Browsing by Author "Cutler, Corey S."

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    An activated Th17-prone T cell subset involved in chronic graft-versus-host disease sensitive to pharmacological inhibition
    (American Society for Clinical Investigation, 2017-06-15) Forcade, Edouard; Paz, Katelyn; Flynn, Ryan; Griesenauer, Brad; Amet, Tohti; Li, Wei; Liu, Liangyi; Bakoyannis, Giorgos; Jiang, Di; Chu, Hong Wei; Lobera, Mercedes; Yang, Jianfei; Wilkes, David S.; Du, Jing; Gartlan, Kate; Hill, Geoffrey R.; MacDonald, Kelli P.A.; Espada, Eduardo L.; Blanco, Patrick; Serody, Jonathan S.; Koreth, John; Cutler, Corey S.; Antin, Joseph H.; Soiffer, Robert J.; Ritz, Jerome; Paczesny, Sophie; Blazar, Bruce R.; Pediatrics, School of Medicine
    Chronic graft-versus-host disease (cGvHD) remains a major complication of allogeneic stem cell transplantation requiring novel therapies. CD146 and CCR5 are expressed by activated T cells and associated with increased T cell migration capacity and Th17 polarization. We performed a multiparametric flow cytometry analysis in a cohort of 40 HSCT patients together with a cGvHD murine model to understand the role of CD146-expressing subsets. We observed an increased frequency of CD146+ CD4 T cells in the 20 patients with active cGvHD with enhanced RORγt expression. This Th17-prone subset was enriched for cells coexpressing CD146 and CCR5 that harbor mixed Th1/Th17 features and were more frequent in cGvHD patients. Utilizing a murine cGvHD model with bronchiolitis obliterans (BO), we observed that donor T cells from CD146-deficient mice versus those from WT mice caused significantly reduced pulmonary cGvHD. Reduced cGvHD was not the result of failed germinal center B cell or T follicular helper cell generation. Instead, CD146-deficient T cells had significantly lower pulmonary macrophage infiltration and T cell CCR5, IL-17, and IFN-γ coexpression, suggesting defective pulmonary end-organ effector mechanisms. We, thus, evaluated the effect of TMP778, a small-molecule RORγt activity inhibitor. TMP778 markedly alleviated cGvHD in murine models similarly to agents targeting the Th17 pathway, such as STAT3 inhibitor or IL-17-blocking antibody. Our data suggest CD146-expressing T cells as a cGvHD biomarker and suggest that targeting the Th17 pathway may represent a promising therapy for cGvHD.
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    Survival following allogeneic transplant in patients with myelofibrosis
    (American Society of Hematology, 2020-05-08) Gowin, Krisstina; Ballen, Karen; Ahn, Kwang Woo; Hu, Zhen-Huan; Ali, Haris; Arcasoy, Murat O.; Devlin, Rebecca; Coakley, Maria; Gerds, Aaron T.; Green, Michael; Gupta, Vikas; Hobbs, Gabriela; Jain, Tania; Kandarpa, Malathi; Komrokji, Rami; Kuykendall, Andrew T.; Luber, Kierstin; Masarova, Lucia; Michaelis, Laura C.; Patches, Sarah; Pariser, Ashley C.; Rampal, Raajit; Stein, Brady; Talpaz, Moshe; Verstovsek, Srdan; Wadleigh, Martha; Agrawal, Vaibhav; Aljurf, Mahmoud; Diaz, Miguel Angel; Avalos, Belinda R.; Bacher, Ulrike; Bashey, Asad; Beitinjaneh, Amer M.; Cerny, Jan; Chhabra, Saurabh; Copelan, Edward; Cutler, Corey S.; DeFilipp, Zachariah; Gadalla, Shahinaz M.; Ganguly, Siddhartha; Grunwald, Michael R.; Hashmi, Shahrukh K.; Kharfan-Dabaja, Mohamed A.; Kindwall-Keller, Tamila; Kröger, Nicolaus; Lazarus, Hillard M.; Liesveld, Jane L.; Litzow, Mark R.; Marks, David I.; Nathan, Sunita; Nishihori, Taiga; Olsson, Richard F.; Pawarod, Attaphol; Rowe, Jacob M.; Savani, Bipin N.; Savoie, Mary Lynn; Seo, Sachiko; Solh, Melhem; Tamari, Roni; Verdonck, Leo F.; Yared, Jean A.; Alyea, Edwin; Popat, Uday; Sobecks, Ronald; Scott, Bart L.; Nakamura, Ryotaro; Mesa, Ruben; Saber, Wael; Medicine, School of Medicine
    Allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for myelofibrosis (MF). In this large multicenter retrospective study, overall survival (OS) in MF patients treated with allogeneic HCT (551 patients) and without HCT (non-HCT) (1377 patients) was analyzed with Cox proportional hazards model. Survival analysis stratified by the Dynamic International Prognostic Scoring System (DIPSS) revealed that the first year of treatment arm assignment, due to upfront risk of transplant-related mortality (TRM), HCT was associated with inferior OS compared with non-HCT (non-HCT vs HCT: DIPSS intermediate 1 [Int-1]: hazard ratio [HR] = 0.26, P < .0001; DIPSS-Int-2 and higher: HR, 0.39, P < .0001). Similarly, in the DIPSS low-risk MF group, due to upfront TRM risk, OS was superior with non-HCT therapies compared with HCT in the first-year post treatment arm assignment (HR, 0.16, P = .006). However, after 1 year, OS was not significantly different (HR, 1.38, P = .451). Beyond 1 year of treatment arm assignment, an OS advantage with HCT therapy in Int-1 and higher DIPSS score patients was observed (non-HCT vs HCT: DIPSS-Int-1: HR, 2.64, P < .0001; DIPSS-Int-2 and higher: HR, 2.55, P < .0001). In conclusion, long-term OS advantage with HCT was observed for patients with Int-1 or higher risk MF, but at the cost of early TRM. The magnitude of OS benefit with HCT increased as DIPSS risk score increased and became apparent with longer follow-up.