Oxidized Lysates as Anti-Cancer Vaccine in Experimental Melanoma Models

• Applicant: Dr. Ramona Clemen
• Subject Area: Dermatology ; Hematology, Oncology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 543338827

Therapeutic vaccination as an anticancer agent yields improved clinical outcomes by induction and proliferation of antigen-specific T cells to promote an immune response. Nevertheless, there is still a need for optimization of anti-melanoma vaccines, as shown by the results of discontinued studies. Different tumor entities show other immunogenicity, and melanoma is highly immunogenic, caused by the excessive prevalence of somatic mutation. These mutations can lead to the generation of tumor-associated antigens (TAA) and neoantigens, which can be recognized by adaptive immunity that can initiate endogenous tumor cell targeting. Studies have shown that immunization with single proteins or multi-peptide vaccines, complete tumor lysate vaccines, or DCs pulsed with lysates promotes immunization and has anticancer effects. Albeit, clinical response rates have room for improvement. We identified cold physical plasma generated reactive oxygen species (ROS) to increase the immunogenicity of proteins and plasma-treated tumors, leading to increased anti-tumor immune response. Furthermore, plasma-inactivated cancer cells provide evidence of immunogenic cell death and vaccination with oxidized lysate protected half of the animals from tumor growth. This proposal outlines a research strategy to elucidate the findings' mechanisms and translational relevance. This includes identifying oxidative protein modifications in tumor lysate and optimizing lysate vaccine by using different feed gas compositions and microvesicle packaging. Apart from characterizing oxidized tumor lysate generated from 3D spheroid model of two human and two mouse melanoma cell lines, the immunogenicity of optimized tumor lysates will be tested in vitro. In addition, we want to study the therapeutic vaccination approach in vivo after isolating and oxidizing primary tumors and investigate potential T cell diversity mechanisms. Using oxidized tumor lysates as a therapeutic vaccine would be an alternative approach with less economic costs. Specifically, the objectives are: - identifying the quality and quantity of oxidative translational protein modification in tumor lysates exposed to either single-agent or multi-ROS technology - generation of liposome-packaged protein cargo vaccines - elucidate the most potent oxidation modes and illuminates the efficacy of oxidized melanoma lysate vaccination to promote adaptive immunity - testing the therapeutic benefits of oxidized autologous melanoma lysate vaccination in vivo - translational approach to elucidate the relevance of immune-activating oxidative modifications in human samples.

• DFG Programme: Research Grants