848 Prime-boost vaccination for the treatment of triple negative breast cancer

Abstract

BackgroundTriple negative breast cancer (TNBC) is currently only treated with surgery and chemotherapy.1 TNBC has higher rates of genetic mutations and contains more tumor infiltrating lymphocytes.2 These characteristics provide a strong rationale to use novel immunotherapies such as immunogenic autologous tumor cell vaccines to therapeutically target TNBC. We have demonstrated that an infected cell vaccine (ICV) that is made from irradiated and oncolytic virus tumor infected cells induces beneficial innate and adaptive immune responses in a syngeneic mouse model of TNBC. Moreover, the efficacy of ICV is improved when combined with checkpoint blockade (anti-PD-1).3 Our goal is to further improve ICV by applying a prime-boost cancer vaccination strategy to further enhance anti-tumor immune responses in preclinical and translational studies.4 5MethodsWe will choose the best ‘prime vaccine’ based on the immunogenicity of TNBC cell lines after treatment with immunomodulators such as chemotherapeutic agents, irradiation, toll-like receptor agonists and anti-viral vaccines. We will measure the release of damage-associated molecular patterns (DAMPs), which act as danger signals to initiate tumor-targeted immune responses,6 after the treatment of TNBC cell lines. We will test the polarization of human monocytes when co-cultured with conditioned media (CM) from treated TNBC cells. We will also analyze the migration of human immune cells (CD56+NK cells and CD8+T cells) toward the CM of treated human TNBC cells. Furthermore, we will evaluate the maturation markers on CD11C+ dendritic (DC) cells differentiated from mouse bone marrow cells when co-cultured with the cell lysate of the mouse TNBC cell line treated with ‘prime vaccine’ candidates. For in vivo studies, we will test our best prime vaccine followed by the ICV as a boost vaccine in our BALB/c-4T1 mouse model. We will analyze the cytotoxicity of T lymphocytes and the secretion of cytokines, and overall survival.ResultsFrom measuring DAMP levels and analyzing immune functions, our preliminary results suggest that oxaliplatin and the seasonal influenza vaccine are the best candidates as strong ‘prime vaccine’ candidates compared to other treatments. DCs differentiated from isolated bone marrow cells exhibited a higher percentage of markers of maturation when co-cutured ex vivo with cell lysate of 4T1 cells were treated with oxaliplatin compared to control groups. In vivo studies in the BALB/c-4T1 model have begun to test the best prime-boost vaccine combinations.ConclusionsThese results demonstrate the therapeutic potential of oncolytic virus-based immunogenic tumor vaccines could be improved by applying the ‘prime-boost’ cancer vaccination approach to treat TNBC.Ethics Approval‘The study was approved by the CRCHUS Human Ethics Board, approval number 2018-2414.’Consent‘Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.’ReferencesYadav BS. Systemic treatment strategies for triple-negative breast cancer. World J Clin Oncol 2014;5(2):125.García-Teijido P, Cabal ML, Fernández IP, Pérez YF. Tumor-infiltrating lymphocytes in triple negative breast cancer: the future of immune targeting. Clinical Medicine Insights: Oncology 2016.Niavarani SR, Lawson C, Boudaud M, Simard C, Tai LH. Oncolytic vesicular stomatitis virus-based cellular vaccine improves triple-negative breast cancer outcome by enhancing natural killer and CD8 + T-cell functionality. J Immunother Cancer 2020.Le DT, et al. Safety and survival with GVAX pancreas prime and listeria monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J Clin Oncol 2015.Pol JG, et al. Preclinical evaluation of a MAGE-A3 vaccination utilizing the oncolytic maraba virus currently in first-in-human trials. Oncoimmunology 2019 Jan;8(1):e1512329.Vandenberk L, Belmans J, Van Woensel M, Riva M, Van Gool SW. Exploiting the immunogenic potential of cancer cells for improved dendritic cell vaccines. Frontiers in Immunology 2016.