Establishment and Operation of a Third-Party Virus-Specific T Cell Bank within an Allogeneic Stem Cell Transplant Program

Barbara Withers; Leighton Clancy; Jane Burgess; Renee Simms; Rebecca Brown; Kenneth Micklethwaite; Emily Blyth; David Gottlieb

doi:10.1016/j.bbmt.2018.08.024

Establishment and Operation of a Third-Party Virus-Specific T Cell Bank within an Allogeneic Stem Cell Transplant Program

Biol Blood Marrow Transplant. 2018 Dec;24(12):2433-2442. doi: 10.1016/j.bbmt.2018.08.024. Epub 2018 Aug 29.

Authors

Barbara Withers¹, Leighton Clancy², Jane Burgess², Renee Simms², Rebecca Brown², Kenneth Micklethwaite³, Emily Blyth³, David Gottlieb⁴

Affiliations

¹ Westmead Institute for Medical Research, University of Sydney, Australia; Blood and Bone Marrow Transplant Unit, Westmead Hospital, Sydney, Australia; Department of Haematology, Westmead Hospital, Sydney, Australia.
² Westmead Institute for Medical Research, University of Sydney, Australia; Sydney Cellular Therapies Laboratory, Westmead Hospital, Sydney, Australia.
³ Westmead Institute for Medical Research, University of Sydney, Australia; Blood and Bone Marrow Transplant Unit, Westmead Hospital, Sydney, Australia; Department of Haematology, Westmead Hospital, Sydney, Australia; Sydney Cellular Therapies Laboratory, Westmead Hospital, Sydney, Australia.
⁴ Westmead Institute for Medical Research, University of Sydney, Australia; Blood and Bone Marrow Transplant Unit, Westmead Hospital, Sydney, Australia; Department of Haematology, Westmead Hospital, Sydney, Australia; Sydney Cellular Therapies Laboratory, Westmead Hospital, Sydney, Australia; Sydney Medical School, University of Sydney, Sydney, Australia. Electronic address: david.gottlieb@sydney.edu.au.

PMID: 30172015
DOI: 10.1016/j.bbmt.2018.08.024

Abstract

Hematopoietic stem cell transplantation (HSCT) donor-generated virus-specific T cells (VSTs) can provide effective treatment for viral infection post-HSCT but are not readily accessible to all patients. Off-the-shelf cryopreserved VSTs suitable for treatment of multiple patients are an attractive alternative. We generated a bank of 17 cytomegalovirus (CMV)-, 14 Epstein-Barr virus (EBV)-, and 15 adenovirus (AdV)-specific T cell products from 30 third-party donors. Donors were selected for expression of 6 core HLA antigens expressed at high frequency in the local transplant population. T cells were generated by co-culturing venous blood or mobilized hematopoietic stem cell (HSC)-derived mononuclear cells with monocyte-derived dendritic cells pulsed with overlapping peptides covering CMV pp65, AdV5 hexon, or EBV BZLF1/LMP2A/EBNA1 proteins. Addition of a CD14⁺ selection step instead of plate adherence to isolate monocytes before culture initiation significantly improved expansion in cultures from HSC material. Phenotyping showed the CD8⁺ subset to have significantly higher numbers of terminal effector T cells (CD45RA⁺62L^-) and lower numbers of effector memory T cells (CD45RA^-62L^-) when compared with the CD4⁺ subset. Increased expression of the immunoinhibitory markers PD-1 and TIM-3 was noted on CD4⁺ but not CD8⁺ cells when compared with the control group. VST showed antiviral activity restricted through a variety of common HLAs, and modelling suggested a suitably HLA-matched product would be available for >90% of HSCT patients. Only a small number of carefully selected third-party donors are required to generate a VST bank of broad coverage, indicating the feasibility of local banking integrated into existing allogeneic HSCT programs.

Keywords: Adoptive immunotherapy; Third party; Virus-specific T cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Female
Humans
Immunotherapy, Adoptive / methods*
Male
Stem Cell Transplantation / methods*
T-Lymphocytes, Cytotoxic / immunology*
Transplantation, Homologous / methods*