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1. Overlap chronic GVHD is associated with adverse survival outcomes compared to classic chronic GVHD.

Author

Gorfinkel, Lev, Raghunandan, Sharmila, Watkins, Benjamin, Hebert, Kyle, Neuberg, Donna, Bratrude, Brandi, Betz, Kayla, Yu, Alison, Choi, Sung, Davis, Jeffrey, Duncan, Christine, Giller, Roger, Grimley, Michael, Harris, Andrew, Jacobsohn, David, Lalefar, Nahal, Farhadfar, Nosha, Pulsipher, Michael, Shenoy, Shalini, Petrovic, Aleksandra, Schultz, Kirk, Yanik, Gregory, Blazar, Bruce, Horan, John, Langston, Amelia, Kean, Leslie, and Qayed, Muna

Subjects
Humans, Graft vs Host Disease, Male, Female, Chronic Disease, Adult, Middle Aged, Disease-Free Survival, Hematopoietic Stem Cell Transplantation, Survival Rate, Aged
Abstract

Chronic graft-versus-host-disease (cGVHD) is divided into two subtypes: classic (absence of acute GVHD features) and overlap cGVHD (ocGVHD), in which both chronic and acute GVHD clinical features are present simultaneously. While worse outcomes with ocGVHD have been reported, there are few recent analyses. We performed a secondary analysis of data from the ABA2 trial (N = 185), in which detailed GVHD data were collected prospectively and systematically adjudicated. Analyses included cumulative incidence of classic versus ocGVHD, their specific organ manifestations, global disease severity scores, non-relapse mortality (NRM), disease-free survival (DFS) and overall survival (OS) in these two cGVHD subtypes. Of 92 patients who developed cGVHD, 35 were classified as ocGVHD. The 1-year cumulative incidence, organ involvement, and global severity of classic and ocGVHD were similar between ABA2 patients receiving CNI/MTX+placebo and CNI/MTX+abatacept; thus, cohorts were combined for ocGVHD evaluation. This analysis identified ocGVHD as having significantly higher severity at presentation and at maximum global severity compared to classic cGVHD. OS and DFS were significantly lower for ocGVHD versus classic cGVHD. OcGVHD is associated with increased cGVHD severity scores, and is associated with decreased OS and DFS compared to classic cGVHD, underscoring the high risks with this cGVHD subtype.

Published
2024

2. Harmonizing definitions for hematopoietic recovery, graft rejection, graft failure, poor graft function, and donor chimerism in allogeneic hematopoietic cell transplantation: a report on behalf of the EBMT, ASTCT, CIBMTR, and APBMT

Author

Sureda, Anna, Carpenter, Paul A., Bacigalupo, Andrea, Bhatt, Vijaya Raj, de la Fuente, Josu, Ho, Aloysius, Kean, Leslie, Lee, Jong Wook, Sánchez-Ortega, Isabel, Savani, Bipin N., Schetelig, Johannes, Stadtmauer, Edward A., Takahashi, Yoshiyuki, Atsuta, Yoshiko, Koreth, John, Kröger, Nicolaus, Ljungman, Per, Okamoto, Shinichiro, Popat, Uday, Soiffer, Robert, Stefanski, Heather E., and Kharfan-Dabaja, Mohamed A.

Published
2024
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3. Correction: Harmonizing definitions for hematopoietic recovery, graft rejection, graft failure, poor graft function, and donor chimerism in allogeneic hematopoietic cell transplantation: a report on behalf of the EBMT, ASTCT, CIBMTR, and APBMT

Author

Sureda, Anna, Carpenter, Paul A., Bacigalupo, Andrea, Bhatt, Vijaya Raj, de la Fuente, Josu, Ho, Aloysius, Kean, Leslie, Lee, Jong Wook, Sánchez-Ortega, Isabel, Savani, Bipin N., Schetelig, Johannes, Stadtmauer, Edward A., Takahashi, Yoshiyuki, Atsuta, Yoshiko, Koreth, John, Kröger, Nicolaus, Ljungman, Per, Okamoto, Shinichiro, Popat, Uday, Soiffer, Robert, Stefanski, Heather E., and Kharfan-Dabaja, Mohamed A.

