Human Papillomavirus Immunogen That Provides Protective Tumor Immunity and Induces Tumor Regression

Abstract

Human papillomavirus (HPV) is associated with premalignant lesions such as high-grade cervical intraepithelial neoplasia (CIN-III) with potential progression to cervical carcinoma. There are now preventive vaccines against HPV. However, no effective therapeutic vaccine or immunological treatment exists for individuals already infected or for the 470,000 women that develop high-grade dysplasia, carcinoma in situ, and cervical cancer each year. More than half of these women die from cervical cancer. Relative non-immunogenicity of HPV infection is one of the main reasons for the difficulty in designing a comprehensive therapeutic vaccine against HPV-induced premalignant lesions and cervical carcinoma. HPV E6 and E7 proteins, the major HPV oncogenes, are highly immunogenic but fail to induce cross-reactive and protective immune responses against heterologous strains. We designed and synthesized a therapeutic peptide vaccine comprised of multivalent peptide mixtures called hypervariable epitope constructs (HECs) that represent the major epitope variants of the oncogenic E7 structural protein, and assessed their immunogenicity and in vivo efficacy in mice. Our results show that this peptide vaccine can induce strong, HPV-specific, T-helper cell and CTL responses. More significantly, we have demonstrated that the vaccine is efficacious as a therapeutic agent in a mouse HPV tumor model. Therefore, the HPV HEC vaccine approach described herein can potentially prevent progression of HPV-associated premalignant lesions, and may also be therapeutic against tumors associated with HPV.

Redirecting the focus of cancer immunotherapy to premalignant conditions

“…After re-vaccination at 1 year, Th1 responses remained, although enthusiasm for the re-vaccination was dampened by the Th2 cytokine response that also developed upon revaccination. In a study using a mouse HPV tumor model to assess both immunological and clinical responses, peptide mixtures of the HPV E7 oncogene were shown to stimulate both antibody and cellular immune responses reactive to HPV constructs and to limit tumor development [ 74 ]. While this latter study demonstrated the feasibility of HPV vaccine approaches to limit tumor development, it did not address the impact of vaccination on eliciting reactivity to premalignant lesions and their progression to cancer.…”