Fostering antigen spread and dissecting tumor evolution in response to neoantigen-specific cancer vaccination

• Applicant: Dr. Mustafa Diken
• Subject Area: Hematology, Oncology ; Immunology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 445265349

The major aim of the second funding period is to assess the therapeutic efficacy of different neoantigen treatment strategies in established heterogenous tumors with a special focus on antigen spread and in vivo heterogenous tumor evolution. In the first funding period, we established a murine tumor model with defined intratumoral heterogeneity (B2905 6 Mix and 3 Mix) and identified immunogenic MHC class I and II-restricted neoantigen candidates that showed therapeutic efficacy in a first proof-of-concept experiment. Within this second funding period, we will i) expand our knowledge of different druggable therapeutic vaccine targets (fusion genes, self-antigens and cryptic MHC class I-associated peptides from non-coding sequences) and ii) further decipher the therapeutic efficacy, tumor evolution and epitope spreading under different vaccine strategies with the tools we have set up. We will expand the current target space of SNV-derived neoantigens with other neoantigen classes such as fusion-genes, self-antigens and antigens derived from non-canonical that all together constitute the possible target space of heterogenous tumors. This setting grants us a complete picture of immune-mediated antigen selection under neutral in vivo evolution and under therapy with therapeutic cancer vaccines. Our second big aim is the identification of a therapeutic setting that fosters epitope spreading after neoantigen vaccination. As a patients’ specific neoantigen repertoire is often determined from single site sequencing, other, relevant neoantigen candidates might not be selected for therapeutic vaccines, posing a risk for the selection and outgrowth of antigen-negative tumor cells. We will specifically study epitope spreading after different vaccine strategies in heterogenous tumors, following global antigen-specific immune responses and responses to secondary, highly heterogenous tumors. To this end, we will engage on investigating the CD4 T helper cell axis to foster epitope spreading, using e.g. MHC class II-restricted helper vaccines and agonistic anti-CD40L, anti-CD27 antibodies to trigger antigen spread.

• DFG Programme: Research Grants
• International Connection: Israel
• International Co-Applicant: Professorin Yardena Samuels, Ph.D.