|Research||Pre-Clinical||Phase I||Phase II||Phase III|
A heterologous therapeutic HPV16 DNA Vaccine is being developed for the treatment of patients with persistent HPV16+ atypical squamous cells of unknown significance or Low-grade squamous intraepithelial lesion (AS-CUS/LSIL). The approach consists of two separate vaccine preparations, pNGVL4aCRTE6E7L2, a naked DNA vaccine (“prime”), and Tissue Antigen-Cervical Intraepithelial Neoplasia (TA-CIN) fusion protein comprised of HPV16 E6, E7 and L2 proteins linked in tandem that are given separately to patients in an immunization regimen. The pNGVL4aCRTE6E7L2 DNA primes the patient’s immune system to respond to the TA-CIN antigen and together they induce HPV-16 E6, E7, and L2-specific cellular immunity, as well as HPV-16 L2-specific antibodies.
The DNA prime and TA-CIN boost immunization regimens have been designed and optimized in a murine tumor model to stimulate cellular and humoral immune responses targeting HPV16. Studies in the mouse TC-1 tumor model (TC-1 cells express the E6 and E7 oncoproteins from HPV-16) show that priming twice with DNA followed by a single TA-CIN protein boost generates potent systemic HPV-specific CD8+ T cell responses. TA-CIN protein vaccination also elicits antigen-specific antibody responses. Priming twice with pNGVL4aCRTE6E7L2 followed by a single TA-CIN protein boost also generated stronger HPV-specific CD8+ T cell responses in naïve mice. In these studies, there were no detectable toxicities.
DNA vaccines are safe, even for immunocompromised individuals, in that they do not contain live pathogen but still elicit cell-mediated and/or humoral immune responses. We have recently shown that CRT profoundly enhances the induction of cellular immunity, and that DNA encoding CRT linked to HPV tumor antigens exhibits a potent E7-specific CD8+ T cell response in CD4-depleted animals. We also demonstrated that naked DNA expressing CRT exhibits an antitumor effect even in nude mice via an anti-angiogenic mechanism. Furthermore, vaccination of mice with pNGVL4aCRTE6E7L2 DNA elicits a potent antitumor effects against E7-expressing tumors even in mice depleted for CD4 T cells, suggesting that this vaccine may still be active even in immune compromised hosts.
TA-CIN protein has been shown to be well tolerated in a number of early phase trials in HPV+ patients, and clinically apparent side effects were not seen when used either alone or in combination in naïve and TC-1 tumor bearing animal studies.
In the proposed human clinical studies, the pNGVL4aCRTE6E7L2 DNA will be evaluated in a dose escalation study (0.3mg, 1.0mg, and 3.0mg.). Each dose level consists of three-time vaccine administration (week 0 Day 1, Week 4 Day 1, Week 8 Day 1). Furthermore, the pNGVL4aCRTE6E7L2 DNA and TA-CIN protein immunization regimen consists of two intramuscular injections of 3 mg pNGVL4aCRTE6E7L2 DNA vaccine (prime; Week 0, Week 4) followed by one intramuscular injection of 0.10 mg TA-CIN fusion protein (boost; Week 8), will be evaluated.