Third-party cytomegalovirus-specific T cells improved survival in refractory cytomegalovirus viremia after hematopoietic transplant
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
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
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Clinical Research and Public Health Infectious disease

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

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Figure 6

Identification of the origin of CMVpp65-specific T cells circulating after infusion.

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Identification of the origin of CMVpp65-specific T cells circulating aft...
Four recipients of CMVpp65-VSTs all had undetectable CMV-specific T cells by IFN-γ and/or tetramer at baseline. (A) UPN 4417 CMV-seropositive recipient and HCT donor. Unique STR profile for recipient, HCT donor, and third-party donor–derived CMVpp65-VSTs with third-party CMVpp65VSTs identified 56 days after infusion. (B) UPN 2386 CMV-seropositive recipient and seronegative HCT donor with identification of HCT donor–derived CMV–specific T cells identified 56 days after initial infusion. (C) UPN 3907.CMV-seropositive recipient and seronegative HCT donor treated for isolated CNS disease and with identification of HCT donor–derived CMV-specific T cells identified 56 days after initial infusion. (D) UPN 5653 CMV–seropositive recipient and seronegative HCT donor with identification of both recipient and HCT donor–derived CMV-specific T cells identified 35 days after initial infusion.