Periodic Reporting for period 1 - MUTAVAC (Targeting cancer with mutanome based stem cell vaccine)
Reporting period: 2022-10-01 to 2023-09-30
The past two decades have seen major breakthroughs in the cancer research with discovery of targeted therapies and, notably, immunotherapies such as immune checkpoint inhibitors (ICIs) and CAR-Ts. However, there are major unmet medical needs in the therapy of advanced cancers. For example, immunotherapies are only suitable for a minority of patients (<20%) within a given cancer type and many advanced cancers remain resistant to treatment.
The limited effectiveness of available immunotherapies may be due, in part to their inability to target Cancer Stem Cells (CSC). The persistence of CSCs fuels the clonal heterogeneity of cancers and their progression by immune escape with high risks of recurrence and metastatic dissemination. In addition, CSCs are known to be intrinsically resistant to conventional cancer therapies (radiotherapy and chemotherapy) and immunotherapies (ICIs and CAR-Ts) as well as to targeted therapies. Moreover, current immunotherapies cannot induce an immune response against the several thousand distinct antigens found in cancer cells and in CSCs.
Thus, targeting CSCs and clonal variation during tumor progression represents one of a major issue in oncology but no immunotherapies or drugs have been developed so far to target specifically this cell population.
IPSirius is a biotechnology company pioneering a new generation of cancer vaccines (iPVAC) using engineered induced pluripotent stem cells (iPSCs) able to target and eradicate CSCs by reengaging the body’s immune system against multiple neo-antigens contained in CSC. iPVAC cancer vaccines trigger a robust and long-lasting immune response involving adaptative and innate immune cells to eradicate CSCs to prevent tumor relapse in addition to prevent or cure metastasis spread. The immunogenicity of iPVAC was demonstrated in vivo, in various aggressive and metastatic cancer models in mice.
The MUTAVAC project aims to develop a new version from iPVAC, ‘iPVAC-Mut’ based on cancer associated mutanome. Our proprietary technology allows to produce ex-vivo high mutational load associated with cancers, specifically expressed in CSCs. ‘iPVAC-Mut’ represent major experimental tools for target discovery in cancers which have inherent genomic instability (such as Brca1 and Brca2 Ret, c-Met, Lynch syndrome).
The MUTAVAC project develops a platform to progress in the value chain of iPVACs, with an in vitro bioassay to predict the immunogenicity of iPVAC products. This bioassay will enable to identify patients that are more likely to respond to iPVAC products and to monitor and predict the clinical outcome of patients.
By strengthening our existing R&D and exploring new horizons and therapeutic approaches, the project will generate new products, services and revenues such as:
1) iPSC-based platform to discover first-in-class cancer targets and produce a pipeline of active immunotherapies
2) Preclinical setting of iPVAC products with robust strategies enhancing immune response
3) Potency assay with a high predictive value for the efficacy of iPVAC products with a comprehensive T-cell immune-monitoring response and biomarkers profiles allowing patient stratification (precision medicine), that will be
applied as surrogate markers in later clinical development.
The project will easily impact many other initiatives with clear consequences for the field of cell therapy overall. Our standardized bioassay will be offered globally to vaccine developers and end users for personalized testing. Our iPSC-based platform should therefore subsequently benefit all of the collaborations carried out by other players in the sector to bring rapidly their innovation into the market.
IPSIRIUS ambitions to become a game changer in the immuno-oncology arena, by developing disruptive universal cellular immunotherapies (IPVAC and IPVAC-Mut) with high industrial potential. The clinical development of IPVAC will be initially in patients with non-small cell lung cancer (NSCLC) which is the leading cause of cancer mortality worldwide. The introduction of immune Check Points inhibitors (ICIs) has improved the management of this cancer but the responses rates are low (30 %) as well as the 5-year survival (10 -15%). There is a strong medical need to increase clinical response rates by combining immunotherapies and to other innovative treatments. After the Phase I/II trials in NSCLC, IPVAC products will allow much wider access for European patients to treat several types aggressive cancers. The ultimate goal is to utilize the power of engineered pluripotent stem cells with our proprietary technology to provide every European citizen with safe, affordable, and ‘off-the-shelf’ iPVAC cancer vaccines.
The limited effectiveness of available immunotherapies may be due, in part to their inability to target Cancer Stem Cells (CSC). The persistence of CSCs fuels the clonal heterogeneity of cancers and their progression by immune escape with high risks of recurrence and metastatic dissemination. In addition, CSCs are known to be intrinsically resistant to conventional cancer therapies (radiotherapy and chemotherapy) and immunotherapies (ICIs and CAR-Ts) as well as to targeted therapies. Moreover, current immunotherapies cannot induce an immune response against the several thousand distinct antigens found in cancer cells and in CSCs.
Thus, targeting CSCs and clonal variation during tumor progression represents one of a major issue in oncology but no immunotherapies or drugs have been developed so far to target specifically this cell population.
IPSirius is a biotechnology company pioneering a new generation of cancer vaccines (iPVAC) using engineered induced pluripotent stem cells (iPSCs) able to target and eradicate CSCs by reengaging the body’s immune system against multiple neo-antigens contained in CSC. iPVAC cancer vaccines trigger a robust and long-lasting immune response involving adaptative and innate immune cells to eradicate CSCs to prevent tumor relapse in addition to prevent or cure metastasis spread. The immunogenicity of iPVAC was demonstrated in vivo, in various aggressive and metastatic cancer models in mice.
