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PhD position in commercial environment: cancer immunotherapy drug screening in 3D

Periodic Reporting for period 1 - 3DPD (PhD position in commercial environment: cancer immunotherapy drug screening in 3D)

Reporting period: 2017-09-01 to 2018-08-31

Immunotherapy has been evolving over the last decades and now offers new and effective treatment modalities for cancer patients. The underlying idea is to harness the patients’ own immune system to fight cancer, based on the premise that tumor cells arising from genetic mutations differ from healthy tissues and can be recognized by immune cells as foreign. However, tumors have developed several methods to stay below the radar of the immune system hampering efficacy of immunotherapeutics, which results in partial or non-responses in the clinic. To overcome these hurdles and increase positive clinical outcomes, a better understanding of mechanisms of action of immunotherapies is required, and for that relevant preclinical models are needed. Therefore to cover this unmet need of cancer immunotherapies developers we designed within this project a screening platform that helps to understand the complex tumor microenvironment. This improved understanding can ultimately help bringing more effective treatments to cancer patients or help selecting right treatments for right patients.
OcellO is a Dutch CRO that offers unique in vitro screening tools for cancer drug development industry. They are based on a 3D cell culture platform that reconstitutes a tissue-like organization of cells retaining the histological characteristics of the original human tumor tissues. In combination with the ability to perform high-content image analysis of these 3D cultures, OcellO has demonstrated to be supreme in forwarding drug compounds to the clinical development phase. Driven by the market needs, OcellO has focused on expanding its portfolio by incorporating assays that include immune cells of different kinds and can support the development of immuno-modulating cancer drugs.
The main objective of this project funded by EU Horizon2020 innovation associate grant was to increase an immunology expertise level at OcellO by hiring and immunology expert and by doing so - improving the immuno-oncology platform and providing innovative tools for testing cancer immunotherapies. These objectives were fully met and resulted in addition to OcellO’s portfolio assays that are able to visualize and analyze the tumor-immune cell interactions and quantify this via functional read-outs such as; tumor killing and immune cell infiltration into the tumors. This innovative, multicellular immuno-oncology platform has potential to test cancer immunotherapies and analyze their mechanism of action in a relevant tumor microenvironment which can help clinical translation of new cancer immunotherapies and better selection of treatments for cancer patients.
This research project built on already existing at OcellO 3D cell culture platform and high throughput image analysis tools. As an outcome of this project, we can add immune cells to 3D cultures allowing the testing of cancer immune therapies. To analyze the effects of these specific therapies we visualize the tumor-immune cell interactions and quantify drugs effect on tumor growth and killing. In the current project we specifically focused on the myeloid cell compartment of the immune system, as they have been demonstrated to play a major role in the anti-tumor immune response. We have achieved a stable reproducible protocol to growth and generate these cells in our 3D cell culture platform. Subsequently, after imaging, analysis of morphological characteristics of these myeloid cells is performed (Figure 1) that results in a selection of features that combined create a phenotypical profile of different myeloid cells that have different functions in the tumor immune-response. This strategy can be used in more complex assay, where myeloid cells are co-cultured with tumor cells in a 3D environment.
In line with that, we also further validated our analysis platform and could confirm that specific engineered immune cells infiltrated and killed colorectal cancer organoids in the presence of their specific activator, while the control immune cells did not respond to this activation (Figure 2). Together these results have enriched our existing platform, allowing testing of possible new candidates for cancer immune therapies. We presented present the obtained results at conferences in the form of scientific posters and handout flyers to potential customers and we posted about them on LinkedIn. With that we hope to further draw the attention of the market and potential customers to our innovative screening platform.
Our innovative in vitro assays are relevant for different potential customers that develop cancer immunotherapies. These assays can be used at every stage of a drug development process; starting from discovery phase all the way to the pre-clinical testing. They can be even used during clinical trials to get additional insights into mechanism of action or to study a potential outcome of approved drug combinations. Several pharmaceutical companies have already demonstrated their interest in our innovation. To further support its development and to increase the impact of our services, we started to collaborate with some of these companies in research agreement settings. The developed assays will contribute to a better understanding of the mechanism of action of specific cancer therapies that target the immune system. Therefore, they will advance clinical development of different portfolio assets for our customers, which will ultimately benefit cancer patients by offering them more specific and more effective treatments. These improvements should have a major socio-economic impact on both, European and global healthcare systems.
Bi-parametric analysis of selected phenotypical features of different cell populations.
Infiltration of engineered T cells (green) into colorectal cancer organoids (red and blue).