Year-end Sale % OFF 
Abstract
Clinical studies suggest that responses to HPV16 E6E7L2 fusion protein (TA-CIN) vaccination alone are modest, and GPI-0100 is a well-tolerated, potent adjuvant. Here we sought to optimize both the immunogenicity of TA-CIN via formulation with GPI-0100 and treatment of HPV16+ cancer by vaccination after cisplatin chemotherapy. HPV16 neutralizing serum antibody titers, CD4+ T cell proliferative and E6/E7-specific CD8+ T cell responses were significantly enhanced when mice were vaccinated subcutaneously (s.c.) or intramuscularly (i.m.) with TA-CIN formulated with GPI-0100. Vaccination was tested for therapy of mice bearing syngeneic HPV16 E6/E7+ tumors (TC-1) either in the lung or subcutaneously. Mice treated with TA-CIN/GPI-0100 vaccination exhibited robust E7-specific CD8+ T cell responses, which were associated with reduced tumor burden in the lung, whereas mice receiving either component alone were similar to controls. Since vaccination alone was not sufficient for cure, mice bearing s.c. TC-1 tumor were first treated with two doses of cisplatin and then vaccinated. Vaccination with TA-CIN/GPI-0100 i.m. substantially retarded tumor growth and extended survival after cisplatin therapy. Injection of TA-CIN alone, but not GPI-0100, into the tumor (i.t.) was similarly efficacious after cisplatin therapy, but the mice eventually succumbed. However, tumor regression and extended remission was observed in 80% of the mice treated with cisplatin and then intra-tumoral TA-CIN/GPI-0100 vaccination. These mice also exhibited robust E7-specific CD8+ T cell and HPV16 neutralizing antibody responses. Thus formulation of TA-CIN with GPI-0100 and intra-tumoral delivery after cisplatin treatment elicits potent therapeutic responses in a murine model of HPV16+ cancer.
Highlights
Vaccination with TA-CIN formulated with GPI-0100 completely protected mice from a subsequent subcutaneous challenge with the HPV16 E6/E7-expressing TC-1 tumor model [16], but treatment of pre-existing and metastatic TC-1 tumor was not tested
Mice vaccinated with TA-CIN formulated with GPI-0100 had significantly fewer pulmonary tumor nodules and a lower lung weight compared to unvaccinated mice (Fig. 1B and C and S2A Fig.)
When HPV16 E6/E7-specific CD8+ T cell responses were analyzed, we found that TC-1 tumor-bearing mice vaccinated with TA-CIN formulated with GPI-0100 induced dramatically higher E7-specific CD8+ T cell responses than either TA-CIN or GPI-0100 only (Fig. 1D and S2B Fig.)
Summary
‘High risk’ human papillomaviruses (hrHPV) cause 5.2% of all cancers worldwide [1]. While persistent hrHPV infection is a necessary cause of cancer, the great majority of infections are spontaneously cleared by the host immunity. The protection afforded by these commercially available vaccines is generally type restricted [6], and vaccination rates remain low in developing countries These vaccines lack therapeutic activity for those patients with persistent HPV infection and established HPV associated cervical dysplasia [7], Therapeutic HPV vaccination has the potential to augment the efficacy of conventional non-specific, surgical and ablative therapies of high grade neoplasia, or even chemoradiation therapy of invasive HPV+ cancers. The E7 peptide-loaded DCs in the draining lymph node could activate E7-specific CD8+ T cells This marked enhancement of E7-specific CD8+ T cells in circulation and antitumor effects was observed when TC-1 tumor-bearing mice were treated with cisplatin and intratumoral TA-CIN vaccination [35]. We compared vaccination alone and cisplatin followed by intratumoral or intramuscular vaccination TA-CIN formulated with GPI-0100 adjuvant for the treatment of established TC-1 tumors
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
