HPV strategy: Lessons from basic science research provide immunotherapy clues

August 1, 2008

Ian H. Frazer, M.D., in collaboration with Jian Zhou, Ph.D., developed the virus-like particle technology that led to the design of effective vaccines for preventing infection with HPV types causing anogenital warts and certain cancers, particularly cervical cancer.

Key Points

National report - Findings from basic science research designed to understand the immunology of human papillomavirus (HPV)-associated epithelial tumors will, hopefully, lead to the development of effective therapeutic vaccines for these malignancies, says Ian H. Frazer, M.D., professor, department of medicine, and director of the Diamantina Institute for Cancer, Immunology and Metabolic Medicine, University of Queensland, Australia.

Dr. Frazer was honored earlier this year by the American Academy of Dermatology (AAD) with the Lila H. Gruber Memorial Cancer Research Award & Lectureship in recognition for his work, in collaboration with his colleague Jian Zhou, Ph.D., in developing the HPV virus-like particle technology that became the basis for creating vaccines to prevent HPV infection (Gardasil, Merck; Cervarix, GSK).

Dr. Frazer says that, while the commercially available HPV vaccines provide highly effective prophylaxis against persistent HPV infection and its sequela of precancerous cervical lesions, a critical need remains for a therapeutic vaccine that can eradicate existing infection with oncogenic HPV subtypes.

"However, in parts of the world where there are no screening programs, cervical precancer is a disease that will eventually progress to cancer. Only a therapeutic intervention, not a prophylactic vaccine, can protect against that progression," Dr. Frazer tells Dermatology Times.

Dr. Frazer describes a series of studies undertaken in an animal model of HPV infection, based on grafting of skin genetically engineered to express papillomavirus antigens, to understand the factors needed to develop effective immunotherapy for HPV-associated cancers.

These studies aimed to explain the paradox of why investigational therapeutic vaccines that were effective in inducing relevant immune responses in humans - including measurable induction of cytotoxic T cells directed against the target tumor nonself antigens - were unsuccessful in clearing precancerous and cancerous cervical lesions.

A first step in the research was to create a better preclinical model, recognizing that the existing assay using mice with transplanted tumors was not rigorous enough to discriminate effective from ineffective vaccines.

Thus, a new model for HPV immunotherapy research was developed using transgenic skin grafts expressing the HPV nonstructural proteins that act as the nonself-tumor antigens.

Using this platform, Dr. Frazer and his colleagues identified several critical factors for a successful therapeutic HPV vaccine, including induction of viral antigen-specific CD4 helper T cells in addition to CD8 cytotoxic T cells, the presence of a local inflammatory environment, and use of strategies that will overcome local immunosuppression in the skin and promote T-cell migration to the tumor.

Dr. Frazer says healthy skin is an immunoprivileged site, as cytokines and other factors constitutive to the skin regulate immune system responses via multiple pathways, including effects on local inflammation and T-cell stimulation, proliferation and trafficking.

In addition, the tumor itself can fight back by expressing proteins leading to the destruction of cytotoxic T cells.

"All of these mechanisms exist to protect us from being damaged by our own immune system, and clearly, it is not a simple case of addressing one of these factors or another. As in all of immunology, these multiple players interact, and all of the proper factors must be in place before the cytotoxic T cells can effectively kill their epithelial target," Dr. Frazer says.

Promising results

Experiments applying this knowledge of basic immunology have yielded promising results in improving the efficacy of immunotherapy for HPV-associated cancer in animal models.

However, manipulating the immune system to enhance the immune response represents a double-edged sword, because the factors that are interfering with the efficacy of immunotherapy also act as regulators of self-reactivity.

"If you take these blocks away, consequences occur beyond those being sought. For example, animals unable to synthesize the immunoregulatory cytokine IL-10 develop colitis, and animals treated with interferons or lacking negative co-stimulators tend to develop autoimmune diseases," Dr. Frazer says.

The solution to optimizing the risk-benefit ratio of immunotherapy appears to lie in implementation of strategies that cause only short-term suppression of intrinsic immunoregulatory mechanisms.

Promising progress has been made in this area with the use of anti-CTLA4 treatment used in combination with vaccines for ovarian cancer, Dr. Frazer says.

He says prophylactic HPV vaccines have the potential to reduce the incidence of HPV-associated cancer, and their rapid deployment in the developing world is a moral responsibility.

Nevertheless, therapeutic vaccines could achieve more immediate benefit by eradicating existing infections that could go on to cause cancer.

"However, the vaccine technology is immature, requires more basic research, and the answers are likely to preclude routine immunotherapy, considering that the necessary immunomodulatory strategies will carry a risk of autoimmunity.

"Therefore, immunotherapy will likely be reserved for treatment of serious disease - i.e., identified existing cancers and possibly identified precancerous lesions - and is unlikely to be used on a population basis for preventing progression of infection," Dr. Frazer says.

Disclosure: Dr. Frazer, as inventor of the virus-like particle technology that is the basis of vaccines for prevention of HPV infection, receives royalties from the sales of Gardasil and Cervarix.

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