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.
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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

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Figure 4

Alterations of CMV viremia and CMV-specific IFN-γ+CD3+ T cells and tetramer+ CMVpp65VSTs in treated subjects.

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Alterations of CMV viremia and CMV-specific IFN-γ+CD3+ T cells and tetra...
Weekly CMV PCR measurements in subjects achieving (A) CR, (B) PR, and (C) not responding to therapy. Shaded bars represent time of response assessment. Maximum expansion of CMV-specific T cells isolated from the blood of treated subjects responding to or not responding to therapy was measured by IFN-γ and tetramer by subtracting the baseline number from the peak. (D) Number of CMVpp65-specific T cells (identified as IFN-γ+CD3+) in recipients of third-party CMVpp65VSTs responding to (blue) and not responding to (red) therapy. CD3+IFN-γ+ T cell numbers were calculated as a fraction of CD3+ T cells/μL. The absolute increase in the number of CD3+IFN-γ+ T cells (i.e., maximum minus baseline) identified in each subject within 70 days of infusion is plotted. The maximum increase of CMVpp65-specific CD3+IFN-γ+ T cells was not different in responders compared with nonresponders (P = 0.96). n = 28. (E) Number of CMVpp65-specific T cells (identified as TET+CD3+) in recipients of third-party CMVpp65VSTs responding to (blue) and not responding to (red) therapy. CD3+TET+ T cell numbers were calculated as a fraction of CD3+ T cells/μL. The absolute increase in the number of CD3+TET+ T cells identified in each subject within 70 days of infusion is plotted. The maximum increase in the number of CMVpp65-specific CD3+TET+ T cells was also not different in responders compared with nonresponders (P = 0.99). n = 21. Comparisons of the increases in CD3+IFN-γ+ T cells and TET+ T cells were analyzed using Wilcoxon’s rank-sum test.