Kurzfassung: Serious viral infections are a leading cause of morbidity and mortality in pediatric recipients of allogeneic hematopoietic cell transplant (allo-HCT). Most available antivirals have significant toxicities and suboptimal efficacy. Posoleucel (PSL) is an allogeneic, off-the-shelf multi-virus specific T cell investigational product to prevent or treat 6 viral infections (AdV, BKV, CMV, EBV, HHV-6, and JCV). In the phase 2 CHARMS trial of PSL in allo-HCT recipients with intractable viral infections, 95% of patients had a clinical response. Here we present the efficacy and safety data in pediatric patients ( & lt; 18 years) enrolled in CHARMS. Methods Allo-HCT patients who had failed antiviral therapy or were unable to tolerate antivirals to control BKV, CMV, AdV, EBV, HHV-6, and/or JCV infection received a single PSL infusion of 2×107 cells/m2. Patients with a response could receive up to 4 more doses after 4 weeks, at 2-week intervals. The primary endpoint of the study was safety and feasibility. Other endpoints included complete and partial clinical response, with complete response (CR) as return to normal range and resolution of signs/symptoms and partial response (PR) defined as ≥50% decrease in viral load and/or ≥50% improvement of clinical signs/symptoms assessed by 6 weeks post infusion. Results 18 pediatric patients received PSL (1 was treated for 2 infections separately). Of the 13 with 1 viral infection, 6 (46%) had BKV, 3 (23%) CMV, 2 (15%) AdV, 2 (15%) HHV-6, and none EBV or JCV. Five (38%) had & gt;1 infection: 3 had 2 infections, 1 had 3 infections, and 1 had 1 viral infection at each of 2 enrollments. 56% of patients received one infusion. PSL was generally well tolerated. Besides fever in 7 patients, we observed no toxicities or symptoms of CRS. Five cases of acute graft-versus-host disease (aGVHD) were observed; 3 in patients with history of aGVHD (2 had aGVHD at baseline). Both de novo cases of GVHD were Grade 1. 100% of patients achieved a clinical response (CR or PR) by 6 weeks including all 5 patients infected with multiple target viruses. Four of 6 patients with AdV infection had CR. Conclusion PSL treatment was well tolerated. All pediatric patients receiving PSL had a clinical response. Phase 3 studies including pediatric patients are in progress. Disclosures Ifigeneia Tzannou, MD, AlloVir: Advisor/Consultant Carlos Ramos, MD, Novartis: Advisor/Consultant Swati Naik, MD, Bellicum: Travel, Accomodation, Expenses Iain Fraser, MD, DPhil, AlloVir: Employee|AlloVir: Stocks/Bonds Marshelle Warren, MD, AlloVir: Advisor/Consultant Badrish Patel, MD, AlloVir: Employee|AlloVir: Stocks/Bonds Dany Ward, RN, AlloVir: Employee|AlloVir: Stocks/Bonds Ann Leen, PhD, AlloVir: Advisor/Consultant|AlloVir: Stocks/Bonds Bilal Omer, MD, AlloVir: Grant/Research Support.

Kurzfassung: Background —Previously, we showed that tumor necrosis factor (TNF) antagonism with etanercept, a soluble TNF receptor, was well tolerated and that it suppressed circulating levels of biologically active TNF for 14 days in patients with moderate heart failure. However, the effects of sustained TNF antagonism in heart failure are not known. Methods and Results —We conducted a randomized, double-blind, placebo-controlled, multidose trial of etanercept in 47 patients with NYHA class III to IV heart failure. Patients were treated with biweekly subcutaneous injections of etanercept 5 mg/m 2 (n=16) or 12 mg/m 2 (n=15) or with placebo (n=16) for 3 months. Doses of 5 and 12 mg/m 2 etanercept were safe and well tolerated for 3 months. Treatment with etanercept led to a significant dose-dependent improvement in left ventricular (LV) ejection fraction and LV remodeling, and there was a trend toward an improvement in patient functional status, as determined by clinical composite score. Conclusion —Treatment with etanercept for 3 months was safe and well-tolerated in patients with advanced heart failure, and it resulted in a significant dose-dependent improvement in LV structure and function and a trend toward improvement in patient functional status.

