SS 04-02Strong T cell responses after vaccination with HPV16 long peptides for late stage cervical cancer are associated with prolonged survival

06. HPV therapeutic vaccines
C. Melief 1, W. Gerritsen 2, M.J. Welters 2, I. Vergote 3, J.R. Kroep 4, G.G. Kenter 5, N. Ottevanger 2, W. Tjalma 6, H. Denys 7, M.I. Van Poelgeest 4, H.W. Nijman 8, A. Reyners 8, T. Velu 9, F. Goffin 10, R. Lalisang 11, B.A. Blumenstein 12, R. Stead 13, S. Van Der Burg 14.
1Leiden University Medical Center & ISA Pharmaceuticals (Netherlands), 2Nijmegen University Medical Center (Netherlands), 3University Hospital, Leuven (Belgium), 4Leiden University Medical Center (Netherlands), 5Center for Gynaecological Oncology (Netherlands), 6University hospital Antwerp (Belgium), 7University hospital Gent (Belgium), 8University Hospital Groningen (Netherlands), 9Chirec Cancer Institute Brussels (Belgium), 10University Hospital, Liege (Belgium), 11University Hospital, Maastricht (Netherlands), 12Trial Architecture Consulting (United States), 13Biopharma Consulting Svcs (United States), 14Biopharma Consulting Svcs (Netherlands)

Background / Objectives

Therapeutic vaccination with HPV type 16 synthetic long peptides (HPV16-SLP) results in T cell–mediated regression of HPV16-induced premalignant lesions but fails to install effective immunity in patients with  advanced HPV16-positive cervical cancer. We showed that HPV16-SLP vaccination in mice and in patients with advanced cervical cancer patients fosters robust HPV16-specific T cell responses, when combined with chemotherapy (Welters et al. Sci. Transl. Med., 2016).


Methods

We have now completed a chemo-immunotherapy study in 70 patients with late stage HPV16+ cervical cancer (clinical trials.gov NCT02128126).  Three HPV16-SLP vaccine doses were given 2 weeks after the second, third and fourth cycle of standard chemotherapy (carboplatin, AUC 6; paclitaxel 175 mg/ m2). Cohorts of 12 patients each were vaccinated with each of 4 dose levels (20, 40, 100 and 300 µg/ per peptide) of 13 overlapping HPV16 synthetic long peptides (HPV16-SLP) together covering the length of the 2 E6 and E7 proteins. Two additional cohorts of 6 patients each were vaccinated with the most promising doses of 40 and 100 µg/ peptide.


Results

Robust vaccine-induced HPV16-specific T cell responses as assessed by interferon-γ Elispot were observed and were sustained until at least 30 days after the 6th cycle of chemotherapy. In addition the chemotherapy augmented recall responses to microbial antigens. Such robust T cell responses were not noted in previous trials when similar patients were vaccinated without timing of vaccination during chemotherapy. A marked and significant positive correlation was observed between the strength of the vaccine-induced immune response and overall survival. No such correlation was observed between the strength of the T cell response against common recall antigens and survival.

In addition a remarkably high proportion of patients survived beyond 2 years after the start of therapy.


Conclusion

The results suggest that survival duration is directly related to the strength of the vaccine-induced HPV16-specific  T cell response and is not due to generally better immuno-competence.


References