Abstract
Background: Allogeneic hematopoietic cell transplant (allo-HCT) recipients are highly susceptible to reactivation of double-stranded DNA viruses. Approximately 70% of high-risk allo-HCT recipients develop clinically significant infections (CSI, defined as viremia + treatment or end organ disease). We present results from a phase 2 trial evaluating the safety and efficacy of posoleucel, a partially HLA-matched, off-the-shelf, multivirus-specific T cell investigational product, for preventing CSIs due to adenovirus (AdV), BK virus (BKV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), or JC virus (JCV).
Methods: This open-label trial enrolled high-risk allo-HCT recipients, including those with grafts from haploidentical, umbilical cord blood, mismatched unrelated donors, and matched unrelated donors with lymphocytes <180/mm3 as well as recipients who underwent T cell depletion. To be eligible, patients had to be engrafted and within 15-49 days of allo-HCT. Those with grade ≥3 GVHD and those requiring steroids (>0.5 mg/kg/day prednisone equivalent) at enrollment were ineligible.
Patients received up to 7 infusions of posoleucel once every 14 days and were tested weekly for viremia using quantitative PCR assays. The primary endpoint was the number of CSIs due to AdV, BKV, CMV, EBV, HHV-6, or JCV by week 14. IFN-γ ELISpot analysis was performed for each targeted virus on serial peripheral blood samples to assess functional T cell immune reconstitution and determine the frequency of circulating virus-specific T cells detected over time. To evaluate the persistence and potential contribution of posoleucel to antiviral immune reconstitution, T-cell receptor (TCR) β immunosequencing was performed at selected timepoints. TCR sequences unique to posoleucel were identified computationally and used to track in vivo persistence in serial samples.
Results: Twenty-six patients were dosed. Posoleucel dosing began a median of 42 days after allo-HCT. Twenty (77%) patients had viral DNA detected in blood (reactivation) from one or more viruses, 13 (50%) had 2 or more viral reactivations, and 7 (27%) had 3 or more viral reactivations in the 14 weeks after the initiation of posoleucel dosing (Figure). However, by week 14, only 3 patients (12%) had CSIs (2 CMV viremia requiring treatment and 1 EBV-post-transplant lymphoproliferative disorder). No patient had a CSI with more than 1 virus.
Nine patients (35%) experienced adverse events that were possibly or probably related to treatment. Eight patients (31%) had serious adverse events (SAEs), 2 of which were judged to be possibly related to treatment (skin and pulmonary GVHD) and 1 probably related to treatment (allergic reaction). Overall, 8 patients (31%) had acute GVHD Grade II-IV. One patient (4%) discontinued posoleucel due to a treatment-emergent SAE of chronic pulmonary GVHD. No patient experienced cytokine release syndrome.
TCR sequencing data (N=12) indicated that posoleucel was detectable in vivo during the dosing phase of the study and for up to 12 weeks after the last infusion, with polyclonal VSTs detected in all 12 patients. Six of the 7 patients with available ELISpot data demonstrated IFN-γ-producing virus-specific T cell responses coincident with viral replication. The confirmed persistence of posoleucel and expansion of IFN-γ-producing virus-specific T cells directed against reactivating viruses, suggests a contribution of posoleucel to functional immune reconstitution.
Conclusion: Results from this open-label phase 2 trial show that high-risk allo-HCT patients who received posoleucel had lower than expected rates of clinically significant viral infections from the 6 targeted viruses despite the observed and expected low-level viral reactivations throughout the study. Repeat dosing of posoleucel was generally safe and well tolerated. Posoleucel VSTs were detected in vivo for up to 26 weeks, and reconstituting T cells demonstrated functional specificity for multiple viruses. A placebo-controlled global phase 3 trial evaluating the safety and tolerability of posoleucel for the prevention of clinically significant AdV, BKV, CMV, EBV, HHV-6, and JCV infections is ongoing (NCT05305040).
Disclosures
Dadwal:AlloVir: Research Funding, Speakers Bureau; Takeda Pharmaceuticals: Research Funding, Speakers Bureau; Gilead Sciences: Research Funding; Ansun Biopharma: Research Funding; Amplyx Pharmaceuticals/Pfizer: Research Funding; Astellas: Speakers Bureau; Merck & Co.: Consultancy, Other: Advisory Board, Speakers Bureau; AseptiScope: Other: Advisory Board; Cidara Therapeutics: Other: Advisory Board. Young:AlloVir: Research Funding. Schuster:AbbVie: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Actinium: Research Funding; AlloVir: Research Funding; MorphSys: Research Funding, Speakers Bureau; Pharmacyclics: Research Funding, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau; Incyte: Research Funding; GSK: Research Funding; Celgene: Speakers Bureau; Epizyme: Speakers Bureau; Genentech: Speakers Bureau; Beigene: Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Seattle Genetics: Speakers Bureau; Astellas: Speakers Bureau; Rafael: Research Funding. Yared:Kite: Honoraria. Myers:Eliana Trial: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Matzko:AlloVir: Current Employment, Current holder of stock options in a privately-held company. Adnan:AlloVir: Current Employment, Current holder of stock options in a privately-held company. Hill:AlloVir: Consultancy, Research Funding; Karius: Research Funding; Octapharma: Consultancy; Allogene Therapeutics: Consultancy; Takeda: Consultancy, Research Funding; Amplyx: Consultancy; Gilead: Consultancy, Research Funding; CLS Behring: Consultancy; Optum Health: Consultancy; CRISPR Therapeutics: Consultancy.
