IMMUNOTHERAPEUTIC MODULATION OF ANGIOGENESIS IN CANCER

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The goal of this project is to develop and clinically apply synergistic strategies combining anti-angiogenesis with tumor-specific immunotherapy for the treatment of neuroblastoma. This proposal will test the hypothesis that an anti-angiogenic, vasculature-specific integrin alpha v peptide antagonist synergizes with tumor-specific antibody-interleukin-2 fusion proteins, that proved very efficient in suppressing growth of disseminated tumors in preclinical metastasis models. The underlying rationale is that integrin alpha v peptide antagonists are potent inhibitors of angiogenesis, which may reduce blood supply to primary tumors and metastases and subsequently facilitate an immunotherapeutic attack in the tumor compartment. Effects and mechanisms of a tumor-specific anti body- interleukin-12 fusion protein will also be evaluated, that combines both anti-angiogenesis with immunomodulation in one molecule, and suppressed tumor metastasis in xenograft models. The validity of our hypothesis is supported by preliminary data, indicating that only the combination of peptide antagonists with fusion proteins induced primary tumor regressions and eradication of spontaneous hepatic neuroblastoma metastases. A simultaneous reduction in blood vessel density and increase in tumor infiltrating leukocytes was demonstrated only in animals treated with this combination. In the first year, we will further optimize and characterize the therapeutic effect of combining integrin alpha v peptide antagonists with antibody interleukin-2 fusion proteins and evaluate effect and mechanism of antibody-interleukin-12 fusion proteins in syngeneic animal models. In the second year, we will initiate a phase I-II clinical trial to investigate the toxicity and immune response of the peptide antagonist/fusion protein combination in patients with stage 4 neuroblastoma and its effect on the clinical course of the disease. These preclinical and clinical studies should contribute to our understanding of the synergy between anti-angiogenesis and active specific cancer immunotherapy and lead to further optimization of adjuvant treatment of cancer.