A landmark therapeutic breakthrough was the preemptive use of antiviral drugs including ganciclovir (GCV) and foscarnet (FOS) to control cytomegalovirus (CMV) viremia in hematopoietic cell transplant (HCT) recipients. These drugs have remarkable properties to limit progression from viremia to disease but also have significant side effects, including exacerbating neutropenia, delay of immune reconstitution, and renal toxicity in the case of FOS. To overcome using these antiviral agents, we proposed a peptide vaccine to stimulate the host immune response to CMV. In the last funding period we conducted a Phase 1 trial of the peptide vaccine with or without Pfizer PF03512676 adjuvant that confirmed the safety of 2 different formulations, with evidence of immunologic activity based upon flow cytometry analysis of CMV-pp65- specific T cells. A limitation of the peptide vaccine is its restriction to individuals with the HLA-A2 haplotype which narrows the target population. While we are seeking to confirm a therapeutic benefit of the peptide vaccine in HCT recipients, broadening the population that would benefit from a vaccination strategy is best approached by employing a delivery vector that expresses full length CMV antigens. We have used modified vaccinia Ankara (MVA) virus for that purpose in collaboration with NCI-NExT to manufacture a candidate for clinical testing. In this revised application, we propose 3 clinical trials that will comprehensively evaluate our clinical vaccine candidate.
In Aim 1, a safety study (Trial 1) will be conducted in healthy volunteers stratified by age and poxvirus exposure who are equivalent health-wise to immunocompetent HCT donors as required by the FDA and will establish the safety and dose level for a 2nd trial in HCT.
In Aim 2, a double-blind Phase 2 trial is described in which 150 HLA matched related HCT donors (MRD) will be randomized equally to receive either vaccine or placebo. Immune responses and clinical correlates of vaccine-stimulated protection will be followed in recipients whose donors are enrolled in Trial 2.
In Aim 3 (Trial 3), we propose to directly immunize 150 HCT recipients undergoing unrelated (8/8 HLA matches) donor (URD) HCT after gaining safety experience by following the clinical course of 30 recipients in Trial 2. This approach is justified since these recipients are at high-risk for CMV reactivation and do not have consistently accessible donors. Trials 2 and 3 will each enroll 150 HCT subjects, randomized equally to vaccine or placebo and both will have 90% power to detect a 50% reduction in viremia (60% to 30%) in the vaccine arm. Safety monitoring employing defined stopping rules will guard against adverse consequences for recipients in both trials. Combined results from carrying out both Trials 2 and 3 will provide a precise immunoprophylaxis strategy for control of CMV disease in the HCT setting. We will discover the optimal formula for immunizing both donors and recipients to prevent CMV viremia and minimize usage of potentially toxic antiviral agents. Success with this CMV vaccine would have a significant clinical and cost-saving effect on recipient management after MRD or URD HCT.

Public Health Relevance

Hematopoietic stem cell transplantation (HCT) is one of the most successful cancer therapeutic approaches that offer the potential of curing hematologic malignancy for many patients. Side effects of HCT include infectious complications as well as graft versus host reactions. Among the infectious complications that are most severe are herpes virus infections including cytomegalovirus (CMV). We propose a vaccine strategy to combat complications of CMV infections by first confirming safety in healthy volunteers, followed by vaccinating healthy HCT donors and following outcomes in their related recipients, and finally providing direct immunization to at-risk HCT recipients with unrelated donors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA077544-13
Application #
8586816
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Merritt, William D
Project Start
1998-04-01
Project End
2016-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
13
Fiscal Year
2014
Total Cost
$615,816
Indirect Cost
$249,259
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
Limaye, Ajit P; La Rosa, Corinna; Longmate, Jeff et al. (2016) Plasma IL-10 Levels to Guide Antiviral Prophylaxis Prevention of Late-Onset Cytomegalovirus Disease, in High Risk Solid Kidney and Liver Transplant Recipients. Transplantation 100:210-6
Nakamura, Ryotaro; La Rosa, Corinna; Longmate, Jeffrey et al. (2016) Viraemia, immunogenicity, and survival outcomes of cytomegalovirus chimeric epitope vaccine supplemented with PF03512676 (CMVPepVax) in allogeneic haemopoietic stem-cell transplantation: randomised phase 1b trial. Lancet Haematol 3:e87-98
Cichocki, F; Cooley, S; Davis, Z et al. (2016) CD56dimCD57+NKG2C+ NK cell expansion is associated with reduced leukemia relapse after reduced intensity HCT. Leukemia 30:456-63
Gibson, Laura; Barysauskas, Constance M; McManus, Margaret et al. (2015) Reduced frequencies of polyfunctional CMV-specific T cell responses in infants with congenital CMV infection. J Clin Immunol 35:289-301
Chiuppesi, Flavia; Wussow, Felix; Johnson, Erica et al. (2015) Vaccine-Derived Neutralizing Antibodies to the Human Cytomegalovirus gH/gL Pentamer Potently Block Primary Cytotrophoblast Infection. J Virol 89:11884-98
Israyelyan, A; Goldstein, L; Tsai, W et al. (2015) Real-time assessment of relapse risk based on the WT1 marker in acute leukemia and myelodysplastic syndrome patients after hematopoietic cell transplantation. Bone Marrow Transplant 50:26-33
Wang, Xiuli; Wong, ChingLam W; Urak, Ryan et al. (2015) CMVpp65 Vaccine Enhances the Antitumor Efficacy of Adoptively Transferred CD19-Redirected CMV-Specific T Cells. Clin Cancer Res 21:2993-3002
Davis, Zachary B; Cooley, Sarah A; Cichocki, Frank et al. (2015) Adaptive Natural Killer Cell and Killer Cell Immunoglobulin-Like Receptor-Expressing T Cell Responses are Induced by Cytomegalovirus and Are Associated with Protection against Cytomegalovirus Reactivation after Allogeneic Donor Hematopoietic Cell Transpla Biol Blood Marrow Transplant 21:1653-62
Bialas, Kristy M; Tanaka, Takayuki; Tran, Dollnovan et al. (2015) Maternal CD4+ T cells protect against severe congenital cytomegalovirus disease in a novel nonhuman primate model of placental cytomegalovirus transmission. Proc Natl Acad Sci U S A 112:13645-50
Wussow, Felix; Chiuppesi, Flavia; Martinez, Joy et al. (2014) Human cytomegalovirus vaccine based on the envelope gH/gL pentamer complex. PLoS Pathog 10:e1004524

Showing the most recent 10 out of 73 publications