Identification of tumor-specific peptides for adjuvant immunotherapy of melanoma patients without distant metastasis

• Applicants: Dr. Stefan Kirsch; Professor Dr. Christoph Klein; Privatdozentin Dr. Melanie Werner-Klein
• Subject Area: Pathology
• Term: from 2016 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 320058447

Malignant melanoma is an aggressive tumor with increasing incidence, frequent metastasis, and poor prognosis. It is also an immunogenic cancer, for which T cell-checkpoint-inhibitors like anti-CTLA-4 or anti-PD-1 antibodies have demonstrated efficacy in stage III and IV melanoma patients. However, adjuvant anti-CLTA-4 therapy was associated with unacceptable side-affects in half of the stage III patients emphasizing the necessity for more specific T cell therapies. Clinical and experimental data point towards a pivotal role of tumor-neoantigens and neoantigen-reactive T cells in the control of melanoma. Disseminated cancer cells (DCCs) are the target cells of adjuvant therapy, however, their genetic evolution diverges from the primary tumor early on. In order to learn how to prevent lethal metastasis, we aim to unravel the foundations of an adjuvant immunotherapy against early systemic cancer, which is based on the molecular characteristics of DCCs, the target cells of minimal residual disease. We will assess whether sentinel lymph node biopsies of non-metastatic patients can be used to identify neo-antigens in DCCs and whether these neo-antigens can be functionally evaluated for suitability for immunotherapy. We will identify neo-antigens in DCCs, assess their degree of conservation among the DCC population of an individual and follow functionally those that may be used to prevent lethal metastasis. Furthermore, we will generate fundamental data on the evolution of systemically disseminated melanoma cells and their early interaction with the adaptive immune system. The project proposal will enable target-identification on metastatic precursor cells and will provide a framework model for the development of adjuvant immunotherapy in melanoma, and possibly also for other types of cancers.

• DFG Programme: Research Grants