Periodic Reporting for period 1 - ImmuNovation (Modular Targeted Nanoplatform for Immune Cell Regulation and Therapy)
Periodo di rendicontazione: 2023-04-01 al 2025-03-31
Cancer is a major cause of disability and mortality worldwide. Despite the promising clinical results of immunotherapies, they suffer from multiple limitations, including manufacturing challenges, limited efficacy, toxicity, and high costs. Recent data highlight the promising role of personalized cancer vaccines in inducing effective antitumor immunity in patients suffering from aggressive forms of cancer. However, systems suitable for the targeted delivery of multiple agents required for long-lasting patient immunity are required. ImmuNovation is focused on TNM (Targeted Nano-immunoModulator), a multifunctional dendritic cell-targeted nanovaccine designed to regulate the function and phenotype of immune cells with a pivotal role in the induction of an effective, specific, and long-lasting antitumor immunity. Here, we evaluate the technical and commercial viability of our novel nanoplatform (developed during my ERC Advanced Grant, 3DBrainStrom) for the targeted therapy of various cancer types. As proof of concept, we focus on immunotherapy for CEACAM5+ gastrointestinal (GI) cancers, which affect more than 5 million new cases per year and cause 3.5 million related deaths worldwide. Our nanovaccines will change the landscape of the standard of care for many cancer types.
ImmuNovation has produced endotoxin-free TNM prototypes with different bioactive molecules, which show formulation versatility and technical reproducibility. These formulations were able to incorporate both MHC I and MHC II peptides discovered using our CEACAM5-positive 3D models of colorectal cancer and PDAC, in combination with CpG adjuvant and PD-L1 siRNA for immune checkpoint modulation.
In vivo toxicology studies confirmed the biocompatibility and safety of all TNM formulations. No systemic toxicity or adverse immune effects were observed, which is important for the progression of studies toward validated IND-enabling studies.
Biodistribution studies confirmed the recognition and extensive uptake of TNM by antigen-presenting cells (APC), particularly dendritic cells, both in peripheral tissues and lymph nodes, demonstrating TNM's capability to accumulate in immunologically relevant sites.
Comparative studies demonstrated that TNM resensitized CEACAM5-positive tumors to immune checkpoint therapy (ICT) and conventional chemotherapy, outperforming the effect of these clinically relevant solutions as monotherapies. This in vivo preclinical data was validated using patient-derived peripheral blood mononuclear cells and 3D-bioprinted CEACAM5+ GI tumor models.
An extensive FTO analysis did not identify major blocking patents, confirming an FTO in the fields of nanovaccines and immunotherapies, and thereby providing a solid basis for further development and licensing.
A targeted IPR strategy was defined and implemented. A patent application (WO2020136657A9) covering the TNM composition and its specific use for CEACAM5+ GI cancers has been filed, which is now published. IP position and licensing terms, in addition to regulatory awareness, and a roadmap are now strengthened, supporting future start-up incorporation and potential public and/or investors’ engagement.
Stakeholder mapping was performed, and several exploratory meetings were held with pharmaceutical and biotech companies. A collaboration protocol has been signed with a leading CDMO, and a manufacturing contract was finalized to pursue the TNM production process development feasibility studies and scale-up under GLP and GMP-like conditions, which constitutes a major step toward clinical translation with funds awarded by the EIC Transition grant.
Of note, the results obtained through this project, including the market analysis and business development plan, supported the development of the new application entitled TIMNano to the European Innovation Council (EIC) Transition program, which has been recently awarded to further support TNM development and scale-up costs under GLP and GMP-like settings and first-in-human clinical trial design to confirm TNM safety and tolerability in patients affected with CEACAM5-positive tumors, namely CRC and PDAC.
In vivo toxicology studies confirmed the biocompatibility and safety of all TNM formulations. No systemic toxicity or adverse immune effects were observed, which is important for the progression of studies toward validated IND-enabling studies.
Biodistribution studies confirmed the recognition and extensive uptake of TNM by antigen-presenting cells (APC), particularly dendritic cells, both in peripheral tissues and lymph nodes, demonstrating TNM's capability to accumulate in immunologically relevant sites.
Comparative studies demonstrated that TNM resensitized CEACAM5-positive tumors to immune checkpoint therapy (ICT) and conventional chemotherapy, outperforming the effect of these clinically relevant solutions as monotherapies. This in vivo preclinical data was validated using patient-derived peripheral blood mononuclear cells and 3D-bioprinted CEACAM5+ GI tumor models.
An extensive FTO analysis did not identify major blocking patents, confirming an FTO in the fields of nanovaccines and immunotherapies, and thereby providing a solid basis for further development and licensing.
A targeted IPR strategy was defined and implemented. A patent application (WO2020136657A9) covering the TNM composition and its specific use for CEACAM5+ GI cancers has been filed, which is now published. IP position and licensing terms, in addition to regulatory awareness, and a roadmap are now strengthened, supporting future start-up incorporation and potential public and/or investors’ engagement.
