional, Lane, Jennifer, additional, Hunt, Daniel J., additional, Zheng, Hengqi, additional, Colonna, Lucrezia, additional, Hoffman, Michelle, additional, Yu, Alison, additional, Kelly, Samantha, additional, Allman, Anneka, additional, Burbach, Brandon, additional, Shimizu, Yoji, additional, Panoskaltsis-Mortari, Angela, additional, Chen, Guoying, additional, Carpenter, Stephen M., additional, Harari, Olivier, additional, Kuhnert, Frank, additional, Thurston, Gavin, additional, Blazar, Bruce R., additional, Kean, Leslie S., additional, and Maillard, Ivan, additional

Published
2022
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45. In Vivo Delivery of RNA By Lipid Nanoparticles (LNP) to Hematopoietic Stem Cells and T Cells in Humanized Mice and Non-Human Primates

Author

Monte, Michael T., Gu, Han, Saunders, Laura, Gupta, Mohit, Liu, Lei, Wangweerawong, Apiwat, Colace, Thomas V., Zannini, Aaron, Tozzi, Lorenzo, Cao, Yu, Schiroli, Giulia, Salomon, William E., Rottman, James B., Palchaudhuri, Rahul, Gerdemann, Ulrike, Gorfinkel, Lev, Alvarez Calderon, Francesca, Kean, Leslie, Pujar, Hari, and Wang, Z. Jane

Published
2023
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46. Enhanced T Cell Function of PTPN2 Deleted CAR-T Cells Comes at a Cost: PTPN2 Knockout CAR-Ts Secrete More Cytokines and Demonstrate Increased Cytotoxicity, but Exhibit More Severe CRS and Icans in a Non-Human Primate Model

Author

Alvarez Calderon, Francesca, Fleming, Ryan A, Gorfinkel, Lev, Michaelis, Katherine, Rui, Xianliang, Kaminski, James, Bonin, Dana, Mallette, Anick, Brodeur, Katherine, Domingues, Heber, Lane, Jennifer, Tkachev, Victor, Kean, Leslie, and Gerdemann, Ulrike

Published
2023
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48. The metabolic function of cyclin D3CDK6 kinase in cancer cell survival

Author

Wang, Haizhen, Nicolay, Brandon N., Chick, Joel M., Gao, Xueliang, Geng, Yan, Ren, Hong, Gao, Hui, Yang, Guizhi, Williams, Juliet A., Suski, Jan M., Keibler, Mark A., Sicinska, Ewa, Gerdemann, Ulrike, Haining, W. Nicholas, Roberts, Thomas M., Polyak, Kornelia, Gygi, Steven P., Dyson, Nicholas J., and Sicinski, Piotr

Subjects
Cell proliferation -- Health aspects, Phosphotransferases -- Health aspects, Cancer cells -- Health aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Haizhen Wang [1, 2]; Brandon N. Nicolay [3]; Joel M. Chick [4]; Xueliang Gao [1, 5]; Yan Geng [1, 2]; Hong Ren [1, 2]; Hui Gao [6]; Guizhi Yang [...]

Published
2017
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50. Spatiotemporal single-cell profiling reveals that invasive and tissue-resident memory donor CD8 + T cells drive gastrointestinal acute graft-versus-host disease

Author

Tkachev, Victor, primary, Kaminski, James, additional, Potter, E. Lake, additional, Furlan, Scott N., additional, Yu, Alison, additional, Hunt, Daniel J., additional, McGuckin, Connor, additional, Zheng, Hengqi, additional, Colonna, Lucrezia, additional, Gerdemann, Ulrike, additional, Carlson, Judith, additional, Hoffman, Michelle, additional, Olvera, Joe, additional, English, Chris, additional, Baldessari, Audrey, additional, Panoskaltsis-Mortari, Angela, additional, Watkins, Benjamin, additional, Qayed, Muna, additional, Suessmuth, Yvonne, additional, Betz, Kayla, additional, Bratrude, Brandi, additional, Langston, Amelia, additional, Horan, John T., additional, Ordovas-Montanes, Jose, additional, Shalek, Alex K., additional, Blazar, Bruce R., additional, Roederer, Mario, additional, and Kean, Leslie S., additional

Published
2021
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