Periodic Reporting for period 1 - ULISES (Immunological incompatibility as a basis for cancer curing and vaccination)
Okres sprawozdawczy: 2020-10-01 do 2021-09-30
According to statistics from the World Health Organization, cancer is a leading cause of death worldwide accounting for approximately 10 million deaths in 2020.
The current scenario of cancer treatments is based on surgical resection of the tumour (when possible), chemotherapy, radiotherapy, targeted-driven therapies and immunotherapy. Although treatments are effective for some types of cancer, their effectiveness is limited because their efficacy depends on many factors including molecular heterogeneity of the tumour, genetic background of the patient, immune system status and tumour microenvironment.
Pancreatic ductal adenocarcinoma is the most common form of pancreatic neoplasia and is one of the most lethal of all adult malignancies with particularly sparse therapeutic options. Currently only 7% of patients achieve a 5-year survival. Because of this devastating situation the implementation and validation of the ULISES therapeutic strategy will focus on pancreatic ductal adenocarcinoma (also referred as pancreatic cancer).
The ULISES project aims to develop an immunologic-based treatment strategy to reprogram cancer cells to become “visible” to the patient’s own immune system. We propose to develop functionalized nanoparticles uploaded with a genetic cargo that when delivered to tumors will reveal cancer cells to the immune system.
The current scenario of cancer treatments is based on surgical resection of the tumour (when possible), chemotherapy, radiotherapy, targeted-driven therapies and immunotherapy. Although treatments are effective for some types of cancer, their effectiveness is limited because their efficacy depends on many factors including molecular heterogeneity of the tumour, genetic background of the patient, immune system status and tumour microenvironment.
Pancreatic ductal adenocarcinoma is the most common form of pancreatic neoplasia and is one of the most lethal of all adult malignancies with particularly sparse therapeutic options. Currently only 7% of patients achieve a 5-year survival. Because of this devastating situation the implementation and validation of the ULISES therapeutic strategy will focus on pancreatic ductal adenocarcinoma (also referred as pancreatic cancer).
The ULISES project aims to develop an immunologic-based treatment strategy to reprogram cancer cells to become “visible” to the patient’s own immune system. We propose to develop functionalized nanoparticles uploaded with a genetic cargo that when delivered to tumors will reveal cancer cells to the immune system.
The report covers one year project. During this year the individual and coordinated work of the different work packages has generated several results that are highlighted below.
• 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.
• The design of the genetic cargo has also focused on the regulatory elements that should constitute the pDNA to bring oncoselectivity. 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.
• Optimization on the synthesis and purification steps of the pDNA.
• Design of an mRNA candidate to attenuate potential side effects due to the unspecific targeting of functionalized nanoparticles to blood cells.
• Development of functional assays to evaluate phagocytosis.
• Synthesis and characterization of nanoparticles from different nanomaterials are being explored.
• 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 store for future studies. The establishment of a humanized mouse model of PDAC is ongoing.
• 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.
• The design of the genetic cargo has also focused on the regulatory elements that should constitute the pDNA to bring oncoselectivity. 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.
• Optimization on the synthesis and purification steps of the pDNA.
• Design of an mRNA candidate to attenuate potential side effects due to the unspecific targeting of functionalized nanoparticles to blood cells.
• Development of functional assays to evaluate phagocytosis.
• Synthesis and characterization of nanoparticles from different nanomaterials are being explored.
• 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 store for future studies. The establishment of a humanized mouse model of PDAC is ongoing.
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 can be particularly relevant in the case of pancreatic cancer, studied in the ULISES Project. This neoplasia is currently the fourth leading cause of cancer death in Western countries, with an incidence, similar between men and women, that almost equals mortality and 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 significantly 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. This will boost Europe’s market presence, having a positive impact on its economy.
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 can be particularly relevant in the case of pancreatic cancer, studied in the ULISES Project. This neoplasia is currently the fourth leading cause of cancer death in Western countries, with an incidence, similar between men and women, that almost equals mortality and 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 significantly 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. This will boost Europe’s market presence, having a positive impact on its economy.