Periodic Reporting for period 1 - CANCERNA (RNA PROCESSING FOR ANTI-CANCER IMMUNOTHERAPY)
Reporting period: 2022-06-01 to 2023-11-30
In the past seven years, RNA therapeutics have witnessed a true revolution. Several RNA-based therapies have been approved for the treatment of genetic diseases, with unprecedented successes, as in spinal muscular atrophy. Moreover, the COVID-19 pandemic showed the world that RNA-based therapies, namely mRNA vaccines, can be the answer to a worldwide pandemic and save the lives of millions. RNA therapies are however lagging in clinical oncology. In parallel, the development of immune checkpoint inhibitors has revolutionized cancer care, but its success remains limited to a subset of patients. The overarching aim of this multi-armed project is to develop RNA-based cancer treatments. Altogether, for 60 percent of the eight million new cancer patients diagnosed in Europe each year, including almost all children with solid tumors, there is no EMA- or FDA-approved immunotherapy option, and they are left out of the circle of hope.
In response, CANCERNA aims to build on these two breakthroughs and apply RNA-based therapeutics to overcome key barriers to unfold successful anti-cancer immune responses. Our two key objectives are: on one hand, harness the modulation of RNA processing to enhance the accessibility and immune susceptibility of the tumour and its microenvironment. While on the other hand, enhance the activity of the immune system by retargeting immune effector cells, modulating RNA splicing of key immune receptors and developing personalized mRNA vaccines. The project will focus on two cancer types harboring splicing factor mutations and being generally refractory to immunotherapy: acute myeloid leukemia, relevant for pediatric cancer, and uveal melanoma.
The collective knowledge of our consortium of RNA scientists, clinicians and biotech-pharma experts in RNA processing, RNA drug design and delivery, biocomputing and immuno-oncology provides a unique opportunity to significantly advance novel RNA technologies into successful cancer therapies.
In response, CANCERNA aims to build on these two breakthroughs and apply RNA-based therapeutics to overcome key barriers to unfold successful anti-cancer immune responses. Our two key objectives are: on one hand, harness the modulation of RNA processing to enhance the accessibility and immune susceptibility of the tumour and its microenvironment. While on the other hand, enhance the activity of the immune system by retargeting immune effector cells, modulating RNA splicing of key immune receptors and developing personalized mRNA vaccines. The project will focus on two cancer types harboring splicing factor mutations and being generally refractory to immunotherapy: acute myeloid leukemia, relevant for pediatric cancer, and uveal melanoma.
The collective knowledge of our consortium of RNA scientists, clinicians and biotech-pharma experts in RNA processing, RNA drug design and delivery, biocomputing and immuno-oncology provides a unique opportunity to significantly advance novel RNA technologies into successful cancer therapies.
In a generalisation, the initial half of the project was dedicated to two major achievements: generate and collect molecular data to support the initial hypothesis, which is that neo-sequences exist in cancers based on aberrant splicing; secondly, that mRNA and oligonucleotides are useful tools in cancer immunotherapy development.
All participants, in a collaborative effort, are sharing material for sequencing or actual data actively and effectively. Importantly, CANCERNA already identified potential neo-epitopes and noted their reproducibility in different patient samples. Oligonucleotides were successfully used in cancers and in effector lymphocytes to manipulate the splicing process and nanobodies were found to affect intracytoplasmic immunosuppressive proteins.
All participants, in a collaborative effort, are sharing material for sequencing or actual data actively and effectively. Importantly, CANCERNA already identified potential neo-epitopes and noted their reproducibility in different patient samples. Oligonucleotides were successfully used in cancers and in effector lymphocytes to manipulate the splicing process and nanobodies were found to affect intracytoplasmic immunosuppressive proteins.
The project yielded the following results:
- Whitepaper containing regulatory considerations for potential consortium products.
- Biobank of tumor samples harboring mutations in splicing factor genes.
- Increased knowledge of the role of splicing during T-cell activation following immunotherapy.
- List of alternative splicing events associated with T-cell activation.
- Detection system to identify and isolate immune cells with enhanced functionality.
- List of top hits of splice isoforms of immune receptors that improve T cell function.
- LNP formulation for encapsulated marker-encoding mRNA.
- Protocol to transfect monocyte-derived dendritic cells with mRNA loaded LNPs.
- Workshop on RNA delivery methods
- Whitepaper containing regulatory considerations for potential consortium products.
- Biobank of tumor samples harboring mutations in splicing factor genes.
- Increased knowledge of the role of splicing during T-cell activation following immunotherapy.
- List of alternative splicing events associated with T-cell activation.
- Detection system to identify and isolate immune cells with enhanced functionality.
- List of top hits of splice isoforms of immune receptors that improve T cell function.
- LNP formulation for encapsulated marker-encoding mRNA.
- Protocol to transfect monocyte-derived dendritic cells with mRNA loaded LNPs.
- Workshop on RNA delivery methods