title: Exploring the Interplay of Oncolytic Measles Vaccines  with the Cancer-Immunity Cycle
creator: Pidelaserra Martí, Gemma
subject: ddc-500
subject: 500 Natural sciences and mathematics
subject: ddc-570
subject: 570 Life sciences
description: Oncolytic vaccine strains of measles virus (MeVac) are studied as novel cancer therapeutics. By preferentially lysing tumor cells, these attenuated viruses induce systemic antitumor immunity. However, MeVac virotherapy alone is insufficient to achieve high rates of complete tumor remissions. Thus, in this study I aimed at identifying immunological mechanisms that limit or restrict the therapeutic potential of oncolytic MeVac.    Following the cancer-immunity cycle, I first focused on antigen presentation and T cell priming. I hypothesized that the immune response elicited by MeVac virotherapy is limited by impaired antigen processing, common in tumor cells, and reasoned that delivering pre-processed antigens to the tumor via MeVac vectors could circumvent this limitation. Using a murine system and chicken ovalbumin as model antigen, I showed that dendritic cells and tumor cells exposed to MeVac vectors encoding antigen-derived epitope variants present the encoded epitopes, especially when exposed to MeVac encoding six epitope copies targeted to the proteasome. Increased epitope presentation enhanced priming of naïve OT-I T cells and activation of cognate cytotoxic T lymphocytes. Thus, I proved the concept of using MeVac encoding antigen-derived epitope variants for T cell priming and activation. This project is now continued in the human context.    Subsequently, I focused on T cell migration and effector function. Based on efficacy and tumor gene expression data from previous studies, I hypothesized that the efficacy of MeVac virotherapy is limited by insufficient intratumoral expression of specific chemokines and cytotoxic molecules. To assess whether intratumoral overexpression of these molecules improves therapeutic efficacy, I conducted gain of function (GOF) efficacy studies in immunocompetent models of murine melanoma and colon adenocarcinoma. GOF studies with MeVac vectors encoding murine CXCL9, CXCL10, CCL19, or CCL21a, which I generated and characterized, showed that these chemokines do not limit the therapeutic efficacy of oncolytic MeVac. Loss of function studies will reveal whether these molecules are essential for MeVac virotherapy despite not being limiting. The identified cytotoxic molecules will be investigated following the same experimental approach.    MeVac virotherapy often results in PD-L1 upregulation on tumor cells. To address whether the PD-1/PD-L1 pathway restricts the efficacy of MeVac virotherapy, I investigated the combination of MeVac with PD-1/PD-L1 blockade in two systems. In an immunocompetent model of murine colon adenocarcinoma, I found that MeVac vectors encoding antibody-like molecules against PD-1 or PD-L1 induce stronger antitumor immune memory compared to MeVac alone. However, this effect was insufficient to improve therapeutic efficacy. In an immunocompetent model of murine pancreatic ductal adenocarcinoma (PDAC), local MeVac plus systemic anti-PD-1 antibody treatment was more effective than either monotherapy. In this model, I showed that MeVac was the main driver of systemic antitumor immunity, but required combination with anti-PD-1 to transiently induce an immune activation gene signature in the tumor. This study provides the basis for a Phase I clinical trial of MeVac plus Pembrolizumab in PDAC patients, currently in preparation.    While this work was conducted in wild-type mice, I also established CD46tg mice as a novel animal model to study oncolytic MeVac therapy. My investigations are the first to show that these mice develop systemic tumor-specific and measles virus-specific immunity upon intratumoral MeVac treatment. In gene expression studies, I identified a MeVac-induced tumor immune gene signature that warrants further investigation. Finally, I worked towards the establishment of patient-derived ex vivo tumor slice cultures as a platform to study early effects of oncolytic MeVac in a setting that preserves the patient-specific tumor heterogeneity and microenvironment.    Overall, identifying limiting factors of MeVac virotherapy will lead to the rational development of combination approaches that tackle treatment resistance. Furthermore, the refined models that I have established will increase the robustness of preclinical findings, thus improving translation into clinical research.    The addendum describes a preclinical study that I conducted to test the cellular immune response of MeVac-susceptible mice to a MeVac-based vaccine candidate against COVID-19.
date: 2024
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/34509/1/2023-10-19_PhD_Thesis_GemmaPidelaserraMarti.pdf
identifier: DOI:10.11588/heidok.00034509
identifier: urn:nbn:de:bsz:16-heidok-345097
identifier:   Pidelaserra Martí, Gemma  (2024) Exploring the Interplay of Oncolytic Measles Vaccines with the Cancer-Immunity Cycle.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/34509/
rights: info:eu-repo/semantics/openAccess
rights: Please see front page of the work (Sorry, Dublin Core plugin does not recognise license id)
language: eng