Abstract

Viral infections remain a major risk in immunocompromised pediatric patients, and virus-specific T cell (VST) therapy has been successful for treatment of refractory viral infections in prior studies. We performed a phase II multicenter study (NCT03475212) for the treatment of pediatric patients with inborn errors of immunity and/or post allogeneic hematopoietic stem cell transplant with refractory viral infections using partially-HLA matched VSTs targeting cytomegalovirus, Epstein-Barr virus, or adenovirus. Primary endpoints were feasibility, safety, and clinical responses (>1 log reduction in viremia at 28 days). Secondary endpoints were reconstitution of antiviral immunity and persistence of the infused VSTs. Suitable VST products were identified for 75 of 77 clinical queries. Clinical responses were achieved in 29 of 47 (62%) of patients post-HSCT including 73% of patients evaluable at 1-month post-infusion, meeting the primary efficacy endpoint (>52%). Secondary graft rejection occurred in one child following VST infusion as described in a companion article. Corticosteroids, graft-versus-host disease, transplant-associated thrombotic microangiopathy, and eculizumab treatment correlated with poor response, while uptrending absolute lymphocyte and CD8 T cell counts correlated with good response. This study highlights key clinical factors that impact response to VSTs and demonstrates the feasibility and efficacy of this therapy in pediatric HSCT.

Viral infection is a common risk for immune-compromised individuals, particularly pediatric patients receiving hematopoietic stem cell transplants. Here the authors report a phase II trial testing adoptive transfer of third party, virus-specific T cells on the feasibility, safety, clinical responses, as well as homeostasis of antiviral immunity in the recipients.

Details

Title
Antiviral cellular therapy for enhancing T-cell reconstitution before or after hematopoietic stem cell transplantation (ACES): a two-arm, open label phase II interventional trial of pediatric patients with risk factor assessment
Author
Keller, Michael D. 1   VIAFID ORCID Logo  ; Hanley, Patrick J. 2 ; Chi, Yueh-Yun 3 ; Aguayo-Hiraldo, Paibel 4   VIAFID ORCID Logo  ; Dvorak, Christopher C. 5   VIAFID ORCID Logo  ; Verneris, Michael R. 6 ; Kohn, Donald B. 7 ; Pai, Sung-Yun 8   VIAFID ORCID Logo  ; Dávila Saldaña, Blachy J. 9 ; Hanisch, Benjamin 10 ; Quigg, Troy C. 11   VIAFID ORCID Logo  ; Adams, Roberta H. 12 ; Dahlberg, Ann 13 ; Chandrakasan, Shanmuganathan 14   VIAFID ORCID Logo  ; Hasan, Hasibul 4 ; Malvar, Jemily 4 ; Jensen-Wachspress, Mariah A. 15 ; Lazarski, Christopher A. 15   VIAFID ORCID Logo  ; Sani, Gelina 15 ; Idso, John M. 15 ; Lang, Haili 15 ; Chansky, Pamela 15   VIAFID ORCID Logo  ; McCann, Chase D. 15 ; Tanna, Jay 15 ; Abraham, Allistair A. 2 ; Webb, Jennifer L. 16 ; Shibli, Abeer 15 ; Keating, Amy K. 17 ; Satwani, Prakash 18 ; Muranski, Pawel 19 ; Hall, Erin 20 ; Eckrich, Michael J. 21 ; Shereck, Evan 22 ; Miller, Holly 12 ; Mamcarz, Ewelina 23 ; Agarwal, Rajni 24 ; De Oliveira, Satiro N. 25   VIAFID ORCID Logo  ; Vander Lugt, Mark T. 26 ; Ebens, Christen L. 27 ; Aquino, Victor M. 28 ; Bednarski, Jeffrey J. 29   VIAFID ORCID Logo  ; Chu, Julia 5   VIAFID ORCID Logo  ; Parikh, Suhag 14 ; Whangbo, Jennifer 30 ; Lionakis, Michail 31   VIAFID ORCID Logo  ; Zambidis, Elias T. 32 ; Gourdine, Elizabeth 4 ; Bollard, Catherine M. 2   VIAFID ORCID Logo  ; Pulsipher, Michael A. 33 

