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Developing an in vitro platform to study the acquisition of tumour resistance to approved treatments
Despite great advances in the field of in vitro modelling, it remains extremely complicated to recreate artificial models which reproduce the very complex and heterogeneous microenvironment of actual tumours. A major challenge is the recreation of a vascular network inside spheroids to mimic normal nutrients and oxygen distribution. Similarly, the modelling of an immune system, which plays an important role in the tumour microenvironment, remains to be developed. These are a few of the challenges which scientists from PERSIST-SEQ’s partner Transgene address in an effort to make their model more relevant and applicable for use in the project.
Transgene S.A. is a clinical-stage biotechnology company which designs and develops novel immunotherapies for the treatment of cancer. Transgene designs immunotherapeutics that harness the mechanisms of the immune response to enable the patient’s body to fight against disease. With their know-how in genome engineering, Transgene scientists design biological products that are capable of inducing an immune response against cancer cells. Transgene has two technological platforms based on these respective approaches: myvac - therapeutic vaccines, and Invir.IO - oncolytic viruses. Moreover, Transgene’s portfolio consists of four products currently in clinical development.
Role in PERSIST-SEQ
Transgene’s activity within the consortium focuses on the development of an in vitro platform to study the acquisition of resistance to approved treatments by tumours. PERSIST-SEQ members from Transgene also aim to study the impact of resistance on the efficacy of oncolytic viruses used in second line. For this purpose, researchers at Transgene have developed a protocol to generate patient-derived tumoroids that can be used either for drug optimization, or for patient stratification. They are currently working on microfluidics platforms, allowing tumoroid culture in fluidic and intra-venous drug administration mimicry. The aim is to treat the tumoroid with a protocol mimicking what patients receive in the clinic. A transcriptome analysis of the tumoroids before and after treatment will then be performed. The objective is to study the modifications induced by the therapeutic stress and uncover the mechanisms behind resistance induction.
Transgene representatives provide patient-derived samples for transcriptome analysis to PERSIST-SEQ, and develop the application of tumour-on-chip technologies in immunotherapy. The in vitro nature of this model allows a controlled environment of culture, reducing the variability between experiments. The advantage of this model is that one can analyse the tumoroid at different stages of the treatment or compare the effect of different treatments, as single agents or within combination regimens.
Experience with the project
Clara Fauveau, a PhD candidate working at Transgene shares: “What I like the most is the trans-disciplinary nature of this project. I am only at the beginning of my PhD project, and I am already discovering a lot on the world of In vitro modelling and fluidics. It’s a rapidly evolving field domain, full of great ideas we wish to try and implement. I am also very much looking forward to receiving our first single cell results. I have studied and practiced a little bit of bioinformatic during my studies and am eager to analyse the data that our model will generate.”
On the challenges she encounters in her work on PERSIST-SEQ, Clara comments: “I have a rather classical biology training. I am thus used to pipettes and plates. Switching to microfluidics meant learning about biophysics, dealing with fluid diffusion, shear stresses, back pressure, or pumping systems. It was all really interesting, but the reality was often very practical, like growing a functional, and reproducible tumour culture on a chip, without any leaks!”
PERSIST-SEQ’s contribution to cancer research
Clara FauveauThis consortium aims to study tumour cell adaptation to the selective pressure induced by the treatment. A better understanding of the resistance and the ability to predict, circumvent or even take advantage of its arrival would be key for the patient management, as well as for drug developers.
The objective for Transgene is to study resistance to Standard-of-care but also to our immuno-virotherapy technology. Furthermore, the discovery of actionable pathways could lead to the development of new therapeutical approaches, able to circumvent the resistance induced by the SOC.” – Clara explains. “This consortium is a great opportunity to advance the research in treatment resistance by developing a standardized single cell workflow and analysis of numerous types of samples. The collaboration with private and public partners offers us a chance to learn from each other and give birth to innovative ideas. It is an exciting opportunity!”