Prophylactic Infusion Of Multi-Virus Specific T Cells For Management Of Viral Reactivation and Infection In Patients Post Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)
Authors: Kris Ma Chun Kei , Blyth Emily , Clancy Leighton , Simms Renee , Burgess Jane , Micklethwaite Kenneth P. , Gottlieb David 
Published: October 2019

Aim
Adoptive antiviral immunotherapy has recently gained popularity as a prophylactic and therapeutic strategy for viral infections post allogeneic stem cell transplant (HSCT). We report the outcomes of 10 patients who received multi-virus specific T cells (CTL) prophylactically post HSCT, and compare the outcomes of these patients to a contemporaneous cohort control.

Methods
Donor derived CMV, EBV, adenoviral and VZV specific T cells were generated in a 21-day culture, which involved stimulation of peripheral blood mononuclear cells by antigen-pulsed monocyte derived dendritic cells (DC) on days 0 and 7 and culture with 20-50units/ml of IL2. DC were transfected with an adenoviral vector encoding the CMV immune-dominant antigen pp65 or epitopes of EBV antigens EBNA1, LMP1 and LMP2. A commercial VZV vaccine (Varivax®, Merck & Co) was used to stimulate VZV specific T cells.
Patients undergoing matched sibling HSCT at Westmead Hospital from Feb 2011 to Jun 2012 were recruited. Patients with no active acute graft versus host disease were given 2x107/m2 multi-virus CTLs from day 35 onwards. After CTL infusion, patients were monitored for 12 months. Clinical outcome measures included adverse events related to CTL infusion, incidence of acute and chronic graft versus host disease and the incidence of CMV, EBV, adenoviral and VZV reactivations and infection. Patients were treated for viral reactivation according to standard institutional guidelines.
A contemporaneous cohort of matched sibling transplant recipients treated during the same period at Westmead Hospital was used for comparison. A landmark analysis was performed on both groups using day 35 as a landmark to focus on outcome events related to CTL infusion.

Results
10 patients who underwent matched sibling donor HSCT from Feb 2011 to Jun 2012 were given multi-virus specific T cells. There were no adverse events in any of the patients within 24 hours of T cell infusion. Three patients developed grade II-IV acute graft versus host disease (aGVHD) after transplant, 1 prior to CTL infusion, and 2 post CTL infusion. 7 patients developed chronic graft versus host disease. 8 patients reactivated CMV at any time post-transplant, 6 prior to CTL infusion of whom 2 required ganciclovir therapy; 5 patients developed low level CMV reactivation (median peak titre 600 copies/ml) post CTL infusion. 1 patient received ganciclovir for CMV PCR positivity on colonic tissue. No CMV disease developed and no evidence of EBV, VZV or adenoviral reactivation was noted during 12 months follow up.
Using the day 35 landmark to exclude patients with grade II-IV acute GVHD, CMV reactivation and premature death in both CTL and control cohorts, 9 patients in the study cohort and 21 patients in the control cohort were available for comparison. 22% in the study cohort and 19% in the control cohort developed grade II-IV acute GVHD. 67% in the CTL cohort and 57% in the control cohort developed chronic GVHD. 7 of 9 patients in the study cohort and 9 of 21 patients in the control cohort had a CMV reactivation post transplant. The median peak CMV copy number was lower in the study cohort (600 vs 2840 copies/ml). 29% and 67% of patients received ganciclovir in the CTL and control cohort respectively. There was no clinically documented CMV disease in either cohort. 1 EBV, 1 adenoviral and 1 VZV reactivation were identified in the control cohort. No reactivations were identified in the study cohort.

Conclusion
Multi-virus T cell therapy appears safe, with no evidence of increased GVHD, or excess of adverse events observed as a result of CTL administration. Patients receiving T cells in this study had a lower median peak CMV copy number during reactivation episodes and fewer required anti-CMV pharmacotherapy. These results confirm out previous data on the efficacy of prophylactically administered CMV specific T cells given post HSCT but a larger study is required to determine their efficacy in preventing EBV, adenovirus and varicella zoster virus disease.

Disclosures:
No relevant conflicts of interest to declare.