Combining a Universal Telomerase Based Cancer Vaccine With Ipilimumab in Patients With Metastatic Melanoma - Five-Year Follow Up of a Phase I/IIa Trial

Abstract

Background: Ipilimumab improves survival for patients with metastatic malignant melanoma. Combining a therapeutic cancer vaccine with ipilimumab may increase efficacy by providing enhanced anti-tumor immune responses. UV1 consists of three synthetic long peptides from human telomerase reverse transcriptase (hTERT). These peptides comprise epitopes recognized by T cells from cancer patients experiencing long-term survival following treatment with a first-generation hTERT vaccine, and generate long-lasting immune responses in cancer patients when used as monotherapy. The objective of this trial was to investigate the safety and efficacy of combining UV1 with ipilimumab in metastatic melanoma.

Patients and methods: In this phase I/IIa, single center trial [NCT02275416], patients with metastatic melanoma received repeated UV1 vaccinations, with GM-CSF as an adjuvant, in combination with ipilimumab. Patients were evaluated for safety, efficacy and immune response. Immune responses against vaccine peptides were monitored in peripheral blood by measuring antigen-specific proliferation and IFN-γ production.

Results: Twelve patients were recruited. Adverse events were mainly diarrhea, injection site reaction, pruritus, rash, nausea and fatigue. Ten patients showed a Th1 immune response to UV1 peptides, occurring early and after few vaccinations. Three patients obtained a partial response and one patient a complete response. Overall survival was 50% at 5 years.

Conclusion: Treatment was well tolerated. The rapid expansion of UV1-specific Th1 cells in the majority of patients indicates synergy between UV1 vaccine and CTLA-4 blockade. This may have translated into clinical benefit, encouraging the combination of UV1 vaccination with standard of care treatment regimes containing ipilimumab/CTLA-4 blocking antibodies.

Keywords: ipilimumab; melanoma; peptide vaccine immunotherapy; phase I/IIa studies; telomerase (hTERT).

Conflict of interest statement

EMI and GG are inventors of a UV1 vaccine patent. EI, WR, GG and SA are shareholders in Ultimovacs ASA. EE, WR, SA and GG are employees of Ultimovacs ASA. MN has received personal honoraria from BMS for lectures. The authors declare that this study received funding from Ultimovacs ASA. The funder had the following involvement with the study: study design of the trial.

Copyright © 2021 Aamdal, Inderberg, Ellingsen, Rasch, Brunsvig, Aamdal, Heintz, Vodák, Nakken, Hovig, Nyakas, Guren and Gaudernack.

Figures

Figure 1

Tumor growth by subject. Spider plot illustrating changes in target lesions from baseline in patients evaluable by RECIST v.1.1 (N=9). *Patient N03 was non-evaluable at 12 weeks PR, partial response; PD, progressive disease.

Figure 2

Efficacy assessment by subject censored on December 1 2020. Swimmers plot depicting individual patients as lines, illustrating duration of overall survival in months. Blue and grey colors indicate alive and deceased patients, respectively (N=12). Responses and new systemic treatment are indicated by designated symbols. Patient N06 received locoregional chemotherapy and surgery, but no further systemic treatment.

Figure 3

Summary of detected pre- and post-vaccination T cell responses against UV1 peptides. (A) T cell proliferation against UV1 peptides in pre- and post-vaccination blood samples from patients evaluable for immune response, depicting the strongest post-vaccination T cell response detected against the hTERT peptide mix for each patient. (N=11). Proliferation was measured in response to peptide-loaded PBMC by 3H-thymidine incorporation. A stimulation index (SI) of >3 was considered as an immune response. The dotted line indicates SI=3. (B) Cumulative percentage of evaluable patients exhibiting immune responses to UV1 peptides. Immune responses at baseline were detected in two patients.

Figure 4

UV1-specific proliferation by T cells at different time points post-vaccination. UV1 peptide-specific proliferation was measured (counts per minute, cpm) at several sampling time points and representative examples are shown for patient N02 (A), patient N07 (B), patient N09 (C) and patient N11 (D). Proliferation was measured in response to peptide-loaded PBMC by 3H-thymidine incorporation. A 3-fold increase in proliferation compared to non-peptide control (T+ APC) was considered as an immune response. Superantigen SEC-3 stimulation was included as a positive control. Dotted line indicates cut-off for positive response, measurements until last positive time point is shown.