Third-party cytomegalovirus-specific T cells improved survival in refractory cytomegalovirus viremia after hematopoietic transplant
Susan E. Prockop, … , James W. Young, Richard J. O’Reilly
Susan E. Prockop, … , James W. Young, Richard J. O’Reilly
Published March 23, 2023
Citation Information: J Clin Invest. 2023;133(10):e165476. https://doi.org/10.1172/JCI165476.
View: Text | PDF
Clinical Medicine Infectious disease Transplantation

Third-party cytomegalovirus-specific T cells improved survival in refractory cytomegalovirus viremia after hematopoietic transplant

Abstract

Background Refractory CMV viremia and disease are associated with significant morbidity and mortality in recipients of hematopoietic stem cell transplant (HCT).Methods In phase I/II trials, we treated 67 subjects for CMV viremia or disease arising after HCT with adoptive transfer of banked, third-party, CMVpp65-sensitized T cells (CMVpp65-VSTs). All were evaluable for toxicity and 59 for response. Evaluable subjects had CMV disease or persisting viremia that had failed at least 2 weeks of induction therapy with a median of 3 antiviral drugs; 84.7% had more than 3 of 11 high-risk features. CMVpp65-VSTs were specific for 1 to 3 CMVpp65 epitopes, presented by a limited set of HLA class I or II alleles, and were selected based on high-resolution HLA matching at 2 of 10 HLA alleles and matching for subject and subject’s HCT donor for 1 or more alleles through which the CMVpp65-VSTs were restricted.Results T cell infusions were well tolerated. Of 59 subjects evaluable for response, 38 (64%) achieved complete or durable partial responses.Conclusions Recipients responding to CMVpp65VSTs experienced an improved overall survival. Of the risk factors evaluated, transplant type, recipient CD4+ and CD8+ T cell levels prior to adoptive therapy, and the HLA restriction of CMVpp65-VSTs infused each significantly affected responses. In addition, CMVpp65-specific T cells of HCT donor or recipient origin contributed to the durability of both complete and partial responses.Trial Registration NCT00674648; NCT01646645; NCT02136797 (NIH).Funding NIH (P01 CA23766, R21 CA162002 and P30 CA008748); Aubrey Fund; Claire Tow Foundation; Major Family Foundation; “Rick” Eisemann Pediatric Research Fund; Banbury Foundation; Edith Robertson Foundation; Larry Smead Foundation.

Authors

Susan E. Prockop, Aisha Hasan, Ekaterina Doubrovina, Parastoo B. Dahi, Irene Rodriguez-Sanchez, Michael Curry, Audrey Mauguen, Genovefa A. Papanicolaou, Yiqi Su, JinJuan Yao, Maria Arcila, Farid Boulad, Hugo Castro-Malaspina, Christina Cho, Kevin J. Curran, Sergio Giralt, Nancy A. Kernan, Guenther Koehne, Ann Jakubowski, Esperanza Papadopoulos, Miguel-Angel Perales, Ioannis Politikos, Keith Price, Annamalai Selvakumar, Craig S. Sauter, Roni Tamari, Teresa Vizconde, James W. Young, Richard J. O’Reilly

×

Figure 3

OS and cumulative incidence of CMV-related deaths in subjects responding and not responding to CMVpp65VST therapy.

Options: View larger image (or click on image) Download as PowerPoint
OS and cumulative incidence of CMV-related deaths in subjects responding...
Kaplan-Meier OS (A) and Aalen-Johnson estimates of the cumulative incidence of CMV-related death (B) in recipients of CMVpp65-VSTs responding to (blue) and not responding to therapy (red) as well as those not evaluable (NO-N/E-Tx) (green) for response. Responders (blue) had longer OS compared with nonresponders (red) (log-rank test P < 0.001), but there was no difference between responders and nonevaluable (green) subjects (log-rank test, P = 0.9). Nonresponders died more of CMV than responders (Gray’s test, P = 0.001), and there was no difference between nonevaluable subjects and responders (Gray’s test, P = 0.42).