Abstract 2938: Synergistic effects of properly timed HPV16 synthetic long peptide vaccination during standard carboplatin-paclitaxel chemotherapy in animals and in patients with metastatic cervical carcinoma

Abstract

We previously developed a synthetic long overlapping HPV16 E6/E7 peptides (HPV16-SLP) vaccine that was clinically active in patients with HPV16+ high-grade vulvar intraepithelial neoplasia. Complete lesion regression was related to a strong vaccine-prompted HPV16-specific effector T-cell response. However, in patients with HPV16-induced metastatic cervical cancer the vaccine-induced T-cell responses were weaker and did not result in clear clinical benefit. A new study on the immune constitution of PBMC of such patients revealed increased numbers of myeloid cells, low T-cell reactivity against common microbial recall antigens and a lower stimulatory capacity of antigen presenting cells, indicating an immunosuppressive status. When these patients were subsequently treated with standard carboplatin-paclitaxel chemotherapy we observed that at a specific time point during chemotherapy this tumor-biased immune profile was normalized to a profile similar to that found in healthy subjects. Experiments in an HPV16+ mouse tumor model showed that the tumor-induced abnormally high myeloid cell level was also normalized by this chemotherapy, not only among PBMC but also locally in the tumor. Residual tumor-present myeloid cells phenotypically mirrored activated non-suppressive antigen presenting cells. Moreover, combined HPV16 SLP vaccination and chemotherapy effectively led to a higher cure rate of mice with established tumors. Together these data indicated that standard chemotherapy has an immune stimulatory effect by deletion of suppressive myeloid cells in the mouse tumor model and in patients with metastatic cervical cancer . Therefore, a clinical trial was started in which such patients were treated with standard chemotherapy in combination with HPV16 SLP (ISA101) vaccination. Comprehensive immune monitoring confirmed the beneficial effect of myeloid cell depletion associated with a robust induction of HPV16-specific T-cell responses that were sustained throughout several cycles of chemotherapy. The data of these studies will be reported. Currently, we have started a multicenter clinical trial (ISA-HPV-01-12) in which vaccination with the HPV16 SLP ISA101 vaccine is combined with carboplatin-paclitaxel and type I interferon to assess clinical and immunological outcome in a group of HPV16+ metastatic cervical cancer patients. Citation Format: Sjoerd H. Van Der Burg, Tetje C. van der Sluis, Helene van Meir, Judith R. Kroep, Gemma G. Kenter, Mariette I.E. van Poelgeest, Koos Burggraaf, Cornelis J.M. Melief, Marij J.P. Welters. Synergistic effects of properly timed HPV16 synthetic long peptide vaccination during standard carboplatin-paclitaxel chemotherapy in animals and in patients with metastatic cervical carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2938. doi:10.1158/1538-7445.AM2014-2938

Effectiveness of combination therapy with ISA101 vaccine for the treatment of human papillomavirus-induced cervical cancer

“…An experimental study reported that carboplatin-paclitaxel chemotherapy in the HPV16 + mouse tumor model increased the frequency of myeloid cells in the circulatory and TME. Combining chemotherapy with ISA101 in patients with metastatic cervical cancer and HPV16 + mouse tumor model improved anti-tumor immune responses via depletion of myeloid cells and modulation of immunosuppressive TME ( 65 ). Another study also demonstrated that carboplatin/paclitaxel chemotherapy could deplete immunosuppressive myeloid cells, improving HPV-16-specific T cells and increasing the effectiveness of ISA101 and tumor regression in patients with HPV-16-induced cervical cancer ( 12 ).…”