Oral Presentation Australasian Cytometry Society 43rd Annual Conference and Workshop

Rapid T-cell recovery is associated with clearance of viraemia in patients administered third-party virus specific T-cells (VSTs) at time of first-line therapy for infections post-allogeneic stem cell transplant (aHSCT): cytometry data from the R3ACT-Quickly Trial (#4)

Wei Jiang 1 2 , Ellis Patrick 1 2 , Adam S Chan 1 , Gaurav Sutrave 2 3 , Selmir Avdic 1 2 , Leighton Clancy 2 , Janine Street 2 , Suat Dervish 2 , David Ritchie 4 , Adrian Selim 3 5 , Caroline M Bateman 2 6 , Peter Shaw 6 , David Gottlieb 1 2 3 , Emily Blyth 1 2 3
  1. The University of Sydney, Sydney, NSW, Australia
  2. Westmead Institute of Medical Research, Westmead, NSW, Australia
  3. Bone Marrow Transplant Unit, Westmead Hospital, Westmead, NSW, Australia
  4. Bone Marrow Transplant Unit, Royal Melbourne Hospital, Melbourne, VIC, Australia
  5. Peter McCallum Cancer Centre, Melbourne, VIC, Australia
  6. Haematology and Bone Marrow Transplant, The Children's Hospital at Westmead, Westmead, NSW, Australia

 Aim: 

To assess immune reconstitution dynamics in recipients of third-party VSTs early in the course of viral infection following aHSCT.

Method: 

Epstein-Barr virus (EBV) and cytomegalovirus (CMV)-specific VSTs were administered to aHSCT recipients within 7 days of commencing antiviral treatment for these viruses. Multiparameter flow immunophenotyping was performed on post-infusion peripheral blood samples using a custom panel of 20 antibody markers covering 32 cell populations, identifying innate and adaptive subsets with a focus on T-subsets and activation markers. Viral antigen specificity in T-cell populations was assessed using virus-specific iTAg MHC class I tetramers where available based on VST and patient HLA-typing. Data was acquired using a BD FACSymphony flow cytometer. Immune reconstitution was assessed to 6 months post-last VST infusion.

Results: 

28/30 treated patients achieved complete virological response (CR), defined as undetectable viral load by quantitative PCR by a median of 25 days post-infusion (range 10-161) without significant toxicity. Cytometry was performed on 162 post-infusion samples at multiple timepoints in 25 patients. CD8+ T-cell expansion (median pre-infusion: 0.31 x 109/L, 100-day post-infusion: 0.72 x109/L) was associated with control of viraemia. The predominant subset within both CD8+ and CD4+ populations was CD45RAnegCD62Lneg effector memory cells, with an increase over time in CD8+ CD45RAposCD62Lneg terminally differentiated effector memory cells. 12/19 patients tested with CMV/EBV-specific tetramers showed a rapid rise of virus-specific T-cells to between 1-13% of CD8+ T-cells, corresponding with virological CR, and persistence of these cells long term. The 2 patients who didn’t achieve CR showed poor recovery of adaptive immunity, with dominance of innate effectors.

Conclusion: 

Early infusion of VSTs to treat infection post-aHSCT was associated with rapid immune reconstitution correlating with complete virological clearance. Immunophenotyping in this study will inform a randomised trial that is underway, comparing VSTs with antivirals to standard-of-care antivirals alone, to confirm clinical benefit.