Rationally designed cancer vaccines from a better understanding of the interaction between neoepitope-specific T cells and intratumoral heterogeneity

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

Cancer medicine is in a golden age of research: checkpoint inhibitor (CPI) therapy proved the potency of the immune system to attack cancer. High-throughput sequencing and computational prediction of neoepitopes allow identification of individual mutations and the design of personalized RNA vaccines that have been shown to prime de novo tumor-specific immune responses. Nevertheless, as cancer is based not on single, but multiple genetic aberrations, the design of more effective therapies requires a deeper understanding of the heterogeneity of these aberrations. Intratumoral heterogeneity (ITH) based on sub-clonal mutations has been demonstrated across a vast spectrum of solid cancer types, as well as haematologic malignancies. It is associated with poor prognosis and relapse. The temporal evolution of cancer leading to ITH presents a challenge to personalized cancer medicine: tumors undergo branched evolution, producing clonal (common to all cells) and sub-clonal (expressed in only a subset of clones) mutations which likely act synergistically to drive survival mechanisms such as therapy evasion. Furthermore, the spatial distribution of such clonal and subclonal mutations, and therein neoepitopes are influencing immune surveillance, as has been demonstrated for CPI therapies.Until now, the interplay between T cells and ITH evolution could not be studied given the lack of controlled preclinical model systems allowing iterative perturbation of the system. Herewith we propose to dissect how ITH develops over time under the pressure of the immune system, as mediated by neoepitope-specific CD8+ and CD4+ T cells. As immunotherapeutic modalities we will use RNA vaccination, adoptive T-cell transfer (ACT) and CPI therapy. Based on the expected findings we will design and validate novel strategies (primarily) addressing ITH for cancer vaccination. Pursuing these goals is enabled by Yardena Samuels (Weizmann Institute of Science, WIS) who recently established a novel experimental system utilizing well-characterized syngeneic murine cell clones, which can be mixed in order to generate tumors of defined ITH. These tumors enable us to evaluate the effect of ITH on both tumor aggressiveness and anti-tumor immunity in a controlled manner. Professor Samuels’ capability to discover neoepitopes by mass spectrometry will also be an asset and complementary to those of Mustafa Diken (TRON) and Ugur Sahin, who developed algorithms for neoepitope prediction-based on sequencing data. Crucially, their pioneer RNA cancer vaccine program, currently in clinical testing, allows investigation of how ITH can be accounted for in cancer vaccination. The research program described in this proposal is planned for 3 years with prospective for 3-year extension, reflecting the complexity of the task defined. We envision a long-term partnership between WIS and TRON will allow synergy of the complementary strengths of both institutions, generating novel spin-off projects.

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