Kurzfassung: Treatment-resistant hematological malignancies remain an area of high unmet need and novel therapeutic approaches will be required. microRNAs are small (~ 22 nt) non-coding RNAs that act as negative regulators of gene expression. These small RNAs impact expression of a substantial fraction of the genome, and have powerful effects on cellular phenotypes and physiological processes. miR-155-5p is a well-described oncomiR associated with poor prognosis in multiple malignancies, particularly lymphoma and leukemia. Cutaneous T-cell lymphoma (CTCL) is a rare hematological malignancy with limited treatment options and a strong mechanistic link to increased miR-155-5p. Because of the accessibility of cutaneous lesions, CTCL provides a unique opportunity to determine if inhibition of miR-155-5p has therapeutic potential in lymphomas associated with elevated miR-155-5p. We optimized a LNA-modified oligonucleotide inhibitor of miR-155-5p, MRG-106, based on the ability to de-repress canonical miR-155-5p targets in multiple cell types in vitro. In mycosis fungoides (MF) cell lines, MRG-106 does not require additional formulation to achieve maximum pharmacodynamic efficacy. Inhibition of miR-155-5p resulted in transcriptome changes consistent with miR-155-5p target gene modulation, reduction in cell proliferation, and activation of the programmed cell death pathway. The gene expression and phenotypic effects were inhibitor dose-dependent and sequence-specific. Based on an informatics approach for the expression profiling of MF cell lines treated with MRG-106, a set of 600 genes was identified to represent the translational pharmacodynamic biomarker signature, both direct and downstream of miR-155-5p. GLP preclinical safety studies have been completed in rats and non-human primates, demonstrating an acceptable safety profile for MRG-106. We plan to initiate a 4-week first-in-human clinical trial in CTCL (MF) patients. The trial design is two-part, with Part A testing the effect of direct intra-tumoral injection of MRG-106 into plaque and nodular skin lesions, and Part B testing the effect of systemic (subcutaneous) administration of higher doses of MRG-106. The primary objective of Part A is to profile the pharmacodynamic effect of MRG-106 on the miR-155-5p gene expression signature, establishing a PK/PD model to guide future development. The primary objective of Part B is to establish the safety, tolerability, PK and skin deposition of MRG-106 after systemic delivery. Exploratory objectives include measures for clinical response, immune system effects, and biomarker validation. Disclosures Seto: miRagen Therapeutics: Employment, Equity Ownership. Beatty:miRagen Therapeutics: Employment, Equity Ownership. Pestano:miRagen Therapeutics: Employment, Equity Ownership. Dickinson:miRagen Therapeutics: Employment, Equity Ownership. Warren:miRagen Therapeutics: Consultancy. Rodman:miRagen Therapeutics: Employment, Equity Ownership. Jackson:miRagen Therapeutics: Employment, Equity Ownership.

Kurzfassung: Background— Anemia is often observed in patients with chronic heart failure (CHF), but its implications for patient outcomes are not well understood. The goal of this study was to investigate the relationship between anemia, severity of CHF, and clinical outcomes. Methods and Results— Hemoglobin concentration (Hb) was measured in 912 subjects with CHF enrolled in the Randomized Etanercept North American Strategy to Study Antagonism of Cytokines (RENAISSANCE) trial. In a subgroup of 69 subjects, cardiac MRI was performed at randomization and 24 weeks later. Anemia (Hb ≤12.0 g/dL) was present in 12% of subjects. Cox regression analysis indicated that for every 1-g/dL-higher baseline Hb, the risk of mortality was 15.8% lower ( P =0.0009) and the risk of mortality or hospitalization for heart failure was 14.2% lower ( P 〈 0.0001). Greater CHF severity was associated with significantly lower Hb concentrations. An increase in Hb over time was associated with a decrease in left ventricular mass and lower mortality, whereas a decrease in Hb over time was associated with an increase in left ventricular mass and higher mortality. In multivariate analysis, anemia remained a significant, independent predictor of death or hospitalization for heart failure, with both outcomes being significantly higher in all NYHA classes. Conclusions— Anemia is frequently present in patients with CHF. Lower Hb is associated with greater disease severity, a greater left ventricular mass index, and higher hospitalization and mortality rates.

Kurzfassung: 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.