Immunological incompatibility as a basis for cancer curing and vaccination

Informations projet

ULISES

N° de convention de subvention: 899708

DOI

10.3030/899708

Projet clôturé

Date de signature de la CE 18 Juin 2020

Date de début 1 Octobre 2020

Date de fin 30 Juin 2024

Financé au titre de

• EXCELLENT SCIENCE - Future and Emerging Technologies (FET)

Coût total

€ 2 977 160,00

Contribution de l’UE

€ 2 977 160,00

Coordonné par

FUNDACIO DE RECERCA CLINIC BARCELONA-INSTITUT D INVESTIGACIONS BIOMEDIQUES AUGUST PI I SUNYER
Spain

Periodic Reporting for period 3 - ULISES (Immunological incompatibility as a basis for cancer curing and vaccination)

Période du rapport: 2023-10-01 au 2024-06-30

Résumé du contexte et des objectifs généraux du projet

The validation of the ULISES therapeutic strategy focuses on pancreatic ductal adenocarcinoma (pancreatic cancer) due to its devastating situation.
The ULISES project works on the development of an immunologic-based treatment strategy to reprogram cancer cells to become “visible” to the patient’s own immune system. We are developing functionalized nanoparticles uploaded with a genetic cargo that when delivered to tumors renders cancer cells visible to the immune system. Current project has developed computational methods to optimize T anb B-cell targeting and has identified selected HLA trios to cover the global population. Moreover, monoclonal antibodies against the HLA candidates have been produced to facilitate immunological monitoring and to be used as a therapy to improve the overall treatment. Several nanoparticles formulation have been studied and finally identified a formulation based on lipid nanoparticles (LNP) as the optimal delivery system. They have been functionalized with two different ligands that provide targeting efficacy and contribute to the elimination of the cancer cells. The genetic cargo has been studied at the DNA and RNA level and different regulatory elements. Regulation by miRNA target sites has been addressed not only to provide specificity but also not to trigger adverse events through the miRNA sponge effect.
PDAC samples from a significant number of patients have been characterized and cells lines have been generated to study patient-mediated response to the therapy. In vitro studies have validated the immune response triggered against selected HLAs through complement-dependent cytotoxicity and NK cell-mediated cytotoxicity, highlighting the role of the proposed therapy enhancing immune-mediated destruction of pancreatic cancer cells. Functionalized LNP deliver the genetic cargo in PDAC tumor in mouse models and HLA candidates are expressed. Preliminary experiments in a humanized model did not show antitumor response. Further experiments are necessary to improve treatment schedule and validate the in vivo activity of the designed therapy.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

The report covers all the project-period:
• It has been established a computational pipeline for the identification of immunogenic HLAs. With this tool it has been possible to identify trios of HLA alleles with maximized immunogenicity that were validated in the context of diverse population.
• Monoclonal anti-HLA_A antibodies have been produced
• The regulatory elements that should constitute the pDNA to bring oncoselectivity have been selected. Enhancer/promoter and miRNA regulatory sequences have been identified to drive expression in cancer cells and mitigate or avoid the expression in normal cells, with a particular focus in blood cells.
• Potential miRNA side effects due to the sponge effects in healthy cells have been addressed.
• Two groups of pDNA and mRNA cargos have been generated and produced at transfection grade
• Expression studies to validate the pDNA and mRNA cargos have been conducted.
• Functional assays to validate the pDNA and mRNA cargos have been performed in vitro.
• The mRNA candidate to attenuate potential side effects due to the unspecific targeting of functionalized nanoparticles to blood cells has been designed.
• Synthesis and characterization of functionalized nanoparticles with different ligands have been prepared and tested in vitro.
• Functional assays to evaluate the value of targeting ligands (phagocytosis assay) have been implemented.
• Candidate nanoparticles have been tested in vivo in xenograft of pancreatic tumors. Tumor targeting, toxicity and biodistribution studies have been conducted
• PDAC models for the validation of the therapeutic strategy have been characterized. Two cellular models of pancreatic cancer have been selected. These cells were HLA genotyped and characterized for the expression of the surface markers to recognize functionalized nanoparticles.
• Patient biological samples (primary cancer cells, tumors and PBMC) have been collected, processed and stored for future studies.
• Characterization of the immune landscape of PDAC tumors has been performed.
• The establishment of a humanized mouse model has been performed.
• Dose-response anticancer effects of the functionalized LNP with HLA candidates have been demonstrated showing higher susceptibility to complement-dependent cytotoxicity and NK cell-mediated cytotoxicity, suggestive of the value of the therapy.
• Preliminary experiments on the validation of the in vivo targeting therapy have been conducted.
Significant number of Dissemination and Communication activities have been conducted. The project website has been updated and publications of scientific and journalist articles, interviews and impacts on social media channels have been the core of the dissemination activities.
To optimally assess the Exploitation of the results as a Consortium we identified a list of Key Exploitable Results (KERs) and obtained legal opinion on IP and IPR issues to 5 specific KERs.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

The ULISES therapeutic strategy aims to provide a technology that makes tumors visible to the immune system, by reprogramming cancer cells and transform the tumor into an incompatible tissue for the patient.
ULISES therapy can be a breakthrough in the field of medical treatments for cancer, probably the most disturbing disease for our society. A technology with the therapeutic advantages provided by the ULISES strategy may translate into improvement in healthcare, reducing worldwide cancer death rate and the global cancer burden, significantly improving patient’s life quality and life expectancy. This neoplasia is currently the third leading cause of cancer death in Western countries, with an incidence expected to rank among the three cancers projected to be the top killers in 2030.
This therapy may provide several advantages such as:
• A significantly much higher efficiency compared to the rest of current therapies.
• Side effects will be minimized since the therapy already provides with mitigation elements.
• It is proposed to be a “global” treatment. Only with three genetic cargos, it should be feasible to target the entire population, without the requirement of a personalized treatment.
• It can be easily and rapidly adapted to any type of cancer with minimal modifications.
• Treatment time might be reduced with a similar effect to a hyperacute rejection in transplants with no compatibility.
• A significant cost saving is planned as it is not a personalized treatment.
The increased effectiveness and the cost and time reduction envisaged by the ULISES therapy will help to reduce the healthcare costs associated with cancer treatments and patients care and hospitalization.
At a European level, the availability of a therapeutic strategy like that proposed in the ULISES project, may allow attracting a wide range of researchers and companies that might be interested in evolving the technology and making it a market reality for the benefit of the society.
The development of the project has shown the potential of the therapy with significant improvements to refine the product. We have demonstrated its value in in vitro models, but further research is needed to validate the in vivo responses in appropriate mouse models.

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