Periodic Reporting for period 1 - RESYNC (Functional chemical reprogramming of cancer cells to induce antitumor immunity)
Okres sprawozdawczy: 2024-01-01 do 2024-12-31
Cellular reprogramming emerged as a promising gene therapy approach for several diseases, in particular regenerative medicine and cancer. To date, cellular reprogramming is commonly achieved using transcription factors delivered by viral vectors, including lentivirus and adenovirus, which allow repeated administration but pose the risk of integrative oncogenesis. Additionally, viral vectors have complex and costly manufacturing processes, limiting their wide applicability.
Small molecules (SM) emerge as promising new candidates to induce cell conversion as they circumvent the safety concerns associated with viral vectors and the limitations of other approaches (e.g.: RNA-based approaches). The radical vision of the RESYNC consortium is to revolutionize cancer immunotherapy through SM-based reprogramming of cancer cells into immunogenic cancer antigen-presenting type 1 conventional dendritic cells (cDC1) to elicit personalized anti-tumor immunity. It envisions to overcome the barriers of current immunotherapies (e.g. lack of clinical response in most patients, safety, high costs and complex manufacturing), through a safe and cost-efficient platform for systemic cancer cell functional reprogramming leveraging SM mimicking transcription factors for reprogramming. By counteracting immune evasion mechanisms, our proposed breakthrough can result in novel therapeutic strategies based on the systemic administration of cancer-targeted SM cocktails to 1) induce personalized anti-tumor immunity as standalone treatment, and 2) synergize with existing immunotherapies to increase their effectiveness. By avoiding the caveats of current ex vivo and viral vector-based reprogramming strategies, our technology has the potential to be quickly adopted and widely applicable in the clinic.
Small molecules (SM) emerge as promising new candidates to induce cell conversion as they circumvent the safety concerns associated with viral vectors and the limitations of other approaches (e.g.: RNA-based approaches). The radical vision of the RESYNC consortium is to revolutionize cancer immunotherapy through SM-based reprogramming of cancer cells into immunogenic cancer antigen-presenting type 1 conventional dendritic cells (cDC1) to elicit personalized anti-tumor immunity. It envisions to overcome the barriers of current immunotherapies (e.g. lack of clinical response in most patients, safety, high costs and complex manufacturing), through a safe and cost-efficient platform for systemic cancer cell functional reprogramming leveraging SM mimicking transcription factors for reprogramming. By counteracting immune evasion mechanisms, our proposed breakthrough can result in novel therapeutic strategies based on the systemic administration of cancer-targeted SM cocktails to 1) induce personalized anti-tumor immunity as standalone treatment, and 2) synergize with existing immunotherapies to increase their effectiveness. By avoiding the caveats of current ex vivo and viral vector-based reprogramming strategies, our technology has the potential to be quickly adopted and widely applicable in the clinic.
The RESYNC project brings together specialists from non-overlapping, different and complementary skill sets that together have the potential to develop a technology that can transform immunotherapy. We have developed a high-content screening that allowed the identification of 94 active SMs that enhance PIB-mediated cDC1 reprogramming efficiency. These lead SMs observed to increase cDC1 reprogramming were further synthetized for further biological evaluation.
Importantly, we observed that the identified compounds enhance PIB-reprogramming across different models, including mouse and human fibroblasts, and different cancer cell lines. Moreover, high-content screening with bicistronic constructs allowed the identification of SMs replacing individual transcription factors in cDC1 reprogramming. Some incomplete activity of SMs replacing one of the transcription factors lead us to develop a set of strategies that we are currently pursuing to improve the screening efficiencies, including AI-based compound selection and foundation models. Some AI-predicted combinations of compounds have been identified so far and are currently under test.
To establish a platform for the systemic delivery of SMs to selected target tissues or cell types, we are developing a novel cancer-targeted lipidic-coated nanoparticles. So far, we have been able to successfully coat the nanoparticles, design and test a scaled-up microfluidic-based production, test the targeting capabilities, and demonstrate the safety of the produced nanoparticles. The next steps include in vivo proof-of-concept and safety studies for chemical cDC1 reprogramming with nanoparticles delivering SMs.
Importantly, we observed that the identified compounds enhance PIB-reprogramming across different models, including mouse and human fibroblasts, and different cancer cell lines. Moreover, high-content screening with bicistronic constructs allowed the identification of SMs replacing individual transcription factors in cDC1 reprogramming. Some incomplete activity of SMs replacing one of the transcription factors lead us to develop a set of strategies that we are currently pursuing to improve the screening efficiencies, including AI-based compound selection and foundation models. Some AI-predicted combinations of compounds have been identified so far and are currently under test.
To establish a platform for the systemic delivery of SMs to selected target tissues or cell types, we are developing a novel cancer-targeted lipidic-coated nanoparticles. So far, we have been able to successfully coat the nanoparticles, design and test a scaled-up microfluidic-based production, test the targeting capabilities, and demonstrate the safety of the produced nanoparticles. The next steps include in vivo proof-of-concept and safety studies for chemical cDC1 reprogramming with nanoparticles delivering SMs.
The RESYNC project is pioneering the use of chemical reprogramming to develop a first-in-class off-the-shelf cancer immunotherapy that elicits a personalized immune response. It is allowing the establishment of a high-screen platform for the identification of key compounds that increase cDC1 reprogramming efficiency and replace individual transcription factors. Current and future efforts will focus on in vivo proof-of-concept and safety studies for chemical cDC1 reprogramming.