1  Children’s National Hospital, Center for Cancer & Immunology Research, Washington, USA (GRID:grid.239560.b) (ISNI:0000 0004 0482 1586); Children’s National Hospital, Division of Allergy and Immunology, Washington, USA (GRID:grid.239560.b) (ISNI:0000 0004 0482 1586); George Washington University School of Medicine, GW Cancer Center, Washington, USA (GRID:grid.253615.6) (ISNI:0000 0004 1936 9510) 
2  Children’s National Hospital, Center for Cancer & Immunology Research, Washington, USA (GRID:grid.239560.b) (ISNI:0000 0004 0482 1586); George Washington University School of Medicine, GW Cancer Center, Washington, USA (GRID:grid.253615.6) (ISNI:0000 0004 1936 9510); Children’s National Hospital, Division of Blood and Marrow Transplantation, Washington, USA (GRID:grid.239560.b) (ISNI:0000 0004 0482 1586) 
3  University of Southern California, Department of Pediatrics and Preventative Medicine, Los Angeles, USA (GRID:grid.42505.36) (ISNI:0000 0001 2156 6853) 
4  Children’s Hospital of Los Angeles, Cancer and blood disease institute, Los Angeles, USA (GRID:grid.239546.f) (ISNI:0000 0001 2153 6013) 
5  University of California San Francisco, Division of Pediatric Allergy, Immunology, and BMT, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
6  Children’s Hospital Colorado and University of Colorado, Department of Pediatrics and Division of Child’s Cancer and Blood Disorders, Denver, USA (GRID:grid.413957.d) (ISNI:0000 0001 0690 7621) 
7  University of California, Los Angeles, Department of Microbiology, Immunology & Molecular Genetics and Department of Pediatrics David Geffen School of Medicine, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718); University of California, Los Angeles, Division of Hematology/Oncology, Los Angeles, USA (GRID:grid.468726.9) (ISNI:0000 0004 0486 2046) 
8  National Cancer Institute, Immune Deficiency Cellular Therapy Program, Center for Cancer Research, Bethesda, USA (GRID:grid.48336.3a) (ISNI:0000 0004 1936 8075) 
9  Children’s National Hospital, Center for Cancer & Immunology Research, Washington, USA (GRID:grid.239560.b) (ISNI:0000 0004 0482 1586); Children’s National Hospital, Division of Blood and Marrow Transplantation, Washington, USA (GRID:grid.239560.b) (ISNI:0000 0004 0482 1586) 
10  Children’s National Hospital, Division of Pediatric Infectious Diseases, Washington, USA (GRID:grid.239560.b) (ISNI:0000 0004 0482 1586) 
11  Helen DeVos Children’s Hospital, Pediatric Blood & Bone Marrow Transplant and Cellular Therapy, Grand Rapids, USA (GRID:grid.413656.3) (ISNI:0000 0004 0450 6121) 
12  Phoenix Children’s/Mayo Clinic Arizona, Center for Cancer and Blood Disorders, Phoenix, USA (GRID:grid.477919.5) (ISNI:0000 0004 0546 4701) 
13  Fred Hutch Cancer Center/Seattle Children’s Hospital/University of Washington, Clinical Research Division, Seattle, USA (GRID:grid.270240.3) (ISNI:0000 0001 2180 1622) 
14  Children’s Healthcare of Atlanta, Aflac Cancer and Blood Disorders Center, Atlanta, USA (GRID:grid.428158.2) (ISNI:0000 0004 0371 6071) 
15  Children’s National Hospital, Center for Cancer & Immunology Research, Washington, USA (GRID:grid.239560.b) (ISNI:0000 0004 0482 1586) 
16  Children’s National Hospital, Center for Cancer & Immunology Research, Washington, USA (GRID:grid.239560.b) (ISNI:0000 0004 0482 1586); Children’s National Hospital, Division of Hematology, Washington, USA (GRID:grid.239560.b) (ISNI:0000 0004 0482 1586) 