Published
2024
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6. 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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8. Major breakthroughs in hematopoietic stem cell transplantation and future challenges in clinical implementation

Author

Kean, Leslie S. and Blazar, Bruce R.

Subjects
Leukemia, Stem cells, B cells, Cancer -- Care and treatment, Hematopoietic stem cells -- Transplantation, Health care industry
Abstract

The Haitian proverb 'Beyond mountains, there are mountains' has many meanings. One that resonates for hematopoietic stem cell transplantation (HCT) over the last 50-plus years is the sense that as [...]

Published
2024
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9. 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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10. Blood and Marrow Transplant Clinical Trials Network State of the Science Symposium 2021: Looking Forward as the Network Celebrates its 20th Year

Author

Heslop, Helen E, Stadtmauer, Edward A, Levine, John E, Ballen, Karen K, Chen, Yi-Bin, DeZern, Amy E, Eapen, Mary, Hamadani, Mehdi, Hamilton, Betty K, Hari, Parameswaran, Jones, Richard J, Logan, Brent R, Kean, Leslie S, Leifer, Eric S, Locke, Frederick L, Maziarz, Richard T, Nemecek, Eneida R, Pasquini, Marcelo, Phelan, Rachel, Riches, Marcie L, Shaw, Bronwen E, Walters, Mark C, Foley, Amy, Devine, Steven M, and Horowitz, Mary M

Subjects
Stem Cell Research, Clinical Trials and Supportive Activities, Transplantation, Clinical Research, Bone Marrow Transplantation, Clinical Trials as Topic, Hematopoietic Stem Cell Transplantation, Humans, Transplants, BMT, Cell Therapy, Clinical Trial
Abstract

In 2021 the BMT CTN held the 4th State of the Science Symposium where the deliberations of 11 committees concerning major topics pertinent to a particular disease, modality, or complication of transplant, as well as two committees to consider clinical trial design and inclusion, diversity, and access as cross-cutting themes were reviewed. This article summarizes the individual committee reports and their recommendations on the highest priority questions in hematopoietic stem cell transplant and cell therapy to address in multicenter trials.

Published
2021

11. The Adverse Event Landscape of Stem Cell Transplant: Evidence for aGVHD Driving Early Transplant Associated Toxicities

Author

Takahashi, Takuto, Watkins, Benjamin, Bratrude, Brandi, Neuberg, Donna, Hebert, Kyle, Betz, Kayla, Yu, Alison, Choi, Sung W, Davis, Jeffrey, Duncan, Christine, Giller, Roger, Grimley, Michael, Harris, Andrew C., Jacobsohn, David, Lalefar, Nahal, Farhadfar, Nosha, Pulsipher, Michael A., Shenoy, Shalini, Petrovic, Aleksandra, Schultz, Kirk R., Yanik, Gregory A., Blazar, Bruce R., Horan, John T., Langston, Amelia, Kean, Leslie S., and Qayed, Muna

Published
2024
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12. Phase II Trial of Costimulation Blockade With Abatacept for Prevention of Acute GVHD.

Author

Norkin, Maxim, Farhadfar, Nosha, Pulsipher, Michael, Shenoy, Shalini, Petrovic, Aleksandra, Schultz, Kirk, Yanik, Gregory, Waller, Edmund, Levine, John, Ferrara, James, Blazar, Bruce, Langston, Amelia, Horan, John, Kean, Leslie, Watkins, Benjamin, Qayed, Muna, McCracken, Courtney, Bratrude, Brandi, Betz, Kayla, Suessmuth, Yvonne, Yu, Alison, Sinclair, Shauna, Furlan, Scott, Bosinger, Steven, Tkachev, Victor, Rhodes, James, Tumlin, Audrey, Narayan, Alexandria, Cribbin, Kayla, Gillespie, Scott, Gooley, Ted, Pasquini, Marcelo, Hebert, Kyle, Kapoor, Urvi, Rogatko, Andre, Tighiouart, Mourad, Kim, Sungjin, Bresee, Catherine, Choi, Sung, Davis, Jeffrey, Duncan, Christine, Giller, Roger, Grimley, Michael, Harris, Andrew, Jacobsohn, David, and Lalefar, Nahal

