Therapeutic Vaccine for HIV/HPV-associated Oropharyngeal and Tonsillar Malignanci

Award Information
Agency: Department of Health and Human Services
Branch: N/A
Contract: 1R43DE021973-01
Agency Tracking Number: R43DE021973
Amount: $163,405.00
Phase: Phase I
Program: SBIR
Awards Year: 2011
Solicitation Year: 2011
Solicitation Topic Code: NIDCR
Solicitation Number: PA10-050
Small Business Information
410 W HARRISON ST, STE 100, SEATTLE, WA, 98119-
DUNS: 154453018
HUBZone Owned: N
Woman Owned: N
Socially and Economically Disadvantaged: N
Principal Investigator
 (206) 838-5110
Business Contact
Phone: (206) 838-5110
Research Institution
DESCRIPTION (provided by applicant): The objective of this project is to develop a therapeutic strategy for H V-associated malignancy based on the role of HPV in the pathogenesis. HPV related cancers express the E6/E7 oncoproteins of HPV that are ideal targets for immune inducing vaccines. We will develop a vaccine based upon a novel adenovirus serotype-S vector (Ads) platform with unique and additional deletions of the viral DNA polymerase and the pre- terminal protein in the early gene 2b (E2b) region (Ads [E1-, E2b-]). In studies employing HIV antigens, we reported that the new Ad5 [E1-, E2b-]-HlV vector vaccine was superior to a current Ads [E1-]-H V vector vaccine (containing deletion in the early gene 1 (E1) region) when used to induce CMI responses ina multiple immunization regimen. Significant antigen specific CMI responses were induced in mice and monkeys despite the presence of pre-existing AdS immunity. We will construct and produce an AdS [E1-, E2b-] vector vaccine that contains the HPV oncoproteins E6/E7 with non-oncogenic function. This new recombinant adenovirus will induce immune responses by expressing the modified HPV-E6/E7 antigens after direct transfection of antigen presenting cells. We will evaluate this in combination with a toll-like receptor agonist (TLRa) designed to enhance immune responses induced by the vaccine. Our pre-clinical data indicate that the AdS [E1-, E2b-] vec*or induces robust CMI responses against tumor associated antigen [fAA), even in the presence of pre- existing AdS immunity. In a murine cancer model employing the carcinoembryonic antigen (CEA) gene insert, tl.g -CEA immunogenicity and in vivo anti-tumor effects of repeated immunizations with i new AdS [E1-, E2b-l- GEA were compared to those observed with a currentgeneration Ads tE1-l-CEA. These AdS vectors were tested in a clinically relevant AdS immune setting. We observed that AdS immune mice immunized multiple times with AdS [E1-, E2b-]-CEA induced CEA-specific CMI responses that were significantly increased over those detected in AdS immune mice immunized multiple times with a current generation AdS tE1-l-CEA. Ads immune mice bearing CEA expressing tumors that were treated with AdS [E1-, E2b-J-CEA had an increased anti-tumor response as compared to AdS [E1-I-CEAtreated mice. These results demonstrate that AdS [E1-, Ezb-l-CEA can induce CMI immune responses that result in tumor growth inhibition despite the presence of pre-existing AdS immunity. We have also utilized the Ads [E1-, Ezb-] vector platform expressingthe TAA HER2lneu as a breast cancer immunotherapeutic agent. Ads [E1-, E2b-l-HERZlneu induced potent CMI against HER2/neu and significantly inhibited progression of established tumors in Ad5 immune mice. These data demonstrate that in vivo delivery of Ad5[E1-, E2b-] vectors expressing TM can induce anti-TAA immunity and inhibit progression of tumors in AdS immune animals. PUBLIC HEALTH RELEVANCE: In this study, we will develop a new adenoviral based drug (AdS [E1-, E2b-I-HPV-E6/7) to treat HtV+ patients with HPv-associated oropharyngeal and tonsillar ,ncers. The treatment platform is needed to overcome pre-existing AdS immunity that has prevented the widespread use of this type of technology.

* Information listed above is at the time of submission. *

Agency Micro-sites

SBA logo
Department of Agriculture logo
Department of Commerce logo
Department of Defense logo
Department of Education logo
Department of Energy logo
Department of Health and Human Services logo
Department of Homeland Security logo
Department of Transportation logo
Environmental Protection Agency logo
National Aeronautics and Space Administration logo
National Science Foundation logo
US Flag An Official Website of the United States Government