17  Dana-Farber Cancer Institute and Boston Children’s Hospital, Pediatric Stem Cell Transplant, Boston, USA (GRID:grid.2515.3) (ISNI:0000 0004 0378 8438) 
18  Columbia University Medical Center, Division of Pediatric Hematology/Oncology and Stem Cell Transplantation, New York, USA (GRID:grid.239585.0) (ISNI:0000 0001 2285 2675) 
19  Columbia University Medical Center, Division of Pediatric Hematology/Oncology and Stem Cell Transplantation, New York, USA (GRID:grid.239585.0) (ISNI:0000 0001 2285 2675); Columbia University Medical Center, Columbia Center for Translational Immunology, New York, USA (GRID:grid.239585.0) (ISNI:0000 0001 2285 2675) 
20  Children’s Mercy Kansas City, Division of Pediatric Hematology/Oncology/Bone Marrow Transplant, Kansas City, USA (GRID:grid.239559.1) (ISNI:0000 0004 0415 5050) 
21  Wake Forest School of Medicine, Pediatric Transplant and Cellular Therapy, Levine Children’s Hospital, Charlotte, USA (GRID:grid.415907.e) (ISNI:0000 0004 0411 7193) 
22  Oregon Health & Science Univ, Division of Hematology and Oncology, Portland, USA (GRID:grid.5288.7) (ISNI:0000 0000 9758 5690) 
23  St. Jude Children’s Research Hospital, Department of Bone Marrow Transplantation and Cellular Therapy, Memphis, USA (GRID:grid.240871.8) (ISNI:0000 0001 0224 711X) 
24  Stanford University, Division of Pediatric Hematology/Oncology, Stem Cell Transplantation and Regenerative Medicine, Palo Alto, USA (GRID:grid.168010.e) (ISNI:0000 0004 1936 8956) 
25  University of California, Los Angeles, Division of Hematology/Oncology, Los Angeles, USA (GRID:grid.468726.9) (ISNI:0000 0004 0486 2046) 
26  University of Michigan, Division of Pediatric Hematology/Oncology/BMT, C.S. Mott Children’s Hospital, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370) 
27  University of Minnesota MHealth Fairview Masonic Children’s Hospital, Division of Pediatric Blood and Marrow Transplant & Cellular Therapy, Minneapolis, USA (GRID:grid.412981.7) (ISNI:0000 0000 9433 4896) 
28  University of Texas, Southwestern Medical Center Dallas, Division of Pediatric Hematology/Oncology, Dallas, USA (GRID:grid.267313.2) (ISNI:0000 0000 9482 7121) 
29  Washington University School of Medicine, Department of Pediatrics, Division of Pediatric Hematology and Oncology, St Louis, USA (GRID:grid.4367.6) (ISNI:0000 0001 2355 7002) 
30  Dana Farber Institute and Boston Children’s Hospital, Cancer and Blood Disorders Center, Boston, USA (GRID:grid.2515.3) (ISNI:0000 0004 0378 8438) 
31  National Institute of Allergy and Infectious Diseases, Laboratory of Clinical Immunology & Microbiology, Bethesda, USA (GRID:grid.419681.3) (ISNI:0000 0001 2164 9667) 
32  Johns Hopkins University School of Medicine, Pediatric Blood and Marrow Transplantation Program, Sidney Kimmel Comprehensive Cancer Center, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
33  Spencer Fox Eccles School of Medicine at the University of Utah, Division of Pediatric Hematology/Oncology, Intermountain Primary Children’s Hospital, Huntsman Cancer Institute, Salt Lake City, USA (GRID:grid.479969.c) (ISNI:0000 0004 0422 3447) 
Pages
3258
Publication year
2024
Publication date
2024
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-024-47057-2
ProQuest document ID
3040992493
Copyright
© The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.