Immune Niches for Cancer ImmunoTherapy Enhancement

Informations projet

INCITE

N° de convention de subvention: 964955

DOI

10.3030/964955

Projet clôturé

Date de signature de la CE 21 Decembre 2020

Date de début 1 Mai 2021

Date de fin 31 Octobre 2025

Financé au titre de

• EXCELLENT SCIENCE - Future and Emerging Technologies (FET)

Coût total

€ 3 998 665,00

Contribution de l’UE

€ 3 998 665,00

Coordonné par

NORGES TEKNISK-NATURVITENSKAPELIGE UNIVERSITET NTNU
Norway

Periodic Reporting for period 2 - INCITE (Immune Niches for Cancer ImmunoTherapy Enhancement)

Période du rapport: 2022-05-01 au 2023-10-31

Résumé du contexte et des objectifs généraux du projet

Immunotherapy is the therapeutic process of harnessing the body´s own immune defenses to fight against infectious diseases and cancer. One approach against cancer is adoptive cell transfer (ACT) immunotherapy, a transformative technology that exploit cytotoxic T cells’ ability to hunt down and kill cancer cells when transferred into a patient. These cells can be isolated from the patient and used directly or be further genetically manipulated to specifically attack cancer cells. Both T cell receptor (TCR) transgenic T cells and chimeric antigen-receptor (CAR) T cells are being developed against various cancers. ACT with T cells has proven very efficient against leukemias but is still not very effective against solid tumors such as melanomas. One of the reasons is that the killer cells get exhausted before being able to finish the job.

One way to make the attacking cells stronger is to transform them into stem-like T cells before transfer back to the patient, so they can multiply and make new and fresh killer T cells during the attack. Even though there is ample proof that this works, we do not yet know how to efficiently and consistently make these stem-like T cells. But we do know that they are naturally appearing in immune niches in lymph nodes and in the tumor surroundings. INCITE is therefore approaching this need to create stem-like T cells by re-creating immune niches, in which the T cells will be educated to become strong, robust, and resilient elite killers of cancer cells.

To recreate the immune niches, we will fabricate 3D printed scaffolds inside perfused microfluidic systems and populate these systems with relevant cell types normally constituting the niche. The outcome of the niche effect on T cells will be monitored in cancer models and by high end transcriptomic bioinformatics. Project outcomes will be both a microsystem to generate robust stem-like T cells for ACT immunotherapy and a transcriptomic description of the process that can be exploited separately from the system.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

In INCITE we aim to build a transformative immune niche to educate robust and resilient stem-like T cells to fight cancer through adoptive cell transfer (ACT) immunotherapy. The niche will be 3D printed as scaffolds in microfluidic chips and populated with cells and infused with environmental factors deduced from cellular and transcriptomic information in natural immune niches from lymph nodes and from tumor microenvironment.

In the first 12 months of the project we focused on two main themes in parallel - 1) design and construction of a 3D printed perfused scaffold and 2) establishing tumor models.

In this second report period of the last 18 months there have been a lot of activities going in parallel. We continue to to evolve and refine the artificial immune niche, to achieve best possible results in the preclinical melanoma cancer models in the coming period. We have made more than 600 copies of 7 different scaffold/chip designs, now approaching a working solution. We have outlined and tested many variations of the cellular and molecular requirements for a best possible immune niche in 3 different system, two from the mouse and one for the human. We have set up assays to probe the T cell phenotypes and activities. All activities have been directed towards the goal of this project, to explore the feasibility of an approach to generated stronger and more robust T cells for cancer T cell therapy.

We have further mined the transcriptomic data from the mouse melanoma models to become better at pinpointing the cellular processes involved in immune rejection of the cancer, and also to enable better identification of the T cell subtypes displaying different anti-tumor activity and robustness.

We have also in this period focused on exploitation activities. Coming mostly from academia, we have entered into several business training programs to learn the language, processes and requirements to succeed in the business world. We are in the process of deliberating on patentable technical solutions as well as business strategies.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

We have progressed beyond the state of the art by successfully incorporating different disciplines into a common goal, in informed understanding between technological abilities and biomedical needs. The overall system performance was specified by biomedical experts within immunotherapy and tissue engineering, and the solution have been formulated by mathematical modelling, material science, 3D printing expertise and chemistry. Through this integrated collaboration, we believe our solutions surpass existing solutions. In the second period we will continue working as coordinated subdisciplines and test our solutions in real world model systems.

At the higher level we address one of the major health issues of todays, cancer, which kills affect 20million people yearly and still results in premature death in half of the patients. Without major breakthroughs, cancer will continue posing significant threats to human health in the coming decades. Our solution can become a robust solution for cellular immunotherapy of cancers. With more than 2000 T cell therapies in development in more than 200 companies, we aim for that our solution will become an integral part of these therapeutic endeavors.

At the level of impact for the participating groups, progress have also benefited greatly from the collaboration between disciplines. Mathematical modeling of flow of cells in a scaffold geometry at the microfluidic level has resulted in new tools to understand biphasic flow, important in many other fields beyond this project. The requirements of the specified scaffold material as defined by us have led to development trajectories ameliorating problems with current materials and surfaces. And our user-oriented system design will aid in easing the implementation of the approach to other initiatives in immunotherapy R&D, cell therapy R&D and ultimately to clinical practice. The bioinformatic project parts will enable an unprecedented level of understanding of the physiological processes in cancer rejection and better vision of the various cell subtypes involved in the process.

INCITE general concept

Project overview

INCITE activities