Subjects
Abatacept, Adolescent, Adult, Aged, Child, Cyclosporine, Graft vs Host Disease, Hematopoietic Stem Cell Transplantation, Humans, Immunosuppressive Agents, Male, Methotrexate, Middle Aged, Tacrolimus, Young Adult
Abstract

PURPOSE: Severe (grade 3-4) acute graft-versus-host disease (AGVHD) is a major cause of death after unrelated-donor (URD) hematopoietic cell transplant (HCT), resulting in particularly high mortality after HLA-mismatched transplantation. There are no approved agents for AGVHD prevention, underscoring the critical unmet need for novel therapeutics. ABA2 was a phase II trial to rigorously assess safety, efficacy, and immunologic effects of adding T-cell costimulation blockade with abatacept to calcineurin inhibitor (CNI)/methotrexate (MTX)-based GVHD prophylaxis, to test whether abatacept could decrease AGVHD. METHODS: ABA2 enrolled adults and children with hematologic malignancies under two strata: a randomized, double-blind, placebo-controlled stratum (8/8-HLA-matched URD), comparing CNI/MTX plus abatacept with CNI/MTX plus placebo, and a single-arm stratum (7/8-HLA-mismatched URD) comparing CNI/MTX plus abatacept versus CNI/MTX CIBMTR controls. The primary end point was day +100 grade 3-4 AGVHD, with day +180 severe-AGVHD-free-survival (SGFS) a key secondary end point. Sample sizes were calculated using a higher type-1 error (0.2) as recommended for phase II trials, and were based on predicting that abatacept would reduce grade 3-4 AGVHD from 20% to 10% (8/8s) and 30% to 10% (7/8s). ABA2 enrolled 142 recipients (8/8s, median follow-up = 716 days) and 43 recipients (7/8s, median follow-up = 708 days). RESULTS: In 8/8s, grade 3-4 AGVHD was 6.8% (abatacept) versus 14.8% (placebo) (P = .13, hazard ratio = 0.45). SGFS was 93.2% (CNI/MTX plus abatacept) versus 82% (CNI/MTX plus placebo, P = .05). In the smaller 7/8 cohort, grade 3-4 AGVHD was 2.3% (CNI/MTX plus abatacept, intention-to-treat population), which compared favorably with a nonrandomized matched cohort of CNI/MTX (30.2%, P < .001), and the SGFS was better (97.7% v 58.7%, P < .001). Immunologic analysis revealed control of T-cell activation in abatacept-treated patients. CONCLUSION: Adding abatacept to URD HCT was safe, reduced AGVHD, and improved SGFS. These results suggest that abatacept may substantially improve AGVHD-related transplant outcomes, with a particularly beneficial impact on HLA-mismatched HCT.

Published
2021

13. Higher abatacept exposure after transplant decreases acute GVHD risk without increasing adverse events

Author

Takahashi, Takuto, Al-Kofahi, Mahmoud, Jaber, Mutaz, Bratrude, Brandi, Betz, Kayla, Suessmuth, Yvonne, Yu, Alison, Neuberg, Donna S., Choi, Sung W., Davis, Jeffrey, Duncan, Christine, Giller, Roger, Grimley, Michael, Harris, Andrew C., Jacobsohn, David, Lalefar, Nahal, Farhadfar, Nosha, Pulsipher, Michael A., Shenoy, Shalini, Petrovic, Aleksandra, Schultz, Kirk R., Yanik, Gregory A., Blazar, Bruce R., Horan, John T., Watkins, Benjamin, Langston, Amelia, Qayed, Muna, and Kean, Leslie S.

Published
2023
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15. Enforced gut homing of murine regulatory T cells reduces early graft-versus-host disease severity

Author

Larson, Jemma H., Jin, Sujeong, Loschi, Michael, Bolivar Wagers, Sara, Thangavelu, Govindarajan, Zaiken, Michael C., McDonald-Hyman, Cameron, Saha, Asim, Aguilar, Ethan G., Koehn, Brent, Osborn, Mark J., Panoskaltsis-Mortari, Angela, Macdonald, Kelli P.A., Hill, Geoffrey R., Murphy, William J., Serody, Jonathan S., Maillard, Ivan, Kean, Leslie S., Kim, Sangwon V., Littman, Dan R., and Blazar, Bruce R.