Stakeholder mapping was performed, and several exploratory meetings were held with pharmaceutical and biotech companies. A collaboration protocol has been signed with a leading CDMO, and a manufacturing contract was finalized to pursue the TNM production process development feasibility studies and scale-up under GLP and GMP-like conditions, which constitutes a major step toward clinical translation with funds awarded by the EIC Transition grant.
Of note, the results obtained through this project, including the market analysis and business development plan, supported the development of the new application entitled TIMNano to the European Innovation Council (EIC) Transition program, which has been recently awarded to further support TNM development and scale-up costs under GLP and GMP-like settings and first-in-human clinical trial design to confirm TNM safety and tolerability in patients affected with CEACAM5-positive tumors, namely CRC and PDAC.
The ImmuNovation approach integrated advanced multicellular 3D-bioprinted tumor models, in addition to nanotechnology and computational techniques, to tackle the challenges of immunotherapy. The combination of these technologies led to the development of the TNM platform that uses antigenic fingerprints specific to each tumor type and gene regulators of major drivers of regulatory pathways involved in antigen presentation and associated effector immune responses, whose presence within the tumor microenvironment (TME) was discovered using human 3D-bioprinted tumor models (ERC AdG 3DBrainStrom) and were now controlled via in vivo gene editing by our TNM platform. TNM platform is based on immune cell-targeted biodegradable polymeric nanoparticles (NP) with multivalent properties (i.e. the ability to carry/deliver different molecules based on the cancer type). It is decorated with sugar (mannose) to mimic cancer cells, and it is full of unique antigenic molecular fingerprints and gene regulators of DC function and phenotype, which guarantees the activation of T- and B-cells specifically against the tumor cells presenting those antigen markers. Our first product, TNM-101, targets CEACAM5+ tumors, the most common type of GI cancer.
TNM feasibility batches were produced using a scalable process and their physicochemical properties were within the defined quality target product profile (QTPP). TNM safety and immunogenicity were confirmed in CEACAM+ colorectal cancer (CRC) as not being affected by production technology feasibility studies. The immune reactivity of the TNM feasibility batch was validated in 3D-bioprinted tumors created using human clinical tissue and blood samples.
The economic burden of cancer goes beyond direct healthcare costs. Substantial costs are associated with productivity losses as patients are unable to continue working, and many rely on relatives for support. TNM is expected to reduce the socio-economic burden by decreasing side effects and treatment costs. This innovation will be exploited by being introduced as new to the market (commercial exploitation), being primarily focused on CEACAM5-positive GI cancers. The modular nature of our precision nano-immunotherapy, in combination with genetic and sequencing advances, indicates that the impact of our breakthrough science-enabled technology will go beyond CRC and PDAC, shifting the paradigm of cancer treatment. We predict that implementing our clinically relevant patient-specific 3D cancer models, together with the plug-and-play nature of the TNM platform, will assist physicians in matching nano-immunotherapy rapidly, efficiently, and safely for each patient or group of patients. TNM data also supports the lack of/reduced non-specific side effects to healthy tissues, thus contributing to reducing the cost of patient care associated with current cancer therapies. TIMNano validation also represents an asset to reinforce the current business model and bring additional opportunities. As a downstream effect of increased work and employment for people who otherwise would suffer needlessly and be viewed as liabilities by employers, we believe that we are helping achieve SDG 8.5 achieving increased full and productive employment and decent work for men and women suffering from relevant cancers.
TNM feasibility batches were produced using a scalable process and their physicochemical properties were within the defined quality target product profile (QTPP). TNM safety and immunogenicity were confirmed in CEACAM+ colorectal cancer (CRC) as not being affected by production technology feasibility studies. The immune reactivity of the TNM feasibility batch was validated in 3D-bioprinted tumors created using human clinical tissue and blood samples.
The economic burden of cancer goes beyond direct healthcare costs. Substantial costs are associated with productivity losses as patients are unable to continue working, and many rely on relatives for support. TNM is expected to reduce the socio-economic burden by decreasing side effects and treatment costs. This innovation will be exploited by being introduced as new to the market (commercial exploitation), being primarily focused on CEACAM5-positive GI cancers. The modular nature of our precision nano-immunotherapy, in combination with genetic and sequencing advances, indicates that the impact of our breakthrough science-enabled technology will go beyond CRC and PDAC, shifting the paradigm of cancer treatment. We predict that implementing our clinically relevant patient-specific 3D cancer models, together with the plug-and-play nature of the TNM platform, will assist physicians in matching nano-immunotherapy rapidly, efficiently, and safely for each patient or group of patients. TNM data also supports the lack of/reduced non-specific side effects to healthy tissues, thus contributing to reducing the cost of patient care associated with current cancer therapies. TIMNano validation also represents an asset to reinforce the current business model and bring additional opportunities. As a downstream effect of increased work and employment for people who otherwise would suffer needlessly and be viewed as liabilities by employers, we believe that we are helping achieve SDG 8.5 achieving increased full and productive employment and decent work for men and women suffering from relevant cancers.