Hyper-targeting CAR NK cells from induced pluripotent stem cells for novel off-the-shelf anti-tumor therapies

Informations projet

HyperTargIPS-NK

N° de convention de subvention: 101099054

DOI

10.3030/101099054

Projet clôturé

Date de signature de la CE 19 Janvier 2023

Date de début 1 Avril 2023

Date de fin 31 Mars 2026

Financé au titre de

• The European Innovation Council (EIC)

Coût total

€ 3 798 713,75

Contribution de l’UE

€ 3 798 713,75

Coordonné par

Magle Biopharma AB
Sweden

Periodic Reporting for period 1 - HyperTargIPS-NK (Hyper-targeting CAR NK cells from induced pluripotent stem cells for novel off-the-shelf anti-tumor therapies)

Période du rapport: 2023-04-01 au 2024-03-31

Résumé du contexte et des objectifs généraux du projet

The HyperTargIPS-NK project aims to combine new technologies from three research laboratories and a stem cell company to develop a revolutionary therapy for patients with devastating recurrent malignancies.
The therapy we are developing is based on allogeneic induced pluripotent stem cells (iPSC) that are differentiated into natural killer (NK) cells, equipped with chimeric antigen receptors (CARs) and further modified to a hyperactive state. In this way, we can produce highly potent tumor-destroying cells.
CAR NK-based cancer treatment is a promising new therapeutic pathway. However, the full potential of CAR NK therapies will only be realized when an off-the-shelf product is available to patients in need. iPSC with their unlimited expansion potential are the ideal cell source for NK-based products. In this project, we use a novel iPSC differentiation system, which easily can be scaled to generate billions of functional designer NK cells.
We will target the NK cells against three life-threatening cancers, for which new treatment options are urgent because they are considered among the most lethal cancers; i.e. pancreatic cancer, glioblastoma and acute myeloid leukemia (AML). This will be done by utilizing novel state-of-the-art CAR, non-CAR and TRUCK-based regulators of NK activation to induce the hyperactivated NK cell state and prolong NK survival, providing enhanced NK response to tumors via tumor microenvironment remodeling.
Our iPSC culture system, NK activation system, gene vector and gene editing system have been designed for GMP compliance and validation of the production steps will be part of the project. The goal is to have a Hyper-Targ-IPS-NK-cell therapy lead ready to prepare for clinical trials.

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

An iPSC differentiation protocol for the production of lymphoid-biased hematopoietic stem and progenitor cells that has been designed to facilitate conversion to a full GMP compatible protocol for the production of NK cells has been developed and tested and validated. We are in the early stages of testing NK cells production under the similar GMP compliant design and will shortly begin functional assessment of the NK cells in in vitro and in vivo assays as per then next stages of differentiation. We are continuously developing the protocol for further increases in efficiency via numerous additional modulations including the metabolic regulators.
We aim to establish and validate designer iPS-NK cells with genetic modification tools to improve functionality and target selected tumors with high medical need. As a first step for this, we validated the most promising vector system for NK cell populations. Here, we generated and validated self-inactivating lentiviral and alpharetroviral vectors that could efficiently deliver genes into NK cells. To target CD123-positive AML cells, we generated genetically modified NK cells with RD114/TR pseudotyped alpharetroviral particles and could express a functional CAR molecule on NK cells. To advance the concept for better functionality in solid tumors, we generated so called TRUCK strategies that harbor (in addition to the CAR) an inducible cytokine cassette to reshape the tumor microenvironment to better destruct solid tumors. In particular, we performed this for a CAR targeting GD2-positive glioblastoma and CEA-positive pancreatic cancer. Finally, we set the basis to engineer designer HyperTargIPS-NK and designed a scheme how to best engineer our iPSC-NK cells using a vector-based or CRISPR-Cas9-based strategy and considered different time points in the differentiation process to genetically engineer these cells.

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)

to reshape the tumor microenvironment to lead to a better anti-tumor attack.