Published
2023
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16. Alemtuzumab and CXCL9 levels predict likelihood of sustained engraftment after reduced-intensity conditioning HCT

Author

Geerlinks, Ashley V., Scull, Brooks, Krupski, Christa, Fleischmann, Ryan, Pulsipher, Michael A., Eapen, Mary, Connelly, James A., Bollard, Catherine M., Pai, Sung-Yun, Duncan, Christine N., Kean, Leslie S., Baker, K. Scott, Burroughs, Lauri M., Andolina, Jeffrey R., Shenoy, Shalini, Roehrs, Philip, Hanna, Rabi, Talano, Julie-An, Schultz, Kirk R., Stenger, Elizabeth O., Lin, Howard, Zoref-Lorenz, Adi, McClain, Kenneth L., Jordan, Michael B., Man, Tsz-Kwong, Allen, Carl E., and Marsh, Rebecca A.

Published
2023
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17. 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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18. Unas memorias ofrecen un vistazo al interior de la caza de ovnis del Pentágono

Author

Blumenthal, Ralph and Kean, Leslie

Subjects
News, opinion and commentary
Abstract

En “Imminent”, un exfuncionario de inteligencia que dirigió un programa otrora secreto comparte algunas de las cosas que sabe. https://whatsapp.com/channel/0029VaYKhdv5q08fphYVt40M Luis Elizondo saltó a los titulares en 2017 cuando renunció [...]

Published
2024

19. One Insider's View Of a Hunt for U.F.O.s

Author

Blumenthal, Ralph and Kean, Leslie

Subjects
Company legal issue, Imminent: Inside the Pentagon's Hunt for U.F.O.s (Nonfiction work) -- Authorship, Unidentified flying objects -- Investigations, Intelligence officers -- Works -- Beliefs, opinions and attitudes, United States. Department of Defense -- Investigations
Abstract

In 'Imminent,' the former intelligence official who ran a once-secret program shares some of what he knows. Luis Elizondo made headlines in 2017 when he resigned as a senior intelligence [...]

Published
2024

20. A Memoir Offers an Insider’s Perspective Into the Pentagon’s U.F.O. Hunt

Author

Blumenthal, Ralph and Kean, Leslie

Subjects
Government contractors, Defense programs, News, opinion and commentary
Abstract

In “Imminent,” the former intelligence official who ran a once-secret program shares some of what he knows. Luis Elizondo made headlines in 2017 when he resigned as a senior intelligence [...]

Published
2024

23. 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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24. Retinoic acid signaling acts as a rheostat to balance Treg function

Author

Thangavelu, Govindarajan, Andrejeva, Gabriela, Bolivar-Wagers, Sara, Jin, Sujeong, Zaiken, Michael C., Loschi, Michael, Aguilar, Ethan G., Furlan, Scott N., Brown, Chrysothemis C., Lee, Yu-Chi, Hyman, Cameron McDonald, Feser, Colby J., Panoskaltsis-Mortari, Angela, Hippen, Keli L., MacDonald, Kelli P., Murphy, William J., Maillard, Ivan, Hill, Geoffrey R., Munn, David H., Zeiser, Robert, Kean, Leslie S., Rathmell, Jeffrey C., Chi, Hongbo, Noelle, Randolph J., and Blazar, Bruce R.

Published
2022
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25. BET-bromodomain and EZH2 inhibitor–treated chronic GVHD mice have blunted germinal centers with distinct transcriptomes

Author

Zaiken, Michael C., Flynn, Ryan, Paz, Katelyn G., Rhee, Stephanie Y., Jin, Sujeong, Mohamed, Fathima A., Saha, Asim, Thangavelu, Govindarajan, Park, Paul M.C., Hemming, Matthew L., Sage, Peter T., Sharpe, Arlene H., DuPage, Michel, Bluestone, Jeffrey A., Panoskaltsis-Mortari, Angela, Cutler, Corey S., Koreth, John, Antin, Joseph H., Soiffer, Robert J., Ritz, Jerome, Luznik, Leo, Maillard, Ivan, Hill, Geoffrey R., MacDonald, Kelli P.A., Munn, David H., Serody, Jonathan S., Murphy, William J., Kean, Leslie S., Zhang, Yi, Bradner, James E., Qi, Jun, and Blazar, Bruce R.

