Project description
Immunotherapy based on innovative combination cancer therapies
The combination of immunotherapy with cytotoxic and molecular therapies represents a novel strategy for cancer treatments. However, toxicity and insufficient efficacy in many cases remain major obstacles and illustrate the need for improvement based on an understanding of the cellular damage and repair responses to therapy. The EU-funded subLETHAL project aims to develop a combination of immunotherapy with cancer therapies at ultra-low, sublethal doses. The approach is based on the assumption that sublethal treatments reveal vulnerabilities that can be exploited by complementary multi-targeted therapies at ultra-low doses. Single-cell analyses, advanced statistics, and mathematical modelling will be used to optimise the damage profile for each modality in tumour cells.
Objective
Immunotherapy combined with cytotoxic and molecular therapies have entered centre stage as novel treatments for cancer. Despite this advance, toxicity and insufficient efficacy in many patients remain major obstacles and illustrate the need for therapy improvement based on a deeper understanding of the cellular damage and repair responses to drugs and immunotherapy.
To overcome this roadblock, I propose a previously unappreciated approach by combining immunotherapy with cancer therapies at ultra-low, sublethal dose. We demonstrated that cytotoxic T cells induce sublethal membrane and DNA damage and oxidative stress which, when repaired, allows for tumor cell survival. However, when damage adds up, the tumor cell dies.
I hypothesize that sublethal effects reveal novel vulnerabilities in cancer cells which can be exploited by complementary multi-targeted therapies at ultra-low dose which are nontoxic individually but, when combined, achieve lethality by an additive mechanism.
Taking advantage of innovative microscopy, I aim to produce a catalogue of damages and repair types, and their combined effects in tumor cells. Single-cell analyses combined with advanced statistics and mathematical modeling will be used to derive the damage profile and duration of damage for each modality in tumor cells, yet without side effects towards immune effector cells. I will design algorithms for multi-targeted regimens to achieve additive damage, reduced repair, and death induction and validate them in immunotherapy models in vitro and in local and disseminated preclinical cancer in vivo. If resistance occurs, survival programs will be detected by single-cell transcriptomics and countered by orthogonal targeting.
subLETHAL will 1) identify sublethal damage as the basis of cytotoxic therapy, 2) enable rational design of multi-targeted ultra-low dose additive regimens and advance 3) the understanding, efficacy and tolerability of chemoimmunotherapy for 4) rapid clinical translation.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences genetics DNA
- medical and health sciences clinical medicine oncology
- medical and health sciences basic medicine immunology immunotherapy
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
MAIN PROGRAMME
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Topic(s)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-ERC - HORIZON ERC Grants
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Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) ERC-2021-ADG
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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.
6525 GA NIJMEGEN
Netherlands
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.