The MUTAVAC project aims to develop a new version from iPVAC, ‘iPVAC-Mut’ based on cancer associated mutanome. Our proprietary technology allows to produce ex-vivo high mutational load associated with cancers, specifically expressed in CSCs. ‘iPVAC-Mut’ represent major experimental tools for target discovery in cancers which have inherent genomic instability (such as Brca1 and Brca2 Ret, c-Met, Lynch syndrome).
The MUTAVAC project develops a platform to progress in the value chain of iPVACs, with an in vitro bioassay to predict the immunogenicity of iPVAC products. This bioassay will enable to identify patients that are more likely to respond to iPVAC products and to monitor and predict the clinical outcome of patients.
By strengthening our existing R&D and exploring new horizons and therapeutic approaches, the project will generate new products, services and revenues such as:
1) iPSC-based platform to discover first-in-class cancer targets and produce a pipeline of active immunotherapies
2) Preclinical setting of iPVAC products with robust strategies enhancing immune response
3) Potency assay with a high predictive value for the efficacy of iPVAC products with a comprehensive T-cell immune-monitoring response and biomarkers profiles allowing patient stratification (precision medicine), that will be
applied as surrogate markers in later clinical development.
The project will easily impact many other initiatives with clear consequences for the field of cell therapy overall. Our standardized bioassay will be offered globally to vaccine developers and end users for personalized testing. Our iPSC-based platform should therefore subsequently benefit all of the collaborations carried out by other players in the sector to bring rapidly their innovation into the market.
IPSIRIUS ambitions to become a game changer in the immuno-oncology arena, by developing disruptive universal cellular immunotherapies (IPVAC and IPVAC-Mut) with high industrial potential. The clinical development of IPVAC will be initially in patients with non-small cell lung cancer (NSCLC) which is the leading cause of cancer mortality worldwide. The introduction of immune Check Points inhibitors (ICIs) has improved the management of this cancer but the responses rates are low (30 %) as well as the 5-year survival (10 -15%). There is a strong medical need to increase clinical response rates by combining immunotherapies and to other innovative treatments. After the Phase I/II trials in NSCLC, IPVAC products will allow much wider access for European patients to treat several types aggressive cancers. The ultimate goal is to utilize the power of engineered pluripotent stem cells with our proprietary technology to provide every European citizen with safe, affordable, and ‘off-the-shelf’ iPVAC cancer vaccines.
Multiple iPSC lines were generated from different human donors with hematological malignancies and from patients with oncogenic somatic mutations or with hereditary cancers. In vitro mutagenesis was induced in all the above iPSCs using the proprietary protocol developed by iPSirius. The genomic landscape was characterized in iPSC lines in the presence and the absence of the mutagenic agent by using different approaches: Karyotype, CGH arrays, gene profiling RNA-seq and exome sequencing. We have developed a mixed lymphocyte reaction (MLR) assay exploring the immunogenicity of the pipeline of IPVACs. This process included the isolation of T cells from human donors and monocyte to produce autologous dendritic cells (MoDC) and the stimulation of T cells by IPVAC’s-loaded dendritic cells. T cell immune response was quantified by an Elispot assays.
Potential impacts: MUTAVAC project has the potential to give rise to a practice change in Oncology with several major impacts:
1) The identification of novel targets of T-cells identified through TCR cloning
2) The development of a potency assay based on patient’s HLA genotype allowing the selection of the eligibility of the patients for future Phase I/II clinical trials
3) The generation of surrogate biomarkers to follow-up immune response in human during clinical trials.
In term of innovation, IPSirius has established a broad patent estate covering the use of pluripotent stem cells, their derivatives and components as the basis of universal cancer vaccines for multiple type of cancer with a family of patents (portfolio of 29 patents in 12 countries, recently granted in major countries). IPSirius will improve the valuation of their intellectual proprietary portfolio with new patents obtained from the MUTAVAC project.
Commercialization: The clinical strategy and commercial viability of our first IPVAC product in key potential markets such as the US, the EU, the UK, Canada, Australia has been reviewed, and the maximum annual revenue potential was estimated in each target country using the price potential for IPVAC.
Access to the market: MUTAVAC project will have a major impact in the access to the market of the IPVAC products, the first of which is already in preparation for regulatory approval of a Phase I/II trial in patients with NSCLC.
For the industrialization phase, IPSirius has already identified a CDMO (Contract Development and Manufacturing Organization), who will support the manufacture of clinical grade IPVAC and a CRO to guarantee that the project will meet all EMA expectations.
1) The identification of novel targets of T-cells identified through TCR cloning
2) The development of a potency assay based on patient’s HLA genotype allowing the selection of the eligibility of the patients for future Phase I/II clinical trials
3) The generation of surrogate biomarkers to follow-up immune response in human during clinical trials.
In term of innovation, IPSirius has established a broad patent estate covering the use of pluripotent stem cells, their derivatives and components as the basis of universal cancer vaccines for multiple type of cancer with a family of patents (portfolio of 29 patents in 12 countries, recently granted in major countries). IPSirius will improve the valuation of their intellectual proprietary portfolio with new patents obtained from the MUTAVAC project.
Commercialization: The clinical strategy and commercial viability of our first IPVAC product in key potential markets such as the US, the EU, the UK, Canada, Australia has been reviewed, and the maximum annual revenue potential was estimated in each target country using the price potential for IPVAC.
Access to the market: MUTAVAC project will have a major impact in the access to the market of the IPVAC products, the first of which is already in preparation for regulatory approval of a Phase I/II trial in patients with NSCLC.
For the industrialization phase, IPSirius has already identified a CDMO (Contract Development and Manufacturing Organization), who will support the manufacture of clinical grade IPVAC and a CRO to guarantee that the project will meet all EMA expectations.