Bedside formulation of a personalized multi-neoantigen vaccine against mammary carcinoma

• DOI: 10.1136/jitc-2021-002927
• Publication Date: 2022-01-11T16:36:07Z
• Authors: Mona O Mohsen; Daniel E Speiser; Justine Michaux; HuiSong Pak; Brian J Stevenson; Monique Vogel; Varghese Philipos...; Simone de Brot; Said Dermime; Georges Coukos; Michal Bassani-St...; Martin F Bachmann
• Keywords: Clinical/Translational Cancer Immunotherapy; 0303 health sciences; 630 Agriculture; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; 610 Medicine & health; Breast Neoplasms; Cancer Vaccines; 3. Good health; Mice; 03 medical and health sciences; Antigens, Neoplasm; Cell Line, Tumor; Animals; Humans; Female; Immunotherapy; Precision Medicine; RC254-282

BackgroundHarnessing the immune system to purposely recognize and destroy tumors represents a significant breakthrough in clinical oncology. Non-synonymous mutations (neoantigenic peptides) were identified as powerful cancer targets. This knowledge can be exploited for further improvements of active immunotherapies, including cancer vaccines, as T cells specific for neoantigens are not attenuated by immune tolerance mechanism and do not harm healthy tissues. The current study aimed at developing an optimized multitarget vaccine using short or long neoantigenic peptides utilizing virus-like particles (VLPs) as an efficient vaccine platform.MethodsMutations of murine mammary carcinoma cells were identified by integrating mass spectrometry-based immunopeptidomics and whole exome sequencing. Neoantigenic peptides were synthesized and covalently linked to virus-like nanoparticles using a Cu-free click chemistry method for easy preparation of vaccines against mouse mammary carcinoma.ResultsAs compared with short peptides, vaccination with long peptides was superior in the generation of neoantigen-specific CD4+and CD8+T cells, which readily produced interferon gamma (IFN-γ) and tumor-necrosis factor α (TNF-α). The resulting anti-tumor effect was associated with favorable immune re-polarization in the tumor microenvironment through reduction of myeloid-derived suppressor cells. Vaccination with long neoantigenic peptides also decreased post-surgical tumor recurrence and metastases, and prolonged mouse survival, despite the tumor’s low mutational burden.ConclusionIntegrating mass spectrometry-based immunopeptidomics and whole exome sequencing is an efficient approach for identifying neoantigenic peptides. Our multitarget VLP-based vaccine shows a promising anti-tumor effect in an aggressive murine mammary carcinoma model. Future clinical application using this strategy is readily feasible and practical, as click chemistry coupling of personalized synthetic peptides to the nanoparticles can be done at the bedside directly before injection.