Co-Administration of 3^rdparty Partially HLA Matched Cytomegalovirus Specific T Cells with Initial Antiviral Pharmacotherapy for Post-Transplant Viral Reactivation

INTRODUCTION Cytomegalovirus (CMV) infection is common after allogeneic haemopoietic stem cell transplant (HSCT), especially in the first 12 months when the recovering immune system is immature. We are conducting an early phase clinical trial of 3^rd party donor-derived, partially HLA matched, virus-specific T cells (VST) for initial reactivation of CMV after HSCT.

RESULTS At data cutoff for this analysis (July 15 2018), we had administered 22 infusions of CMV VST to 15 HSCT recipients (age 1-70 years, median 57; male n=9, female n=6) with reactivation of CMV within 7 days of first commencement of antiviral pharmacotherapy. Up to 3 VST infusions were given (1 infusion n=9, 2 n=5 and 3 n=1). Diagnoses include AML/MDS (n=5), ALL (n=2), NHL (n=3), CML, CMML, MDS/MPN, mucopolysaccharidosis type 1 and ARPC1B deficiency (n=1 each). Patients received reduced intensity conditioning (n=10) and myeloablative conditioning (n=5) and were transplanted from matched unrelated donors (n=9), mismatched unrelated donors (n=3), a matched sibling (n=1) and haploidentical donors (n=2). Haploidentical graft recipients received graft versus host disease (GVHD) prophylaxis with post-transplant cyclophosphamide, cyclosporine and mycophenolate mofetil. All other patients with the exception of the sibling graft recipient and two pediatric graft recipients received thymoglobulin. Two pediatric graft recipients received alemtuzumab in vivo and CD34 ex vivo selected stem cells respectively. Eleven patients were CMV D+/R+, 4 patients were D-/R+. Median day of first VST infusion was day 49 post-transplant (range 34-83). There were no significant infusion related reactions. Of the fifteen patients who received treatment for CMV, median maximum CMV copy number prior to first VST infusion was 6088 copies/ml (range 2342 to 53140). 12 patients (80%) achieved a complete virological response (defined as at least one negative PCR test after infusion). The remaining 3 patients achieved a virological PR (at least 50% reduction in CMV copy number); in 2 of these 3 cases CMV fell below the level of assay quantitation but remained detectable. Median time to CR was 21 days (range 9-53) and to PR was 20.5 days (range 12-48). Twelve of the 22 infusions (55%) were followed by complete virological response. Median number of days in hospital after VST infusion was 0 (0-83). Median number of days of CMV antiviral administration was 21 (range 7-72). All but 2 patients had additional non-bacterial pathogens isolated post-transplant (1 n=4, 2 n=5, ≥3 n=4). 3 patients developed acute graft versus host disease, 2 post VST infusion (grades I and II skin), 1 both before (grade IV gut GVHD) and after VST infusion (grade IV gut GVHD) on steroid weaning. One patient has developed mild chronic GVHD affecting mouth and liver. CMV pneumonitis was observed in 1 patient after VST infusion as part of complex lung pathology comprising pulmonary veno-occlusive disease, pulmonary fibrosis and positive lung PCR testing for CMV, EBV and HHV6. 5 patients were censored at post-transplant days 111 (relapse CMML), 122 (secondary graft rejection after CD34 selected transplant), 155 (unmanipulated DLI for falling myeloid chimerism), 160 (relapse ALL) and 275 (ATG for second line therapy of grade IV gut GVHD). At a median follow up of 165 days (42-279) 14 of 15 patients (93%) remain alive (1 death due to relapse). At date of last follow up, 12 patients had ECOG status 0, 1 had ECOG 2 and 2 had ECOG 4.

Post VST infusion CMV specific immune reconstitution was observed with a rise in pp65 specific cellular immune response measured by IFN-g elispot (median 152 spot forming unitsx10⁴/L before infusion to median peak of 2710 after infusion; p=0.006; Fig 1). HLA mismatched 3^rd party cells were detectable in the peripheral blood in 4 of 9 patients at low levels (mean 0.012%) by a high sensitivity digital PCR chimerism assay up to day 97 post infusion.

CONCLUSION Early administration of 3^rd party partially HLA matched CMV-specific T-cells in association with standard antiviral treatment is non-toxic and does not induce a high rate of acute GVHD. These preliminary data suggest that this approach is associated with good viral control and performance status in allogeneic transplant recipients. Recruitment of additional patients, longer follow up and ultimately a randomized study will be required to determine whether addition of early cell therapy of this kind adds value to standard antiviral treatment.

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