Vaccine for cancer and infectious diseases. Free

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Recent analyses of influenza vaccination clinical data shows that there is no survival advantage above the age of 55 and a 4 fold lower antibody response to the multivalent inactivated particle influenza vaccination in individuals over the age of 55. This poor response to vaccines may be due to decreased numbers of antigen naïve CD8 and CD4 T cells, and the acquisition of functional defects in CD4 helper cells, like decreased expression of the CD40L in activated CD4 cells. In order to develop a method to overcome these defects in the immune response in older individuals, we have designed an adenoviral vector (Ad-sig-TAA/ecdCD40L) for the in vivo activation and tumor antigen loading of dendritic cells (DCs). This adenoviral vector encodes a fusion protein composed of an aminoterminal tumor associated antigen (TAA) fragment fused to the extracellular domain (ecd) of the CD40 ligand (CD40L) at the carboxyl terminal end. Two sc injections of this vector have broken tolerance to specific tumor associated antigens in two separate TAA.Tg transgenic mouse models (mice transgenic for rat Her-2-Neu (rH2N) and human MUC-1 (hMUC-1)). Her-2-Neu and MUC-1 are tumor associated antigens which are overexpressed in poor prognosis epithelial neoplasms such as adenocarcinomas of the breast , prostate, ovary, colon and lung. The immunoprotection extends for over a year and is independent of CD4 cells. We showed that the sc injection of the hMUC-1/ecdCD40L protein following the sc injection of the Ad-sig-TAA/ecdCD40L vector (this vector prime-protein boost is called VPP) increases the levels of both the cellular and humoral immune response over that achievable with just the vector injections alone in the hMUC-1.Tg mice. The antibodies from hMUC-1 VPP vaccinated mice bind to biopsy specimens of human cancers of the breast and prostate. Importantly, the VPP vaccination can induce an immune response even in 18 month old mice which completely suppresses tumor growth in old (18 month old) mice. The Ad-sig-rH2N/ecdCD40L vaccination suppresses the evolution of spontaneous breast cancer in the rH2N.Tg mouse model. We also tested the immune response induced by the Ad-sig-HA/ecdCD40L vector prime-HA/ecdCD40L protein boost which is directed to the H5N1 hemagglutinin (HA) antigen and the Ad-sig-M2/ecdCD40L vector prime-M2/ecdCD40L protein boost vaccine against the M2 antigen, which has a common sequence among human and avian influenza strains. Both induced a robust cellular and humoral response in old (18 month) mice as well as in young (2 month) mice. The serum of mice vaccinated with 3 sc injections of HA/ecdCD40L contained neutralizing antibodies against the H5N1 486 avian influenza virus at 1/4000 dilution of the serum. The Ad-sig-TAA/ecdCD40L vector prime-TAA/ecdCD40L protein boost strategy may be of value in the prevention and treatment of cancer and infectious diseases.