HPV16 synthetic long peptide (HPV16-SLP) vaccination therapy of patients with advanced or recurrent HPV16-induced gynecological carcinoma, a phase II trial

Abstract

Background: Human papilloma virus type 16 (HPV16)-induced gynecological cancers, in particular cervical cancers, are found in many women worldwide. The HPV16 encoded oncoproteins E6 and E7 are tumor-specific targets for the adaptive immune system permitting the development of an HPV16-synthetic long peptide (SLP) vaccine with an excellent treatment profile in animal models. Here, we determined the toxicity, safety, immunogenicity and efficacy of the HPV16 SLP vaccine in patients with advanced or recurrent HPV16-induced gynecological carcinoma.

Methods: Patients with HPV16-positive advanced or recurrent gynecological carcinoma (n = 20) were subcutaneously vaccinated with an HPV16-SLP vaccine consisting of a mix of 13 HPV16 E6 and HPV16 E7 overlapping long peptides in Montanide ISA-51 adjuvant. The primary endpoints were safety, toxicity and tumor regression as determined by RECIST. In addition, the vaccine-induced T-cell response was assessed by proliferation and associated cytokine production as well as IFNγ-ELISPOT.

Results: No systemic toxicity beyond CTCAE grade II was observed. In a few patients transient flu-like symptoms were observed. In 9 out of 16 tested patients vaccine-induced HPV16-specific proliferative responses were detected which were associated with the production of IFNγ, TNFα, IL-5 and/or IL-10. ELISPOT analysis revealed a vaccine-induced immune response in 11 of the 13 tested patients. The capacity to respond to the vaccine was positively correlated to the patient's immune status as reflected by their response to common recall antigens at the start of the trial. Median survival was 12.6 ± 9.1 months. No regression of tumors was observed among the 12 evaluable patients. Nineteen patients died of progressive disease.

Conclusions: The HPV16-SLP vaccine was well tolerated and induced a broad IFNγ-associated T-cell response in patients with advanced or recurrent HPV16-induced gynecological carcinoma but neither induced tumor regression nor prevented progressive disease. We, therefore, plan to use this vaccine in combination with chemotherapy and immunomodulation.

Figure 1

Vaccination results in stronger HPV16-specific immune responses. The strength (median + interquartile range) of the indicated immune response to all 6 pools of HPV16 E6 and E7 peptides for the whole group measured before vaccination (pre-vac), after 2 vaccinations (2-vac) and after the 3^rd or 4^th vaccination (3/4-vac) is given. Only when the strength of the immune response was significantly different, this is indicated by the p-value. Measured was the vaccine-induced proliferation as indicated by the stimulation index using the lymphocyte stimulation test, the antigen-specific increase in the numbers of IFNγ-producing T cells by ELISPOT, and the antigen-specific production of cytokines (IFNγ, IL-5, TNFα and IL-10) in the supernatant of the lymphocyte stimulation test detected by cytokine bead array.

Figure 2

The group of relatively longer living patients displays a stronger HPV16-specific immune response upon vaccination. The patients are grouped according to the median survival time (12.6 months) of the whole group. The strength (median + interquartile range) of the indicated immune response to all 6 pools of HPV16 E6 and E7 peptides for the group of patients with survival time equal or less than 12.6 months versus that of the group of patients with a survival time beyond 12.6 months measured before vaccination (pre-vac), after 2 vaccinations (2-vac) and after the 3^rd or 4^th vaccination (3/4-vac) is given. Only when the strength of the immune response was significantly different, this is indicated by the p-value.

Figure 3

Comparison of overall survival after cervical cancer recurrence between vaccinated patients and a matched cohort of non-vaccinated cervical cancer patients. The survival of the group of 16 vaccinated patients with a cervical carcinoma was compared to a cohort group of non-vaccinated patients who where primarily matched for FIGO stage, time to recurrence, primary treatment and salvage therapy after recurrence and which turned out to be matched also for age of diagnosis, age of recurrence, the type of primary and salvage chemotherapy as well as for adjuvant therapy. Both the log-rank and the Wilcoxon signed rank test revealed no difference in survival between the two groups.