Session: 722. Clinical Allogeneic Transplantation: Acute and Chronic GVHD, Immune Reconstitution: Poster I
Hematology Disease Topics & Pathways:
Biological, Therapies, Clinically relevant, vaccines
After obtaining informed consent, 18-75 year old HCT recipients (CMV seropositive) with matched related donors underwent T cell replete HCT. Donors received one Triplex injection 10-60 days prior to start of stem cell mobilization, and recipients underwent HCT within 9 weeks of donor vaccination. As per standard of care, Triplex vaccinated donors were mobilized with granulocyte colony-stimulating factor, prior to apheresis. The study has a target of 18 HCT donor/recipient pairs. All HCT recipients are followed until day 365 post-HCT for safety, virologic and immunologic assessment. All donors are monitored for vaccine induced adverse events. Antiviral treatment for viremia is considered a failure of donor vaccination to provide protection to the recipient.
As of July 2020, we have safely vaccinated 9 MRD with Triplex, and infused mobilized peripheral blood stem cells, with T cells by volume approximately 10-25% to their recipients. No adverse events, possibly or likely related to the vaccine were reported. No preemptive antiviral treatment was administered to any of the HCT recipients. Six donor/recipient pairs have reached study end, and immune monitoring has been completed. Two donor/recipient pairs have been evaluated immunologically for up to 6 months and one to day 100 post-HCT. The flow cytometry panel of cellular immune assays included measuring concentrations of CMV-specific T cells expressing the 4-1BB (CD137) activation marker, and assessing the memory phenotype profiles (performed as detailed in La Rosa et al., Blood 2017). Peripheral blood mononuclear cells (PBMC) were stimulated for 24 hours with either pp65, IE1 and IE2 overlapping 15mer peptide libraries and then stained with fluorescently tagged antibodies against CD137, CD3, CD8, CD4, combined with CD28 and CD45RA memory markers by using a Beckman-Coulter Gallios cytometer with Kaluza software. Early post-HCT development of robust and long-lasting frequency of pp65-, IE1- and IE2-specific CD4 and CD8 T cells was observed in all recipients (Figure 1A). Memory profiles of CMV specific T cells had marked prevalence of effector memory phenotype early post-HCT, which persisted over time. Interestingly, on day 28 post-HCT, pp65-specific CD8 T cell levels were significantly higher in the 9 recipients who received an HCT from a Triplex vaccinated MRD compared to a control cohort of consecutively enrolled MRD HCT recipients (Figure 1B).
In summary, this is the first clinical trial to assess the possible benefit of vaccinating MRD, to elicit early CMV immune recovery in CMV seropositive HCT recipients, at high risk for developing CMV serious complication after HCT. The approach is feasible and highly tolerable, with promising evidence of efficacy, indicating that Triplex vaccination of the MRD confers early protective anti-CMV immunity to the HCT recipient. Clinical and immunological outcomes from the ongoing study indicate that this novel immune therapeutic strategy provides a safer alternative to antivirals, including letermovir prophylaxis and may find application in higher CMV risk patients, such as haploidentical HCT recipients.
Disclosures: Nakamura: Viracor: Consultancy; Celgene: Other: Support on seminar; Kyowa-Kirin: Other: Support on a meeting presentation; Alexion: Other: Support on a meeting presentation; Merck: Other: advisory board meeting; Magenta Therapeutics: Other: Advisory board meeting; NapaJen Pharma: Consultancy; Kadmon Corporation: Other: Advisory board meeting. Diamond: Helocyte: Consultancy.
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