Project 1

Evaluation of safety and correlative immunogenicity studies of CMVPepVax co-injected with PF03512676 adjuvant in recipients of allogeneic stem cell transplant

Allogeneic hematopoietic cell transplantation (HCT) is an effective therapy for a range of life-threatening hematologic malignancies. Since the inception of HCT four decades ago, more than 800,000 patients have been transplanted worldwide. The majority of allogeneic HCT recipients are patients with leukemia, lymphoma, myeloma, myelodysplasia, bone marrow failure conditions, severe red blood cell disorders or solid tumors. In allogeneic HCT, hematopoietic cells are obtained from suitably HLA matched related or unrelated volunteer donors (URD) or from umbilical cord blood. Pretransplant, the patient is treated with chemotherapy, with or without radiation therapy, to eradicate cancerous cells, and for suppressing the patient’s immune system to prevent it from attacking donor hematopoietic cells. As a result, patients are vulnerable to pathogens termed opportunistic infections. Among them is cytomegalovirus (CMV) infection, which is the cause of significant morbidity at early and late times post-HCT in the recovery of immune-compromised recipients. CMV is a highly prevalent β-herpes virus that rarely causes disease in healthy individuals. In contrast, HCT patients are vulnerable to herpes virus infections, including CMV, as a result of immunosuppression associated with treatment strategies aimed at preventing rejection or graft-versus-host disease (GVHD). Despite advances in development of antiviral drugs and substantial reduction of CMV disease with pre-emptive antiviral treatment, CMV remains one of the most difficult-to-treat infections post-HCT, which strongly impacts the course of recovery and success rate of this curative treatment for cancer. Furthermore, antiviral therapy has major side effects, including nephrotoxicity, neutropenia and delayed immune reconstitution, which exposes HCT recipients to other opportunistic viral, bacterial and fungal infections. Additionally, costs associated with usage of antivirals are significant, with a single course reaching $25,000. Next-generation prophylactic antiviral drugs are undergoing clinical testing and might effectively reduce CMV infection rates, although a phase III study assessing a promising antiviral did not show a reduction in CMV infection. Thus, alternative strategies to control CMV are eagerly sought, since use of antivirals does not address the major risks of late-onset CMV disease, including reactivation and failure to reconstitute CMV-specific immunity. Substituting toxic antivirals with a vaccine that harnesses the abundant native immune response to CMV may improve outcomes for HCT recipients. Our group has identified a repertoire of CD8 T cell epitopes from the CMV-pp65 protein that can expand human CMV-pp65-specific memory CD8 T cells in vitro. In HLA A*0201 transgenic mice, two candidate vaccine peptides containing the HLA A*0201  pp65495-503 CD8+ T cell epitope fused to universal T-help epitopes (either the synthetic PADRE or a natural Tetanus sequence) showed favorable immunogenicity profiles. The vaccine peptides were named PADRE-CMV and Tet-CMV, respectively, and were developed with support of the National Cancer Institute sponsored Rapid Access to Interventional Development (NCI-RAID, currently called NCI-NExT). Co-injection with PF-03512676 adjuvant (a synthetic single stranded DNA containing bacterial CpG DNA motifs with immunostimulatory activity, produced by Pfizer) further augmented activity at a lower vaccine dose. cGMP-grade PADRE-CMV (NSC-721433) and Tet-CMV (NSC-721434) vials were produced, tested for stability and preclinically assessed for toxicology at all investigated dosages (Southern Research Institute). After obtaining approval from FDA (BB-IND13124), PADRE-CMV and Tet-CMV, with or without PF-03512676 adjuvant were clinically evaluated for safety and immunogenicity. The phase Ib dose-escalation clinical trial (registry number: NCT00722839@www.clinicaltrials.gov) was conducted in HLA A*0201 healthy adults and indicated that the CMV peptides co-injected with PF-03512676 were safe and immunogenic. In particular, Tet-CMV + PF-03512676 had a favorable safety profile and led to substantial expansion of pp65495-503 T cells after two subcutaneous vaccine injections. The achievement of the central goal of our phase Ib study in healthy adults supports further evaluation of Tet-CMV combined with PF-03512676 (renamed CMVPepVax)  in the HCT setting. A summary of the results of the trial was published in 2012 (see La Rosa et al, 2012). These promising results are the basis for CMVPepVax as a therapeutic vaccine, to improve outcomes of HCT recipients with uncontrolled CMV viremia.
 
Summary of IRB12022-approved Phase Ib Randomized Open Label Clinical Trial in HCT recipients. The phase Ib pilot trial is powered to evaluate safety of administering CMVPepVax to HLA matched allogeneic (MRD or URD) patients at risk for CMV complications (NCT01588015@www.clinicaltrials.gov). The target enrollment is ≤36 patients with the goal of assessing feasibility to conduct a larger phase II trial (see Project 2). Computer generated 1:1 randomization assigns each patient either to the vaccine or to the non-interventional (prospective) immune monitoring arm. In the vaccine arm, patients will be vaccinated twice (d28 and d56 post-HCT) with CMVPepVax. Safety (10 endpoint) will include continuous post-immunization assessment until d100 for GVHD and as necessary until d180 for any AE in ≤18 immunized patients. We initiated this trial and have administered vaccine to three patients and enrolled an additional four observational patients. CMV-specific vaccine function (20 endpoint) will be monitored in all enrolled patients in both trial arms (n≤36) biweekly from d28-100 post-HCT and every 30d thereafter by measuring numbers of CD8+ T cells binding to HLA-tetramers. Additional correlative studies will include assessment of PD-1 expression on CMV-specific T cells (as a measure of exhaustion), measuring proliferative capacity (CFSE dilution method) by cell division and cell death. Reduction of apoptosis markers and increased proliferation of CMV-specific T cells is expected in vaccinated compared to unvaccinated patients. Immune assessments will be done in batch at the conclusion of six months of observation. Pending success of the pilot trial, NCI will provide a fresh lot of vaccine to support a large multi-center phase II study jointly with the University of Minnesota Comprehensive Cancer Center (see Project 2).

Personnel
Ryotaro Nakamura, M.D.
Principal Investigator of IRB12022
 
Jennifer Drake, C.C.R.P.
Study Coordinator

Cindy Slape, R.N.
Clinical Research Nurse
 
Corinna La Rosa, Ph.D.
Associate Research Professor
Conducts the laboratory investigations

Staff of the Department of Hematology & Hematopoietic Cell Transplantation