CMV infection of hematopoietic stem cell transplant (HSCT) recipients is a continuing problem that impacts the outcome of this very successful therapy. Anti-viral treatment with ganciclovir/foscarnet is the main treatment strategy to prevent CMV disease post-transplant (Tx). Despite significant advances in formulation and delivery of anti-virals, their use complicates and extends the post-Tx recovery period and risk for CMV disease. The period of immunologic incompetence, pre- and post-Tx complicates the timing of administering immunotherapy. Considering these caveats, we are pursuing a novel therapeutic strategy that focuses on priming or enhancing CMV-specific T cell immunity in healthy adults and HSCT donors. The approach utilizes peptide fusions combining CMV-specific CTL and promiscuous HLA-DR-binding T-help epitopes, whose activity has been demonstrated in transgenic (Tg) HLA A2 mouse models. Clinical studies will focus on the safety and immunogenicity of two candidate peptides manufactured under NCI/RAID auspices. Attaining a frequency of 108/liter CMV-specific CTL in peripheral blood of vaccine recipients is an important quantitative goal that translates into an eventual post-infusion level of (107/liter CMV-specific CTL in HSCT recipients, a level associated with disease protection. A two-stage Phase 1 trial design is proposed in which 1) the safety of two peptide vaccines given at 4 time-points with dose escalation will determine the Maximum Tolerated Dose (MTD) in healthy CMV-positives and negatives and 2) the safety of both peptides with a novel adjuvant, CpG 7909 DNA will be defined. A secondary objective will be to measure immunologic correlates, especially the frequency of CMV-specific CTL following each booster, continuing for one year. The best peptide and adjuvant combination based on immunogenicity to enhance recall and primary immune responses will be selected for further Phase 2 evaluation in HSCT donor-recipient pairs. HSCT donors will receive 3 doses of peptide pre-Tx, followed by a single booster in the recipient, 28d post-Tx. The primary endpoint will be reduction in CMV viremia without ganciclovir treatment. The trial is sufficiently powered to detect a 40% decrease in viremia, distinguishable between vaccines and those offered standard of care. A secondary objective is quantitative measurement of CMV-specific cellular immunity in HSCT recipients for one-year post-Tx. In this trial, protection from CMV disease will be compared between recipients receiving vaccine or standard of care. The goal of developing a universal repertoire of CMV-specific vaccine candidates will be the object of a developmental study of new fusion peptides in Tg mouse models that cover population subsets other than HLA A2 that would be applicable to a majority of HSCT recipients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA077544-08S1
Application #
7231174
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Ogunbiyi, Peter
Project Start
1998-04-01
Project End
2009-02-28
Budget Start
2006-04-01
Budget End
2007-02-28
Support Year
8
Fiscal Year
2006
Total Cost
$107,229
Indirect Cost
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
Wussow, Felix; Chiuppesi, Flavia; Meng, Zhuo et al. (2018) Exploiting 2A peptides to elicit potent neutralizing antibodies by a multi-subunit herpesvirus glycoprotein complex. J Virol Methods 251:30-37
Diamond, Don Jeffrey; La Rosa, Corinna; Chiuppesi, Flavia et al. (2018) A fifty-year odyssey: prospects for a cytomegalovirus vaccine in transplant and congenital infection. Expert Rev Vaccines 17:889-911
Chiuppesi, Flavia; Nguyen, Jenny; Park, Soojin et al. (2018) Multiantigenic Modified Vaccinia Virus Ankara Vaccine Vectors To Elicit Potent Humoral and Cellular Immune Reponses against Human Cytomegalovirus in Mice. J Virol 92:
Wussow, Felix; Chiuppesi, Flavia; Contreras, Heidi et al. (2017) Neutralization of Human Cytomegalovirus Entry into Fibroblasts and Epithelial Cells. Vaccines (Basel) 5:
Fan, Qihua; Nelson, Cody S; Bialas, Kristy M et al. (2017) Plasmablast Response to Primary Rhesus Cytomegalovirus (CMV) Infection in a Monkey Model of Congenital CMV Transmission. Clin Vaccine Immunol 24:
La Rosa, Corinna; Longmate, Jeff; Martinez, Joy et al. (2017) MVA vaccine encoding CMV antigens safely induces durable expansion of CMV-specific T cells in healthy adults. Blood 129:114-125
Chiuppesi, Flavia; Kaltcheva, Teodora; Meng, Zhuo et al. (2017) Identification of a Continuous Neutralizing Epitope within UL128 of Human Cytomegalovirus. J Virol 91:
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

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