Published
2022
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26. 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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28. Standardizing Definitions of Hematopoietic Recovery, Graft Rejection, Graft Failure, Poor Graft Function, and Donor Chimerism in Allogeneic Hematopoietic Cell Transplantation: A Report on Behalf of the American Society for Transplantation and Cellular Therapy

Author

Kharfan-Dabaja, Mohamed A., Kumar, Ambuj, Ayala, Ernesto, Aljurf, Mahmoud, Nishihori, Taiga, Marsh, Rebecca, Burroughs, Lauri M., Majhail, Navneet, Al-Homsi, A. Samer, Al-Kadhimi, Zaid S., Bar, Merav, Bertaina, Alice, Boelens, Jaap J., Champlin, Richard, Chaudhury, Sonali, DeFilipp, Zachariah, Dholaria, Bhagirathbhai, El-Jawahri, Areej, Fanning, Suzanne, Fraint, Ellen, Gergis, Usama, Giralt, Sergio, Hamilton, Betty K., Hashmi, Shahrukh K., Horn, Biljana, Inamoto, Yoshihiro, Jacobsohn, David A, Jain, Tania, Johnston, Laura, Kanate, Abraham S., Kansagra, Ankit, Kassim, Adetola, Kean, Leslie S., Kitko, Carrie L., Knight-Perry, Jessica, Kurtzberg, Joanne, Liu, Hien, MacMillan, Margaret L., Mahmoudjafari, Zahra, Mielcarek, Marco, Mohty, Mohamad, Nagler, Arnon, Nemecek, Eneida, Olson, Timothy S., Oran, Betul, Perales, Miguel-Angel, Prockop, Susan E., Pulsipher, Michael A., Pusic, Iskra, Riches, Marcie L., Rodriguez, Cesar, Romee, Rizwan, Rondon, Gabriela, Saad, Ayman, Shah, Nina, Shaw, Peter J., Shenoy, Shalini, Sierra, Jorge, Talano, Julie, Verneris, Michael R., Veys, Paul, Wagner, John E., Savani, Bipin N., Hamadani, Mehdi, and Carpenter, Paul A.

Published
2021
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29. Repurposing a novel anti-cancer RXR agonist to attenuate murine acute GVHD and maintain graft-versus-leukemia responses

Author

Thangavelu, Govindarajan, Wang, Chao, Loschi, Michael, Saha, Asim, Osborn, Mark J., Furlan, Scott N., Aoyama, Kazutoshi, McDonald-Hyman, Cameron, Aguilar, Ethan G., Janesick, Amanda S., Chandraratna, Roshantha A., Refaeli, Yosef, Panoskaltsis-Mortari, Angela, MacDonald, Kelli P., Hill, Geoffrey R., Zeiser, Robert, Maillard, Ivan, Serody, Jonathan S., Murphy, William J., Munn, David H., Blumberg, Bruce, Brown, Chrysothemis, Kuchroo, Vijay, Kean, Leslie S., Hippen, Keli L., Noelle, Randolph J., and Blazar, Bruce R.

Published
2021
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30. 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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32. Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality

Author

Saha, Asim, O’Connor, Roddy S, Thangavelu, Govindarajan, Lovitch, Scott B, Dandamudi, Durga Bhavani, Wilson, Caleph B, Vincent, Benjamin G, Tkachev, Victor, Pawlicki, Jan M, Furlan, Scott N, Kean, Leslie S, Aoyama, Kazutoshi, Taylor, Patricia A, Panoskaltsis-Mortari, Angela, Foncea, Rocio, Ranganathan, Parvathi, Devine, Steven M, Burrill, Joel S, Guo, Lili, Sacristan, Catarina, Snyder, Nathaniel W, Blair, Ian A, Milone, Michael C, Dustin, Michael L, Riley, James L, Bernlohr, David A, Murphy, William J, Fife, Brian T, Munn, David H, Miller, Jeffrey S, Serody, Jonathan S, Freeman, Gordon J, Sharpe, Arlene H, Turka, Laurence A, and Blazar, Bruce R

