Characterization of the immunological mechanisms induced in blood and tumor following treatment with the therapeutic cancer vaccine UV1.

The purpose of this project was to characterize the immunological mechanisms induced by the therapeutic cancer vaccine candidate UV1 in combination with other immunotherapies. UV1 is a cancer vaccine candidate developed by the Norwegian biotechnology company Ultimovacs. By vaccinating with UV1, an immune response targeting cancer cells is generated which, in combination with other immunotherapy, may lead to increased killing of cancer cells and improved clinical outcomes for the treated patients. UV1 has been investigated across four completed phase I clinical trials, either as a single therapy or in combination with other immunotherapies. Patients included in these trial have donated tumor biopsies and blood samples for immune response analyses. Comprehensive analyses on the immune response induced by UV1 has been investigated using high-technology og modern methods. We compared the dynamic of the immune response across three clinical trials with UV1, either as single therapy or in combination with other immunotherapy (ipilimumab). We observed that the immune response appeared earlier and more frequently when the vaccine was given in combination with other immunotherapy. The immune response was very durable, and lasted up to 7.5 years and demonstrated considerable fluctuations over time. In some instances, the fluctuation of the immune response correlated with clinical observations such as disease relapse. We also observed that the immune response correlated with longer survival time for the patients. These results were included in a scientific publication in the prestigious Journal for ImmunoTherapy of Cancer in May 2022. We have concluded our analyses on patient material from a clinical trial investigating UV1 in combination with the immunotherapy ipilimumab. We have investigated the expression of the vaccine target (telomerase) in patients biopsies, and established the infiltration of T cells before and after therapy. We have also characterized the patients tumor by gene sequencing. The results from these anlayses have been published in a scientific paper in Journal of Translational Medicine in September 2022. The most recent clinical trial with UV1 investigated the vaccine in combination with other immunotherapy (pembrolizumab) in 30 patients with malignant melanoma. We have performed similar analyses; comprehensive characterization of the patients tumor and immune response in blood. The clinical results and tissue analyses were presented as an oral presentation during the plenary session of the Society for Melanoma Research conference in Edinburgh in October 2022. A scientific paper will be published in a peer-reviewed journal.

The results generated from the project have had a considerable impact on the research field. The project uncovered previously unknown characteristics of the UV1 vaccine, including the durability and phenotype of the immune response. These findings are very important for understanding the mechanisms of action of a therapeutic vaccine, and how the immune response may translate into clinical efficacy. We have also uncovered the expression pattern of the target antigen, telomerase, gaining new knowledge relevant for its targeting through both vaccination and other modalities. We discovered novel biomarker data that may be important in guiding the further development of telomerase-targeting therapeutic cancer vaccines. We have also established international relationships with key academic and industrial researchers within our field. These collaborations will continue beyond this project.

This industrial Ph.D. project is a collaboration between Ultimovacs AS, located in Oslo Cancer Cluster Incubator, Oslo University Hospital and The University of Oslo. The Ph.D. candidate for this project is Espen Basmo Ellingsen, employed by Ultimovacs. The project aims to characterize the immunological mechanisms induced by treatment with a peptide-based therapeutic cancer vaccine. The research project will be based on analyses of biological material collected in clinical trials sponsored by Ultimovacs, and will be accomplished by implementation of genetic, molecular and computational approaches. The results of the analyses will be correlated with radiologically assessed tumor response and clinical outcome of the patients. The objective of this research project is to elucidate the immunological mechanisms underlying the interplay between immune activation provoked by vaccination with UV1 and inhibition of tumor resistance mechanisms and peripheral immune tolerance induced by immune checkpoint blockade, and how biological factors affect the efficacy of the combination therapy. The primary research objective is to investigate whether epitope spreading, seen as diversification of the recognition of cancer neoantigens, is the immunological mechanisms underlying tumor response and clinical benefit from vaccine and immune checkpoint blockade combination therapy. The secondary objective is to establish the intratumoral role of these induced T cells by quantitatively and qualitatively assess the tumor-infiltrating lymphocytes. This project will give an increased understanding of the immunological mechanisms induced with this type of therapy and provide knowledge to further develop the field of immunotherapy. This industrial Ph.D. project will be centered at Ultimovacs AS and Oslo University Hospital, Department of Tumor Biology, but will include collaborations with OUS, Department of Cellular Therapy; Martin Luther University of Halle-Wittenberg and OncoImmunity AS.