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MAnufacturing of TUmour-REactive Natural Killer cells

Periodic Reporting for period 1 - MATURE-NK (MAnufacturing of TUmour-REactive Natural Killer cells)

Reporting period: 2018-06-01 to 2020-05-31

The MATURE-NK project is designed as a research training network for 13 early stage researchers (ESRs, PhD students) to perform research encompassing basic, translational and clinical aspects of tumor-reactive natural killer (NK) cells. Improved procedures for NK cell manufacturing for clinical application are developed. In a wider context the general objectives are i) to fortify NK cell anti-tumor cytotoxicity, ii) to develop NK cell-engineering technology and an improved manufacturing process for NK cell products and iii) to prepare for follow-up clinical trials.

The project is based on evidence suggesting that NK cells play an important role in the defense against tumor cells. For example, it has been shown that NK cells from hematopoietic stem cell transplants or NK cells ex vivo amplified and infused into patients can contribute to tumor rejection for certain leukemia. It is to be anticipated that with the appropriate process for manufacturing and clinical application NK cell therapies will be important additions to the better treatment of leukemia refractory to standard therapy. It is also promising as new treatment modality for incurable forms of solid cancer.
"In the first year 13 ESRs were hired following a recruitment assessment center meeting. All students were enrolled in respective university PhD programs and were trained in the required technics by their home laboratories. Work on their specific research topics was initiated.
In the second year work consolidated to give progress as follows.
In the subproject ""Selection and modification of NK cells"" the best alloreactive NK cells and appropriate NK cell donor choice has been further investigated. The recent results have been summarized and submitted as Deliverable 1.1. This highlighted that, in regard of donor choice, certain strongly alloreactive NK cells, further so-called adaptive NK cells and of NK cells with certain activating NK receptors should be present and preferentially amplified. As alternative strategy for direct ex vivo amplification of peripheral NK cells, the best cell sources for human induced pluripotent stem cells (hiPSC) to be used for generation of tumor-reactive NK cell were explored and a number of chimeric antigen receptor (CAR) constructs were prepared to fortify NK cell reactivity. Various strategies to upregulate NK cell reactivity in the hypoxic environment of solid tumors and to boost tumor antibody-triggered NK reactivity were evaluated.
In subproject 2 ""Modulation of NK receptor/ligand interaction"" obtained data further support that anti-tumor reactivity of NK could be increased by antibodies to the inhibitory receptor NKG2A. Such an antibody is available from the project partner Innate Pharma. In addition, we have have work in progress to define reactivities/ligands of activating NK receptors.
In supbproject 3 ""Analysis of NK cell-based clinical trial data"" we have performed an analysis of data from previous and ongoing clinical trials of two of our partners which has been summarized in Deliverable 3.1. as summarized in deliverable D3.1. This highlights the potential importance of adaptive NK cells and of the improving of homing and in vivo persistence of NK cells. It supports the implementation of off-the-shelf donor strategies and combination therapies with inhibitory receptor blockade (e.g. Monalizumab).
Furthermore, in subproject 4 ""Preclinical evaluation of fortified NK cell-based therapies"" human immune system (HIS) mouse models and corresponding leukemia and head and neck squameous cell carcinoma (HNSCC) models were further developed for evaluation of experimental NK cell therapies.
In subproject 5 ""Manufacturing large-scale GMP-compliant NK products"" we have continued ongoing efforts to improve processes of NK cell manufacturing. These will be adapted to certain specific promising procedures.
Taken together, currently the projects have settled to give progress as planned along the lines described in the Technical Annex. We want to emphasize that the consortium comprising all principal investigators and ESRs joined twice during Winter School 1 and Summer School 2 for progress reports, theses committee sessions, work shop lectures and intense discussions. Also Complementary Skills and Intellectual Property Courses were performed.
Unfortunately, the Covid-19 crisis interrupted the work progress as most of the students had to stay for home office work between 4 and 12 weeks in the period from March to May 2020, depending on the individual countries and rules. Similarly, planned consortium meetings had to be cancelled and planned secondments could not be performed. This clearly has so far caused several months of delay in the project and it still is not clear when this will completely normalize. Therefore we will switch to virtual meetings in September 2020 to monitor progress and ensure that collaborations and further work will proceed as planned."
Considering that most of the students have been working in the individual labs for only about one year when the Covid-19 crisis started, only initial progress has been achieved. This is related for example, as described above, to improved donor choice, the generation of NK cells from hiPSC cells, adaptive NK cells, inhibitory receptor blockade and definition of important activating receptors. But all ESR projects are on track and corresponding progress beyond the state-of-the-art will be obtained in the second period.
Among the expected results of the project as a whole is the selection of a most promising experimental NK cell-based therapy from the available possibilities in the consortium, its evaluation in an HIS mouse tumor model and the development of a corresponding manufacturing process for the needed respective NK cell product.
Taken together, the expected impacts of the project will include in regard of the ESRs and PhD programs: improvements of their career prospects in- and outside the academia; provision of skills necessary in research institutions and in private enterprises; lasting programs of initial research training at the European level. Further, we expect impact in regard of exploitation of the results via IP protection leading to product development; dissemination of results at company, clinical and basic research&development level up to marketing authorization; communication with the general public to increase awareness of importance of science. In regard of cancer therapies we foresee improvements in regard of cellular therapies of leukemia and solid cancers with corresponding impact on quality of life and life expectancy for certain forms of so far untreatable malignancies. These impacts will develop over the course of the project, which is now still in its first stage.