Abstracts

Immunotherapy of HPV-Induced Diseases by HspE7, a Heat Shock Fusion Protein

Abstract presented at the Walker's Cay Colloquium on Cancer Vaccines and Immunotherapy - Walker's Cay, Bahamas, March 5^th to 8^th, 2003

G. Rowse(1), R. Chu(1), B. Wu(1), H. Liu(1), A. Recktenwald(1), L. Boux(2), J. Neefe(2),  L. Mizzen(1),  M. I. Siegel(2);

(1) Stressgen Biotechnologies Corporation, Victoria, BC, CANADA. 
(2) Stressgen Biotechnologies Inc., Collegeville, PA.

Despite many years of research, effective immunotherapeutic treatments for cancer remain elusive. It is generally accepted that cell mediated immunity plays an important role in the surveillance and rejection of tumors. One approach to cancer immunotherapy is the administration of therapeutic “vaccines” composed of tumor associated antigens (TAAs). It is thought that such cancer vaccines should optimally elicit TAA-specific CTL with concomitant production of type 1 cytokines to amplify innate and adaptive immune responses. However, there are a number of challenges in the construction of therapeutic cancer vaccines, including choice of TAA and the mode of antigen delivery. With respect to antigen delivery, a variety of approaches have been developed to augment cellular immune responses, including inclusion of adjuvant, cytokines or formulation into viral or nucleic acid vectors. Despite these advances, there remain very few safe and effective alternatives for robust induction of CTL to vaccine antigens.

Hsp fusion proteins (also called CoVal™ fusions) represent a novel technology platform for the induction of antigen-specific cellular immune responses. This has been demonstrated in numerous animal models with viral and cancer antigens. Notably, class I-restricted CTL are induced in the absence of adjuvant in both normal and CD4-deficient mice.  With these features in mind, we have developed a therapeutic vaccine against Human papillomavirus (HPV), a ubiquitous pathogen associated with benign and malignant anogenital diseases. HspE7, a recombinant fusion protein comprised of M. bovis BCG heat shock protein (Hsp) 65 covalently linked to HPV16 E7 (designated SGN-00101), is in clinical development by Stressgen Biotechnologies and its partner Roche. We have demonstrated that immunization with HspE7 can induce cellular and humoral immune responses and eradicate established HPV16 E7 expressing tumors in mice. In addition, as predicted by preclinical experiments, treatment with HspE7 provides clinical benefit in phase II immunotherapy trials of anogenital HPV diseases.  The mechanisms by which Hsp fusion proteins induce therapeutic tumor rejection are under investigation, but current evidence suggests they may act by bridging innate and acquired immune responses. CoVal™ fusions activate antigen-presenting cells and induce antigen-specific CD8+ CTL which secrete interferon and tumor necrosis factor . Therefore, Hsp fusion proteins represent a promising platform for the immunotherapeutic treatment of viral diseases and cancer.