MATURE-NK — MAnufacturing of TUmour-REactive Natural Killer cells

Results in brief

MAnufacturing of TUmour-REactive Natural Killer cells

Standard therapies of leukemia include remission chemotherapy and hematopoietic stem cell transplantation. More recently, immunotherapies with checkpoint inhibitors and chimeric antigen receptor (CAR)-modified cytotoxic T lymphocytes have evoked striking successes. Despite these important improvements, significant fractions of leukemia patients are either unresponsive or will relapse from these treatments. Therapy options for most solid cancer types are even less promising. Natural killer (NK) cell-based therapies are emerging as novel attractive therapeutic approaches to improve the efficacy of cancer treatment and to overcome resistance to current therapies of leukemia and solid cancers. NK cells are a type of lymphocytes and form an important part of the innate immune system with the ability to kill harmful cells. Whereas T lymphocytes can have toxic side effects, NK cell usually are well tolerated. The main objective of the MATURE-NK project was to further develop and improve technology and reagents for NK cell-based immunotherapies. This included improving selection of tumor-reactive NK cell subtypes and developing technology for enhancing their anti-tumor cytotoxicity as well as manufacturing of therapeutic NK cells for clinical NK cell infusions. The project was designed to combine expert laboratories in basic, clinical and company-related research and development in the NK cell field. Thirteen early stage researchers performed the research work as part of their PhD theses and were trained to become experts for the growing area of cellular immunotherapies. In conclusion, the project has achieved significant progress in NK subtype selection, modification and manufacturing of therapeutic NK cells that will impact on the further development of NK cell-mediated cancer therapies. This includes improvements in selection of NK cell donors, tumor-reactive NK subsets and amplification of NK reactivity by CAR-modification, checkpoint inhibitors and NK cell engagers. Exemplary therapies were successfully tested in animal cancer models, GMP-compliant manufacturing of CAR-modified NK cells was improved and an exemplary protocol for a clinical leukemia trial drafted. The results have been described in numerous scientific manuscripts and in a priority application filed in 2022 by an industrial partner.

Data: CORDIS, © European Union

Project objective

This project will provide future-oriented translational research training designed to bridge the gap between basic research and applied development of new cell-based therapeutic products by the biotech industry and their clinical use for incurable diseases. This will be done on the example of activated/genetically manipulated natural killer (NK) cells, which are classified as Advanced Therapy Medicinal Products (""ATMPs""), and their use in treatment of cancer refractory to classical therapies. For this we combine experts in NK cell biology supported by bioinformatics, clinical groups pioneering NK cell therapies and biotech companies with NK cell-based portfolios. A student exchange will ensure training in basic, clinical and private sectors. Network-wide training modules organized in summer/winter schools include immunotechnology, business management and intellectual property rights. This will train competences important to translate research findings to personalized medicine.In research we build on information from clinical trials of NK cell-based therapies. We will improve anti-tumor reactivity of NK cells including selection of NK subsets and modulation of NK receptor/ligand interactions. First, this will comprise i) improved donor/recipient combination and NK subsets and ii) modification of NK cells by chimeric antigen receptors (""CAR"") and bispecifc antibody reagents to cross-link NK cells to tumor targets. Second, it will fortify NK cell reactivity by i) blocking ligand interactions of inhibitory receptors (""checkpoint inhibitors"") and ii) defining unknown ligands of activating NK receptors on tumor cells. Third, procedures and NK products in their best combination will be developed by i) evaluation in humanized mouse models, ii) building a GMP-compliant manufacturing process and iii) design of a clinical trial protocol. The project should provide for manufacturing of NK cell-based therapeutic products and their evaluation in clinical trials. ""

Original text from CORDIS.

Participants

MEDIZINISCHE HOCHSCHULE HANNOVER · HannoverCoordinatorGermany
FRAUNHOFER GESELLSCHAFT ZUR FORDERUNG DER ANGEWANDTEN FORSCHUNG EV · MunchenGermany
GLYCOSTEM-THERAPEUTICS B.V. · OssNetherlands
INNATE PHARMA · MarseilleFrance
INSTITUT PASTEUR · ParisFrance
IRCCS AZIENDA OSPEDALIERA METROPOLITANA · GenovaItaly
MEDIZINISCHE UNIVERSITAET WIEN · WienAustria
MILTENYI BIOTEC BV & CO KG · Bergisch GladbachGermany
MILTENYI BIOTEC GMBH · Bergish GladbachGermany
OSLO UNIVERSITETSSYKEHUS HF · OsloNorway
RUPRECHT-KARLS-UNIVERSITAET HEIDELBERG · HeidelbergGermany
THE HEBREW UNIVERSITY OF JERUSALEM · JerusalemIsrael
UNIVERSIDAD POMPEU FABRA · BarcelonaSpain
UNIVERSITAT BASEL · BaselSwitzerland

MATURE-NK · MAnufacturing of TUmour-REactive Natural Killer cells

Results in brief

MAnufacturing of TUmour-REactive Natural Killer cells

Project objective

Participants

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