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

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.eCollection. Cited Medium: Print. NLM ISO Abbr: Blood Adv. PubMed Central ID: PMC5737128. Linked References: J Infect Dis. 2008 Sep 15;198(6):818-26. (PMID: 18666855); Clin Infect Dis. 2009 Dec 15;49(12):1851-60. (PMID: 19911966); Cytotherapy. 2015 Oct;17(10):1406-20. (PMID: 26349000); Blood. 2012 Mar 15;119(11):2644-56. (PMID: 22138512); Blood. 2017 Apr 20;129(16):2316-2325. (PMID: 28209721); Blood. 2013 May 2;121(18):3745-58. (PMID: 23435462); Blood. 2003 Jan 15;101(2):407-14. (PMID: 12393659); Blood. 2010 Dec 2;116(23):5045-9. (PMID: 20826724); Blood. 2010 Nov 18;116(20):4360-7. (PMID: 20625005); Blood. 2017 Jul 13;130(2):221-228. (PMID: 28468799); Bone Marrow Transplant. 2013 Jun;48(6):803-8. (PMID: 23178547); Bone Marrow Transplant. 2016 Sep;51(9):1268-70. (PMID: 27111048); Clin Microbiol Infect. 2016 Mar;22(3):289.e1-7. (PMID: 26627339); Clin Infect Dis. 2012 Oct;55(8):1064-73. (PMID: 22806594); Clin Infect Dis. 2011 Jan 1;52(1):49-57. (PMID: 21148519); Bone Marrow Transplant. 2007 Mar;39(5):293-9. (PMID: 17262060); J Virol. 2004 Jun;78(11):5535-45. (PMID: 15140950); Transpl Infect Dis. 2007 Dec;9(4):286-94. (PMID: 17511819); Biol Blood Marrow Transplant. 2013 May;19(5):725-34. (PMID: 23380344); Blood. 2013 Jun 27;121(26):5113-23. (PMID: 23610374); Leukemia. 2017 Oct;31(10 ):2161-2171. (PMID: 28090089); Blood. 2010 Feb 4;115(5):925-35. (PMID: 19880495); Bone Marrow Transplant. 2007 Jul;40(2):125-36. (PMID: 17530009). Linking ISSN: 24739529. Subset: PubMed not MEDLINE; Date of Electronic Publication: 2017 Nov 02. ; Original Imprints: Publication: Washington, DC : American Society of Hematology, [2016]- <br />