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-specifie T cell immunity in healthy adults and HSCT donors. The approach utilizes pepfide 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 immunogerdcity of two candidate peptides manufactured under NCI/RAID auspices. Attaining a frequency of 10S/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 pepfide 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 vaccinees 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. PEFORMANCSEITE(S)(organizationc,ity,state) Beckman Research Institute of the City of Hope, Duarte, CA 91010 KEYPERSONNELS. eeinstructionUs.secontinua#opnagesasneededtoprovidetherequireidnformatiointheformasthownbelow. StartwithPrincipaInl vestigatoLri.stallotherkeypersonneinlalphabeticoarlderl,astnamefirst. Name Organization RoteonProject Don J. Diamond, Ph.D. Beckman Research Institute Principal Investigator John A. Zaia, M.D. Beckman Research Institute Co-investigator Ryotaro Nakamura, M.D. City of Hope National Medical Center Co-Investigator Joy Fridey, M.D. City of Hope National Medical Center Co-Investigator Simon F. Lacey, Ph.D. Beckman Research Institute Co-Investigator Cofinna La Rosa, Ph.D. Beckman Research Institute Senior Fellow Jeff Longmate, Ph,D. Beckman Research Institute Bio-statistician Wahajul Haq, Ph.D. Beckman Research Institute Peptide Chemist Stephen J. Forman, M.D. City of Hope National Medical Center Consultant Arthur M. Krieg, M.D. Coley Pharmaceuticals Consultant DisclosurePermissionStatementApplicabletoSBIR/STTROnly.Seeinstructions.[] Yes [] No PHS398(Rev.05/01) Page 2 FormPage2 Principal InvestigatodProgram Director (Last, first, middle): Diamond Don J. The name of the principal investigatodprogram director must be provided at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page .................................................................................................................................................. 1 Description,
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