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Therapeutic cancer vaccines have effectively induced durable regressions of premalignant oncogenic human papilloma virus type 16 (HPV16)-induced anogenital lesions. However, the treatment of HPV16-induced cancers requires appropriate countermeasures to overcome cancer-induced immune suppression. We previously showed that standard-of-care carboplatin/paclitaxel chemotherapy can reduce abnormally high numbers of immunosuppressive myeloid cells in patients, allowing the development of much stronger therapeutic HPV16 vaccine (ISA101)-induced tumor immunity. We now show the clinical effects of ISA101 vaccination during chemotherapy in 77 patients with advanced, recurrent, or metastatic cervical cancer in a dose assessment study of ISA101. Tumor regressions were observed in 43% of 72 evaluable patients. The depletion of myeloid suppressive cells by carboplatin/paclitaxel was associated with detection of low frequency of spontaneous HPV16-specific immunity in 21 of 62 tested patients. Patients mounted type 1 T cell responses to the vaccine across all doses. The group of patients with higher than median vaccine-induced immune responses lived longer, with a flat tail on the survival curve. This demonstrates that chemoimmunotherapy can be exploited to the benefit of patients with advanced cancer based on a defined mode of action.

The therapeutic synthetic long peptide (SLP) vaccine ISA101 selectively enlarges the pool of tumor-specific T cells recognizing the human papillomavirus type 16 (HPV16) antigens E6 and E7. Vaccine monotherapy for HPV16-induced pre-malignant anogenital lesions is effective, inducing durable complete regressions in approximately 50% of treated patients. However, cancer treatment requires appropriate countermeasures to overcome the suppression of T-cell activation, expansion and effector function imposed by suppressive myeloid cell populations, regulatory T cells and co-inhibitory molecule expression. We recently showed that carboplatin/paclitaxel chemotherapy can normalize the abnormally high levels of immune suppressive myeloid cells, allowing the development of much stronger therapeutic ISA101-induced tumor immunity1. Here we show the effects of ISA101 vaccination during chemotherapy in 77 patients with advanced, recurrent or metastatic cervical cancer in a dose assessment study. Study design involved a single arm dose escalation study with four different ISA101 doses (20, 40, 100 and 300 µg per peptide) with or without immunomodulator pegylated interferon alpha (Pegitron), given concomitantly with standard of care chemotherapy (carboplatin, AUC 6; paclitaxel, 175 mg/m2). Objective regressions were observed in 43% of 72 evaluable patients. The depletion of myeloid suppressive cells by carboplatin/paclitaxel was associated with detection of low level spontaneous HPV16-specific immunity in 26 of the 61 tested patients. Patients mounted type 1 T-cell responses to the vaccine across all doses. No significant differences were observed between the different doses and strength of vaccine-induced T cell responses; the results were therefore combined. Patients with an above median HPV16-specific T cell immune response to ISA101, measured by a validated IFNγ-Elispot, displayed a significantly prolonged median overall survival (OS) of 16.8 months compared to those with a lower HPV-specific immune response (OS 11.2 months, logrank p=0.012). Importantly, this effect was not due to differences in general immune status, as measured by T-cell reactivity to unrelated common microbial recall antigens. In conclusion, our study demonstrates that chemo-immunotherapy can be exploited to the benefit of patients with cervical cancer and warrants confirmation of the benefit of this type of chemo-immunotherapy in a randomized controlled study in HPV16-induced cancer patients. 1Welters, M. J. et al. Vaccination during myeloid cell depletion by cancer chemotherapy fosters robust T cell responses. Sci Transl Med 8, 334ra352, doi:10.1126/scitranslmed.aad8307 (2016). Citation Format: Cornelis J M Melief, Marij J. Welters, Ignace Vergote, Judith R. Kroep, Gemma G. Kenter, Nelleke Ottevanger, Wiebren A. Tjalma, Hannelore Denys, Mariette van Poelgeest, Hans W. Nijman, Anna K. Reyners, Thierry Velu, Frederic Goffin, Roy Lalisang, Willem-Jan Krebber, Leon Hooftman, Sonja Visscher, Brent A. Blumenstein, Richard B. Stead, Winald Gerritsen, Sjoerd van der Burg. A strong HPV-specific T-cell response after chemo-immunotherapy for advanced cervical cancer is associated with prolonged survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT002.

5525 Background: 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. Conclusions: 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. Clinical trial information: NCT 02128126.

140 Background: 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. In this study we noted that a single dose of vaccine 2 weeks into the 2nd cycle of chemotherapy was optimal, because at this time the immunosuppressive myeloid cells were down. Methods: We now completed a chemo-immunotherapy study in a larger number of patients with late stage HPV16+ cervical cancer. Three HPV16-SLP vaccine doses were given 2 weeks after the second, third, and fourth cycles of standard chemotherapy. 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. Results: Robust vaccine-induced HPV16-specific T cell responses as assessed by interferon-g Elispot were observed and were sustained throughout the cycles of chemotherapy. These T cell responses were substantially increased in all patients who received HPV16-SLP . 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 correlation was observed between the strength of the vaccine-induced immune response and longer-term clinical outcomes such as overall survival. No such correlation exists between the strength of the T cell response against common recall antigens and survival. In addition, a remarkably high proportion of patients survived beyond 20 months after the start of therapy. Conclusions: These results indicate that the survival advantage is specifically related to the strength of the vaccine-induced T cell response and is not due to generally better immuno-competence. Clinical trial information: NCT02128126.