Posoleucel (ALVR105), an Off-the-Shelf, Multivirus-Specific T-Cell Therapy, for the Prevention of Viral Infections Post-HCT: Results from an Open-Label Cohort of a Phase 2 Trial
Authors: Dadwal Sanjeet S , Shuster Michael , Myers Gary Douglas , Boundy Keith , Warren Marshelle , Stoner Elizabeth , Truong Thuy , Hill Joshua A. 
Published: November 2021

Abstract
Background: Patients who undergo allogeneic hematopoietic cell transplantation (allo-HCT) are at high risk of reactivation or de novo infection with double-stranded (ds) DNA viruses such as cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), adenovirus (AdV), BK virus (BKV), and JC virus (JCV). After allo-HCT, up to 90% patients develop detectable viremia by PCR. EMR data collected between 2018 and April 1, 2021, from over 1400 high-risk allo-HCT patients at 21 US centers suggest that 40-50% develop clinically significant viral infection or disease associated with ≥1 of these dsDNA viruses within 200 days of transplant. Multiple studies demonstrate increased morbidity and mortality associated with viremia, with or without end-organ disease. Prophylactic and preemptive therapies have substantial side effects and can lead to the development of resistance, especially in CMV. HCT donor-derived virus-specific T-cells have shown promise in preventing single virus infections in prior clinical trials but were infeasible for wide-scale use. There is an urgent unmet medical need for preventive strategies targeting multiple viruses in patients undergoing high-risk allo-HCT.
Methods: We are conducting a clinical trial (NCT04693637) to evaluate the safety and efficacy of posoleucel (ALVR105, Viralym-M) for preventing clinically significant viral infections due to CMV, EBV, HHV-6, AdV, BKV, and JCV in high-risk allo-HCT recipients. Posoleucel is an ex-vivo expanded, partially HLA-matched, off-the-shelf, multivirus-specific T cell investigational product generated from healthy, third-party donors targeting CMV, EBV, HHV-6, AdV, BKV, and JCV. In the open-label portion of the study, patients receive up to seven infusions of 4×10 7 cells of posoleucel administered once every 14 days. High-risk patients are those who received a graft from a sibling or unrelated donor with ≥1 HLA mismatch; from a haploidentical donor; from umbilical cord blood or with T-cell-depletion; as well as patients with lymphocytes &lt;180/mm 3 or CD4 T cells &lt;50/mm 3 at enrollment. Patients must be engrafted and within 15-49 days of allo-HCT. Those with grade ≥3 GVHD as well as those requiring steroids (&gt;0.5 mg/kg/day prednisone equivalent) at enrollment are ineligible. Patients are tested weekly for viremia using quantitative PCR assays and are monitored every other week for adverse events. The primary endpoint is the number of clinically significant viral infections or episodes of end-organ disease due to CMV, EBV, HHV6, AdV, BKV, or JCV by week 14.
Results: Data are available for 12 of 25 planned participants thus far (Table 1). No patient developed a clinically significant infection within 14 weeks, the primary study endpoint. Over the entire study duration, defined as the primary 14-week treatment period plus the additional 12-week follow-up, 11 (92%) patients have remained free of any clinically significant viral infections, the key secondary endpoint. One patient, a 49-year-old female haploidentical transplant recipient, developed clinically significant AdV viremia after receiving over a month of high-dose methylprednisolone exceeding 0.5 mg/kg/day for recurrent aGVHD. This patient was administered IV cidofovir in week 15 of the study. During the primary study efficacy period one participant received 2 doses of valganciclovir following transient CMV viremia deemed not to be clinically significant by the principal investigator.
Posoleucel has been well tolerated to date, with no drug-related serious adverse events, new-onset acute GVHD, or cytokine release syndrome. Safety and efficacy data from the entire open-label cohort will be presented.
Conclusions: Preliminary results in this open-label cohort show that in high-risk allo-HCT patients receiving off-the-shelf posoleucel, clinically significant viral infections or disease from the 6 targeted dsDNA viruses were uncommon. No clinically significant infections were observed among participants treated in accordance with the protocol. These results, combined with the favorable safety and tolerability profile of posoleucel, support its continued evaluation in high-risk allo-HCT recipients for the prevention of CMV, EBV, HHV6, AdV, BK virus, or JC virus infection and disease.
Figure 1 Figure 1.

Disclosures
Dadwal: Shire/Takeda: Research Funding; Astellas: Speakers Bureau; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AlloVir: Research Funding; Aseptiscope: Consultancy; Janssen: Other: Investigator; Karius: Other: Investigator. Shuster: Bristol Myers Squibb: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Intellisphere: Consultancy, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company; Rafael: Research Funding; Celgene: Consultancy, Current equity holder in publicly-traded company; Incyte: Research Funding; Beigene: Consultancy; Seattle Genetics: Consultancy, Speakers Bureau; Actinium: Research Funding; GSK: Research Funding; Pharmcyclics: Consultancy, Research Funding, Speakers Bureau; Epizyme: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; AlloVir: Research Funding; Janssen: Consultancy, Speakers Bureau; Astellas: Consultancy, Research Funding, Speakers Bureau; MorphSys: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau. Myers: Novartis: Consultancy, Speakers Bureau; AlloVir: Research Funding; Eliana: Consultancy, Membership on an entity's Board of Directors or advisory committees. Boundy: AlloVir: Current Employment, Current equity holder in publicly-traded company. Warren: AlloVir: Consultancy. Stoner: AlloVir: Current Employment, Current equity holder in publicly-traded company. Hill: Octapharma: Consultancy; OptumHealth: Consultancy; CRISPR therapeutics: Consultancy; CLS Behring: Consultancy; Allogene therapeutics: Consultancy; Gilead: Consultancy, Research Funding; Allovir: Consultancy, Research Funding; Amplyx: Consultancy; Takeda: Consultancy, Research Funding; Karius: Research Funding.