Subjects
Transplantation, Cancer, Rare Diseases, Orphan Drug, Stem Cell Research, Stem Cell Research - Nonembryonic - Non-Human, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Animals, Apoptosis, B7-H1 Antigen, Bone Marrow Cells, Bone Marrow Transplantation, Cytokines, Female, Glucose, Glutamine, Glycolysis, Graft vs Host Disease, Humans, Inflammation, Leukocytes, Mononuclear, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Oxygen, Phosphorylation, Programmed Cell Death 1 Receptor, Signal Transduction, T-Lymphocytes, Treatment Outcome, Medical and Health Sciences, Immunology
Abstract

Programmed death ligand-1 (PD-L1) interaction with PD-1 induces T cell exhaustion and is a therapeutic target to enhance immune responses against cancer and chronic infections. In murine bone marrow transplant models, PD-L1 expression on host target tissues reduces the incidence of graft-versus-host disease (GVHD). PD-L1 is also expressed on T cells; however, it is unclear whether PD-L1 on this population influences immune function. Here, we examined the effects of PD-L1 modulation of T cell function in GVHD. In patients with severe GVHD, PD-L1 expression was increased on donor T cells. Compared with mice that received WT T cells, GVHD was reduced in animals that received T cells from Pdl1-/- donors. PD-L1-deficient T cells had reduced expression of gut homing receptors, diminished production of inflammatory cytokines, and enhanced rates of apoptosis. Moreover, multiple bioenergetic pathways, including aerobic glycolysis, oxidative phosphorylation, and fatty acid metabolism, were also reduced in T cells lacking PD-L1. Finally, the reduction of acute GVHD lethality in mice that received Pdl1-/- donor cells did not affect graft-versus-leukemia responses. These data demonstrate that PD-L1 selectively enhances T cell-mediated immune responses, suggesting a context-dependent function of the PD-1/PD-L1 axis, and suggest selective inhibition of PD-L1 on donor T cells as a potential strategy to prevent or ameliorate GVHD.

Published
2016

33. Innovations present in the primate interneuron repertoire

Author

Krienen, Fenna M., Goldman, Melissa, Zhang, Qiangge, C. H. del Rosario, Ricardo, Florio, Marta, Machold, Robert, Saunders, Arpiar, Levandowski, Kirsten, Zaniewski, Heather, Schuman, Benjamin, Wu, Carolyn, Lutservitz, Alyssa, Mullally, Christopher D., Reed, Nora, Bien, Elizabeth, Bortolin, Laura, Fernandez-Otero, Marian, Lin, Jessica D., Wysoker, Alec, Nemesh, James, Kulp, David, Burns, Monika, Tkachev, Victor, Smith, Richard, Walsh, Christopher A., Dimidschstein, Jordane, Rudy, Bernardo, S. Kean, Leslie, Berretta, Sabina, Fishell, Gord, Feng, Guoping, and McCarroll, Steven A.

Published
2020
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35. Concerted changes in the pediatric single-cell intestinal ecosystem before and after anti-TNF blockade

Author

Zheng, Hengqi Betty, primary, Doran, Benjamin A., additional, Kimler, Kyle, additional, Yu, Alison, additional, Tkachev, Victor, additional, Niederlova, Veronika, additional, Cribbin, Kayla, additional, Fleming, Ryan, additional, Bratrude, Brandi, additional, Betz, Kayla, additional, Cagnin, Lorenzo, additional, McGuckin, Connor, additional, Keskula, Paula, additional, Albanese, Alexandre, additional, Sacta, Maria, additional, de Sousa Casal, Joshua, additional, van Esch, Ruben, additional, Kwong, Andrew C., additional, Kummerlowe, Conner, additional, Taliaferro, Faith, additional, Fiaschi, Nathalie, additional, Kou, Baijun, additional, Coetzee, Sandra, additional, Jalal, Sumreen, additional, Yabe, Yoko, additional, Dobosz, Michael, additional, Wipperman, Matthew F., additional, Hamon, Sara, additional, Kalliolias, George D., additional, Hooper, Andrea, additional, Lim, Wei Keat, additional, Haxhinasto, Sokol, additional, Wei, Yi, additional, Ford, Madeline, additional, Ambartsumyan, Lusine, additional, Suskind, David L., additional, Lee, Dale, additional, Deutsch, Gail, additional, Deng, Xuemei, additional, Collen, Lauren V., additional, Mitsialis, Vanessa, additional, Snapper, Scott B., additional, Wahbeh, Ghassan, additional, Shalek, Alex K., additional, Ordovas-Montanes, Jose, additional, and Kean, Leslie S., additional

