Research remains the principal activity of
the Division. The main area of investigation is the development of procedures
for active immunization against self and non self molecules as a means to treat cancer, infectious diseases. Projects active in the division:
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Development of Vaccines (HER-2/neu) for the Prevention or Therapy of Cancer
- Development of Angiogenic (VEGF) Inhibitors for Cancer Therapy
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Phase 1 Clinical Trial: Active Immunotherapy with HER-2 Multiepitope Vaccine
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Peptide and Protein Design to Define Antigenic Determinants
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Human T-cell Lymphotropic Virus Type 1 (HTLV-1) Vaccine Development
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Structural and Conformational Aspects in Vaccines
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Novel Peptide Therapeutic Approaches for Immune Tolerance
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Development of
non-human primate model for HTLV-1 infection and prevention
In addition to the continuous support for
vaccine development by the The National Cancer Institute,
The National Institutes of Health, Omnimmune Corporation, the Division of
Reproductive Biology and Vaccine Research has received
a permanent funding award from the Ohio Board of Regents for the enhancement of
the Division's research activities in the field of vaccine development and
protein engineering.
Projects
active during the past year are:
Phase 1b Active Immunotherapy with HER-2 Multi-epitope Vaccine
The overall objective of this proposal is to test a multi-epitope combination
vaccine targeting the HER-2/neu proto-oncogene. The main objective is to assess
immunological response, safety and toxicity in patients with confirmed
metastatic and/or recurrent cancer for which there is no therapy to improve
survival.
Chimeric and Multivalent HER-2 Cancer Vaccine Strategies
The long range goal is develop novel and innovative approaches to antigen
specific vaccination targeting the HER-2 extracellular domains, to elucidate the
underlying mechanisms of anti-tumor effects elicited by peptide vaccines against
a self protein, and to suggest an immunization strategy that might be effective
in human cancer vaccines.
Angiogenic Therapy with VEGF and HER-2 Peptide Mimics.The present VEGF goals focuses on the development of therapeutic approaches for the treatment of established cancer by the use of novel peptide mimics as viable therapeutics. The first goal is to create novel molecules based on the known crystal structures of HER-2 in complex with pertuzumab, and VEGF with Avastin and VEGFR2. The second goal is to develop retro-inverso D-amino acid peptide mimics which will avoid the major drawbacks in the use of L-amino acid peptide therapeutics such as high susceptibility to proteases in vivo. Such modifications will generate synthetic peptide molecules that are water soluble, highly resistant to proteases, have higher biological half-life thus requiring lower dosage and are nonimmunogenic. The impact of such molecules is such that they would avoid the associated toxicity of present therapeutic regimens in use in the clinic. The overall objectives stems from the following observations: i) that the overexpression of HER-2 is associated with increased expression of VEGF at both the RNA and protein level in human breast cancer cells; ii) exposure of HER-2 over-expressing cells to trastuzumab significantly decreases VEGF expression; iii) a positive association between HER-2 and VEGF expression in breast cancer patients has been identified as well as in established breast cancer cell lines in vitro (20, 21). The main hypothesis to be tested is whether combination treatment with novel conformational peptides of HER-2/neu and VEGF can inhibit anti-tumor and anti-angiogenic responses in vitro and in vivo. Because of the potential synergy between therapy with HER-2 inhibitors and antiangiogenic therapy with VEGF inhibitors, studies are aimed at testing whether the effects of combination of the two therapies interact in a synergistic or additive manner in killing tumor cells, or retarding tumor development. The knowledge to be gained from this research will contribute toward efficient therapeutics for breast cancer.
Structural and Conformational Aspects in Peptide VaccinesThe long range goal is to continue to focus our research efforts on the HTLV-1 env and tax proteins as important targets of both humoral and cell-mediated immune responses against HTLV-1 infection. We propose to exploit these combined approaches to provide structural detail and to define conformationally dependent protective epitopes of selected human T-lymphotropic virus type 1(HTLV-1) enevelope (env) and transactivator (tax) proteins. We propose to develop effective, non-toxic adjuvant systems and adjuvant-free approaches. his multidisciplinary approach should yield a candidate vaccine for testing its immunoprotective nature.
Myocardical Injury Associated with Mitochondria-derived Oxygen Free Radical(s) We are collaborating with Drs. Chen and Zweier to develop conformational anti-peptide antibodies to study the mechanism of enzyme-mediated oxygen free radical generation and the function of enzyme as well as develop therapeutics for prevention and treatment of ischemic injury caused by oxidative stress.
Structural and Conformational Aspects in Peptide VaccinesThe long range goal is to continue to focus our research efforts on the HTLV-1 env and tax proteins as important targets of both humoral and cell-mediated immune responses against HTLV-1 infection. We propose to exploit these combined approaches to provide structural detail and to define conformationally dependent protective epitopes of selected human T-lymphotropic virus type 1(HTLV-1) enevelope (env) and transactivator (tax) proteins. We propose to develop effective, non-toxic adjuvant systems and adjuvant-free approaches. his multidisciplinary approach should yield a candidate vaccine for testing its immunoprotective nature.
