Abstract A110: Mutant MHC class II epitopes drive therapeutic immune responses to cancer

Abstract

Mutations are regarded as ideal targets for cancer immunotherapy. As neoepitopes with strict lack of expression in any healthy tissue, they are expected to be safe and could bypass the central tolerance mechanisms. Recent advances in nucleic acid sequencing technologies have revolutionized the field of genomics, allowing the readily targeting of mutated neoantigens for personalized cancer vaccination. We demonstrated in three independent murine tumor models that a considerable fraction of non-synonymous cancer mutations is immunogenic and that unexpectedly the immunogenic mutanome is pre-dominantly recognized by CD4+ T cells. RNA vaccination with such MHC class II restricted immunogenic mutations leads to infiltration of CD4+ and CD8+ T cells into the tumor, reduces intratumoral regulatory T cells and ultimately confers strong anti-tumor activity. Encouraged by these findings we set up a process comprising mutation detection by exome sequencing, selection of vaccine targets by solely bioinformatical prioritization of mutated epitopes predicted to be abundantly expressed and presented on MHC class II molecules. Synthetic mRNA vaccines encoding multiple of these prioritized mutated epitopes induce potent tumor control and complete rejection of established aggressively growing tumors in mice. Moreover, we demonstrate that CD4+ T cell neoepitope vaccination primes CTL responses against an independent immunodominant antigen in tumor bearing mice indicating orchestration of antigen spread. Our findings reveal that cancer mutation based MHC class II restricted epitopes are attractive vaccination targets and provide the preclinical proof of concept for an integrated process from tumor sample to a cancer vaccine customized to the unique repertoire of each patient`s tumor. Citation Format: Mathias Vormehr, Sebastian Kreiter, Niels van de Roemer, Mustafa Diken, Martin Löwer, Fulvia Vascotto, Jan Diekmann, Sebastian Boegel, Barbara Schroers, Arbel D. Tadmor, Özlem Türeci, Ugur Sahin. Mutant MHC class II epitopes drive therapeutic immune responses to cancer. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A110.

Generation of liver tissue-resident memory T cells with novel NKT cell agonists and mRNA vaccines

“…These cellular immune responses have been exploited in cancer vaccine settings for both CD8 + and CD4 + T cell epitopes [70,77] . CD4 + T cell epitopes were designed from neoantigens, with 13 amino acids flanking a tumour-specific mutation.…”

“…Whilst the efficacy of the SARS-CoV-2 mRNA vaccines has mostly been accredited to the production of neutralising antibodies against the spike protein, prior research shows mRNA vaccines can also be exploited for their ability to generate CD8 + T cell responses [76] . One of the most attractive features of mRNA vaccines is that in theory any antigen can be encoded into the mRNA, facilitating targets to include cancer antigens (including neoantigens), disordered proteins that are not amenable to soluble expression, and specific antigens from pathogens containing 100-1000s of protein antigens, such as bacteria or protozoa [77,84] . It was previously demonstrated by Kranz et al (2016) that lipoplexes (LPXs), which are formed through the complexation of cationic liposomes and mRNA, are an effective delivery vehicle for mRNA and the induction of T cell responses.…”