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

Projektinformationen

HyperTargIPS-NK

ID Finanzhilfevereinbarung: 101099054

DOI

10.3030/101099054

Projekt abgeschlossen

EK-Unterschriftsdatum 19 Januar 2023

Startdatum 1 April 2023

Enddatum 31 März 2026

Finanziert unter

• The European Innovation Council (EIC)

Gesamtkosten

€ 3 798 713,75

EU-Beitrag

€ 3 798 713,75

Koordiniert durch

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)

Berichtszeitraum: 2023-04-01 bis 2024-03-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

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.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

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.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

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