Therapeutic vaccines targeted at HPV-associated tumors

Therapeutic vaccines targeted at HPV-associated tumors

Therapeutic vaccines are designed to treat preexisting HPV infection cases. The potential vaccines focus on E6 and E7, the HPV oncoproteins. Since both of these are required to maintain the transformed states of HPV-induced neoplastic cells, they are the prime targets for therapeutic vaccine intervention.

Emphasis in developing vaccines have been placed on:

minimizing presentation of E6 and E7 to the inductive arm of the immune response
introducing cytokine-encoding genes into ex vivo to induce tumor-specific CTL response
vaccinating with autologous tumor cells which have been engineered to create cytokines
eliciting Th1--which induces IgG2a antibody-- to confer antibody-dependent lymphocyte activated killer (LAK)

Tumors have evasion mechanisms, which result from:

point mutations in genes encoding CTL epitopes within HPV proteins
down-regulation of endogenous peptide processing machinery (TAP), required for antigen stimulated CTL response

Experiments in animal models have shown the ability of E6 and E7 to prevent tumor formation. BPV4 E7 has been shown to be a successful target for BPV4-induced papillomas, and areas of homology in the conserved regions of BPV4 E7 and HPV16 E7 suggests that HPV16 E7 may be successful target in humans.

Therapeutic Vaccine Trials in Humans

Cervical Cancer:

One Phase I trial underway uses peptides containing proven immunogenic HPV16 E7 CTL epitopes restricted by HLA A* 0201 in cervical carcinoma patients expressing this haplotype. The peptide is administered in adjuvant known to predispose to Th1 response.

A trial of HPV16 E7 as bacterial fusion protein administered in alum demonstrated Th2-type immunogenicity and lack of toxicity.

Issues which require special attention for cervical cancer trials:

For peptide vaccines adjuvants should be optimized to elicit Th1 rather than Th2 response.
Therapeutic vaccines must establish specific CTL memory, and should avoid need for repeated immunization.

Anogenital warts:

There are no prospective therapeutic vaccines against genital warts in clinical trials. There are many treatments for HPV associated genital warts, though none are universally effective. One non-vaccine possibility is a topical ointment called imiquimod that acts to reduce wart infection by stimulating the host’s Th1 immune response, notably INFg (Beutner KR et al 1997). Since HPV type 6 and 11 are responsible for anogenital warts, a prospective therapeutic vaccine must be type specific. Researchers are investigating the possibility of combined therapies using a vaccine along with topical and/or surgical therapies.

Return to Main Menu

Continue to Vaccine Trials Underway