Published
2023
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36. 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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37. 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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38. Reduced-intensity conditioning for hematopoietic cell transplant for HLH and primary immune deficiencies

Author

Allen, Carl E., Marsh, Rebecca, Dawson, Peter, Bollard, Catherine M., Shenoy, Shalini, Roehrs, Philip, Hanna, Rabi, Burroughs, Lauri, Kean, Leslie, Talano, Julie-An, Schultz, Kirk R., Pai, Sung-Yun, Baker, K. Scott, Andolina, Jeffrey R., Stenger, Elizabeth O., Connelly, James, Ramirez, Alyssa, Bryant, Christopher, Eapen, Mary, and Pulsipher, Michael A.

Published
2018
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42. Overlap chronic GVHD is associated with adverse survival outcomes compared to classic chronic GVHD

Author

Kean, Leslie, primary, Gorfinkel, Lev, additional, Raghunandan, Sharmila, additional, Watkins, Benjamin, additional, Hebert, Kyle, additional, Neuberg, Donna, additional, Bratrude, Brandi, additional, Betz, Kayla, additional, Yu, Alison, additional, Choi, Sung Won, additional, Davis, Jeffrey, additional, Duncan, Christine, additional, Giller, Roger, additional, Grimley, Michael, additional, Harris, Andrew, additional, Jacobsohn, David, additional, Lalefar, Nahal, additional, Farhadfar, Nosha, additional, Pulsipher, Michael, additional, Shenoy, Shalini, additional, Petrovic, Aleksandra, additional, Schultz, Kirk, additional, Yanik, Greg, additional, Blazar, Bruce, additional, HOran, John, additional, Langston, Amelia, additional, and Qayed, Muna, additional

Published
2023
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43. Abatacept for The Prevention of GVHD in Patients Receiving Mismatched Unrelated Transplants: A Real-World Analysis

Author

Raghunandan, Sharmila, primary, Gorfinkel, Lev, additional, Graiser, Michael, additional, Bratrude, Brandi, additional, Suessmuth, Yvonne, additional, Gillespie, Scott, additional, Westbrook, Adrianna L, additional, Williams, Kirsten M., additional, Schoettler, Michelle L, additional, Kean, Leslie S, additional, Horan, John T, additional, Langston, Amelia A, additional, Qayed, Muna, additional, and Watkins, Benjamin, additional

Published
2023
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45. Omics

Author

Paczesny, Sophie, primary and Kean, Leslie, additional

Published
2019
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46. Contributors

Author

Aguilar, Ethan George, primary, Alatrash, Gheath, additional, Anasetti, Claudio, additional, Arvindam, Upasana Sunil, additional, Blazar, Bruce R., additional, Bousso, Philippe, additional, Byersdorfer, Craig, additional, Chilkulwar, Abhishek R., additional, Coghill, James M., additional, Cooke, Kenneth R., additional, Crain, Alyssa K., additional, Drobyski, William R., additional, Dudakov, Jarrod A., additional, Edinger, Matthias, additional, Felices, Martin, additional, Fry, Terry J., additional, Fowler, Daniel H., additional, Goulmy, Els, additional, Hanash, Alan M., additional, Hill, Geoffrey R., additional, Hoffmann, Petra, additional, Holler, Ernst, additional, Holtan, Shernan, additional, Jacoby, Elad, additional, Jenq, Robert R., additional, Kean, Leslie, additional, Levy, Robert B., additional, Markey, Kate A., additional, Martin, Paul J., additional, Michonneau, David, additional, Miller, Jeffrey, additional, Molldrem, Jeffrey J., additional, Murphy, William, additional, Mutis, Tuna, additional, Negrin, Robert S., additional, Paczesny, Sophie, additional, Penack, Olaf, additional, Petersdorf, Effie, additional, Piper, Clint, additional, Reddy, Pavan, additional, Ritz, Jerome, additional, Sarantopoulos, Stefanie, additional, Serody, Jonathan S., additional, Socié, Gérard, additional, Takashima, Shuichiro, additional, van den Brink, Marcel R.M., additional, Weber, Daniela, additional, Wu, Yongxia, additional, Yu, Xue-Zhong, additional, and Zeiser, Robert, additional

