Long-term control of recurrent or refractory viral infections after allogeneic HSCT with third-party virus-specific T cells

Barbara Withers; Emily Blyth; Leighton E. Clancy; Agnes Yong; Chris Fraser; Jane Burgess; Renee Simms; Rebecca Brown; David Kliman; Ming-Celine Dubosq; David Bishop; Gaurav Sutrave; Chun Kei Kris Ma; Peter J. Shaw; Kenneth P. Micklethwaite; David J. Gottlieb

Blood Advances (Nov 2017)

Long-term control of recurrent or refractory viral infections after allogeneic HSCT with third-party virus-specific T cells

Barbara Withers,
Emily Blyth,
Leighton E. Clancy,
Agnes Yong,
Chris Fraser,
Jane Burgess,
Renee Simms,
Rebecca Brown,
David Kliman,
Ming-Celine Dubosq,
David Bishop,
Gaurav Sutrave,
Chun Kei Kris Ma,
Peter J. Shaw,
Kenneth P. Micklethwaite,
David J. Gottlieb

Affiliations

Barbara Withers: Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia;; Blood and Bone Marrow Transplant Unit,; Department of Haematology, and
Emily Blyth: Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia;; Blood and Bone Marrow Transplant Unit,; Department of Haematology, and; Sydney Cellular Therapies Laboratory, Westmead Hospital, Sydney, NSW, Australia;
Leighton E. Clancy: Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia;; Sydney Cellular Therapies Laboratory, Westmead Hospital, Sydney, NSW, Australia;
Agnes Yong: Department of Haematology, Royal Adelaide Hospital, SA Pathology, Adelaide, SA, Australia;; School of Medicine, University of Adelaide, Adelaide, SA, Australia;; Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia;
Chris Fraser: Department of Oncology, Lady Cilento Children's Hospital, Brisbane, QLD, Australia;
Jane Burgess: Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia;; Sydney Cellular Therapies Laboratory, Westmead Hospital, Sydney, NSW, Australia;
Renee Simms: Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia;; Sydney Cellular Therapies Laboratory, Westmead Hospital, Sydney, NSW, Australia;
Rebecca Brown: Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia;; Sydney Cellular Therapies Laboratory, Westmead Hospital, Sydney, NSW, Australia;
David Kliman: Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia;; Blood and Bone Marrow Transplant Unit,; Department of Haematology, and
Ming-Celine Dubosq: Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia;; Blood and Bone Marrow Transplant Unit,; Department of Haematology, and
David Bishop: Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia;; Blood and Bone Marrow Transplant Unit,; Department of Haematology, and
Gaurav Sutrave: Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia;; Blood and Bone Marrow Transplant Unit,; Department of Haematology, and
Chun Kei Kris Ma: Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia;; Blood and Bone Marrow Transplant Unit,; Department of Haematology, and
Peter J. Shaw: Cancer Centre for Children, Children's Hospital at Westmead, Sydney, NSW, Australia; and
Kenneth P. Micklethwaite: Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia;; Blood and Bone Marrow Transplant Unit,; Department of Haematology, and; Sydney Cellular Therapies Laboratory, Westmead Hospital, Sydney, NSW, Australia;
David J. Gottlieb: Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia;; Blood and Bone Marrow Transplant Unit,; Department of Haematology, and; Sydney Cellular Therapies Laboratory, Westmead Hospital, Sydney, NSW, Australia;; Department of Medicine, Westmead Hospital, Sydney, NSW, Australia; David J. Gottlieb, Department of Medicine, Westmead Hospital, Corner Hawkesbury Rd and Darcy Rd, Sydney, NSW 2145, Australia;

Journal volume & issue: Vol. 1, no. 24
pp. 2193 – 2205

Abstract

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Abstract: Donor-derived adoptive T-cell therapy is a safe and effective treatment of viral infection posttransplant, but it is limited by donor serostatus and availability and by its personalized nature. Off-the-shelf, third-party virus-specific T cells (VSTs) appear promising, but the long-term safety and durability of responses have yet to be established. We conducted a prospective study of 30 allogeneic hemopoietic stem cell transplant (HSCT) patients with persistent or recurrent cytomegalovirus (CMV) (n = 28), Epstein-Barr virus (n = 1), or adenovirus (n = 1) after standard therapy. Patients were treated with infusions of partially HLA-matched, third-party, ex vivo–expanded VSTs (total = 50 infusions) at a median of 75 days post-HSCT (range, 37 to 349 days). Safety, viral dynamics, and immune recovery were monitored for 12 months. Infusions were safe and well tolerated. Acute graft versus host disease occurred in 2 patients, despite a median HLA match between VSTs and the recipient of 2 of 6 antigens. At 12 months, the cumulative incidence of overall response was 93%. Virological control was durable in the majority of patients; the reintroduction of antiviral therapy after the final infusion occurred in 5 patients. CMV-specific T-cell immunity rose significantly and coincided with a rise in CD8+ terminal effector cells. PD-1 expression was elevated on CD8+ lymphocytes before the administration of third-party T cells and remained elevated at the time of viral control. Third-party VSTs show prolonged benefit, with virological control achieved in association with the recovery of CD8+ effector T cells possibly facilitated by VST infusion. This trial was registered at www.clinicaltrials.gov as #NCT02779439 and www.anzctr.org.au as #ACTRN12613000603718.

Published in Blood Advances

ISSN: 2473-9529 (Print); 2473-9537 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine
Website: https://ashpublications.org/bloodadvances

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