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Exploiting Therapy-Induced Neo-Epitopes to Overcome Drug Resistance in Triple-Negative Breast Cancer

Project description

Therapy-induced neo-antigens for precision cancer vaccines

Cancer treatments can create new tumour-specific targets. These therapy-induced neo-antigens can arise from mutations, RNA splicing errors, or post-translational modifications triggered by chemotherapy or targeted therapies. Recognised as foreign by the immune system, they offer a path for personalised immunotherapy, although distinguishing them from normal tumour antigens is challenging. In this context, the ERC-funded TI-uORFe project will develop mRNA vaccines and immunotherapies for triple-negative breast cancer, where drug resistance is common. Using ribosome profiling, researchers will identify non-canonical peptides presented by MHC-I molecules to trigger immune responses. The goal is to boost chemotherapy efficacy and improve patient survival through precision immunotherapy.

Objective

Therapy-induced neo-antigens represent a novel class of tumor-specific antigens that arise from therapeutic interventions such as chemotherapy and targeted therapies. These neo-antigens, resulting from genomic mutations, aberrant post-translational modifications, and dysregulated RNA splicing, are recognized by the immune system as foreign, prompting an immune response that bypasses central tolerance mechanisms. Despite advancements in next-generation sequencing and bioinformatics that facilitate the identification of these neo-antigens, distinguishing drug-induced neo-antigens from inherent tumor antigens remains a significant challenge. This proof-of-concept proposal aims to leverage therapy-induced neo-antigens to develop personalized cancer vaccines and immunotherapies, particularly targeting triple-negative breast cancer (TNBC), where drug resistance is prevalent.

By utilizing ribosome profiling, we have identified non-canonical peptides translated from therapy-induced changes in cancer cells, which are presented by MHC-I molecules and recognized by T lymphocytes, leading to specific tumor cell killing. Our approach focuses on generating mRNA vaccines based on these neo-epitopes, with the goal of enhancing chemotherapy responses and overcoming drug resistance. The proposed research will address critical bottlenecks in neo-epitope therapy, including accurate identification of immunogenic neo-epitopes and validation of immunogenicity in preclinical models. Ultimately, this innovative strategy aims to improve therapeutic efficacy and patient outcomes in TNBC, offering a transformative approach to combat drug resistance and enhance survival rates.

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HORIZON-ERC-POC - HORIZON ERC Proof of Concept Grants

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Call for proposal

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(opens in new window) ERC-2025-POC

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Host institution

DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 150 000,00
Address
IM NEUENHEIMER FELD 280
69120 Heidelberg
Germany

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Region
Baden-Württemberg Karlsruhe Heidelberg, Stadtkreis
Activity type
Research Organisations
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Total cost

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