Published
2019
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48. CD28 blockade controls T cell activation to prevent graft-versus-host disease in primates

Author

Watkins, Benjamin K., Tkachev, Victor, Furlan, Scott N., Hunt, Daniel J., Betz, Kayla, Yu, Alison, Brown, Melanie, Poirier, Nicolas, Zheng, Hengqi Betty, Taraseviciute, Agne, Colonna, Lucrezia, Mary, Caroline, Blancho, Gilles, Soulillou, Jean-Paul, Panoskaltsis- Mortari, Angela, Sharma, Prachi, Garcia, Anapatricia, Strobert, Elizabeth, Hamby, Kelly, Garret, Aneesah, Deane, Taylor, Blazar, Bruce R., Vanhove, Bernard, and Kean, Leslie S.

Subjects
Graft vs. host disease -- Care and treatment -- Models, Immune response -- Health aspects, Membrane proteins -- Physiological aspects -- Health aspects, T cells -- Physiological aspects -- Health aspects, Health care industry
Abstract

Controlling graft-versus-host disease (GVHD) remains a major unmet need in stem cell transplantation, and new, targeted therapies are being actively developed. CD28-CD80/86 costimulation blockade represents a promising strategy, but targeting CD80/CD86 with CTLA4-Ig may be associated with undesired blockade of coinhibitory pathways. In contrast, targeted blockade of CD28 exclusively inhibits T cell costimulation and may more potently prevent GVHD. Here, we investigated FR104, an antagonistic CD28-specific pegylated-Fab', in the nonhuman primate (NHP) GVHD model and completed a multiparameter interrogation comparing it with CTLA4-Ig, with and without sirolimus, including clinical, histopathologic, flow cytometric, and transcriptomic analyses. We document that FR104 monoprophylaxis and combined prophylaxis with FR104/sirolimus led to enhanced control of effector T cell proliferation and activation compared with the use of CTLA4-Ig or CTLA4- Ig/sirolimus. Importantly, FR104/sirolimus did not lead to a beneficial impact on Treg reconstitution or homeostasis, consistent with control of conventional T cell activation and IL-2 production needed to support Tregs. While FR104/sirolimus had a salutary effect on GVHD-free survival, overall survival was not improved, due to death in the absence of GVHD in several FR104/ sirolimus recipients in the setting of sepsis and a paralyzed INF-[gamma] response. These results therefore suggest that effectively deploying CD28 in the clinic will require close scrutiny of both the benefits and risks of extensively abrogating conventional T cell activation after transplant., Introduction Graft-versus-host disease (GVHD) represents a major cause of mortality after hematopoietic stem cell transplant (HCT) (1-4), and despite substantial effort, the control of GVHD remains one of the key [...]

Published
2018
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49. Insights from integrating clinical and preclinical studies advance understanding of graft-versus-host disease

Author

Socie, Gerard, Kean, Leslie S., Zeiser, Robert, and Blazar, Bruce R.

Subjects
Immunological research, Graft versus host reaction -- Development and progression -- Care and treatment -- Research, Hematopoietic stem cells -- Transplantation, Translational research, Health care industry
Abstract

As a result of impressive increases in our knowledge of rodent and human immunology, the understanding of the pathophysiologic mechanisms underlying graft-versus-host disease (GVHD) has dramatically improved in the past 15 years. Despite improved knowledge, translation to clinical care has not proceeded rapidly, and results from experimental models have been inconsistent in their ability to predict the clinical utility of new therapeutic agents. In parallel, new tools in immunology have allowed in-depth analyses of the human system and have recently been applied in the field of clinical GVHD. Notwithstanding these advances, there is a relative paucity of mechanistic insights into human translational research, and this remains an area of high unmet need. Here we review selected recent advances in both preclinical experimental transplantation and translational human studies, including new insights into human immunology, the microbiome, and regenerative medicine. We focus on the fact that both approaches can interactively improve our understanding of both acute and chronic GVHD biology and open the door to improved therapeutics and successes., Introduction Graft-versus-host disease (GVHD) remains the leading cause of nonrelapse death in patients who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) (1). While GVHD classically was clinically divided into acute [...]

Published
2021
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