P1395: pentavalent-specific t-cells post haplo-identical transplantation for the treatment of opportunistic infections

Topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical Background: Opportunistic infections present a major cause of morbidity and mortality after allogeneic transplantation. Conventional therapies are limited and associated with toxicity and resistance development. Adoptive transfer of pathogen-specific T cells (pSTs) has recently emerged as an appealing alternative strategy. Aims: We present the results of an on-going phase I/II study, evaluating the safety and efficacy of donor-derived pentavalent-specific T cells (penta-STs) simultaneously targeting cytomegalovirus-CMV, Epstein Barr virus-EBV, BK virus-BK, adenovirus-AdV and Aspergillus fumigatus-AF (EudraCT2020-004725-23, NCT05471661) Methods: Penta-STs were generated after pulsing blood mononuclear cells from immunocompetent donors with peptides spanning immunogenic EBV (LMP2, EBNA1, BZLF1), Adv (Hexon, Penton), CMV (pp65, IE1), BK (Large T, VP1) and AF (Gel1, SHMT, Crf1) antigens and 10-day culture with IL4 + 7. The specificity of cell products and the circulating specific T-cells were assessed by Elispot. Penta-STs were infused at 2x107/m2/dose in haplo-transplanted (with post-transplant cyclophosphamide) patients developing an infection from the targeted pathogens and receiving no or <0.5mg/kg methylprednisolone at the time of infusion. Results: So far, 11 GMP-grade products have been generated. The final products were expanded ~5.4 fold over baseline reaching on average 162±27x106cells. They were enriched in CD3+cells(93±1%) and comprised of CD4+(59±6%) and CD8+cells(34±6%) expressing central(52±7%) and effector memory markers(32±8%). All penta-STs were specific against the pathogens for which the donor was seropositive; 9/11 presented activity against CMV[912±241 spot forming cells (SFC)/2x105], 11/11 against EBV(1023±210 SFC/2x105), 11/11 against Adv(1243±195 SFC/2x105), 11/11 against BK(476±103 SFC/2x105) and 9/11 against AF(151±41 SFC/2x105). To date, 6 patients received penta-STs for single (EBV n=2, CMV n=1, BK n=1), double (CMV+EBV n=1) and triple viral infection (CMV+EBV+BK n=1) that were developed at median 90 days post-transplant. No patient had ADV or AF infection. Four patients were on corticosteroids at the time of infusion due to GVHD(n=3) and ciclosporin toxicity(n=1). Penta-ST infusion was safe, with no infusion-related toxicity, aGVHD occurrence or cGvHD exacerbation, attributed to the cells. From a total of 10 infections (including 2 EBV diseases), there were 9 complete responses (EBV n=3, CMV n=3, BK n=3) and 1 partial response (EBV). Best response was achieved at median 3.5 weeks post-infusion and correlated with expansion of circulating respective pSTs. Importantly, 2/10 infections (EBV, BK) resolved without additional drug therapy and a patient with EBV-PTLD received only a short course of anti-CD20 treatment due to rapid and complete resolution of lymphadenopathy post-infusion. Notably, at a median follow up of 5.5 months(3-12) post infusion, no reactivations from the targeted pathogens were developed, except of 2 patients who reactivated viruses other than those they had received the cells for; CMV and EBV were reactivated in a patient whose product was CMV seronegative donor-derived and another one with poor in vivo expansion of EBV-specific T cells who received a 2nd infusion, respectively Summary/Conclusion: Although preliminary, our data show that pST therapy is a feasible and safe option for patients at high risk for opportunistic infections after allogeneic transplantation, potentially minimizing the need for drug therapy and preventing reactivations Funding: State Aid Action “RESEARCH -CREATE - INNOVATE” (T2EΔK-02437) Keywords: Transplant, Haploidentical stem cell transplantation, Adoptive immunotherapy, Infection