NaturiMunn

Natural killer cells for fighting cancer

Natural killer (NK) cells are an important part of the innate immune system, helping to defend the body against tumours and infections. The NATURIMMUN project combines both fundamental and applied research into NK cells, work which could lead to effective new anticancer therapies, as Professor Erhard Hofer, the initiator of the project, explains

A type of lymphocyte, natural killer (NK) cells play a central role in the body’s defence against disease, helping to identify and destroy alien and infected cells. While NK cells are not homogenous, they share common features. “NK cells can do two main things. One is a kind of immune regulatory function, where they use certain cytokines to help activate other immune cells,” says Professor Hofer. “The second major function, which is especially important in terms of therapy, is that they can kill cells that they recognise as virally infected or abnormal, such as tumour cells.”

These attributes make them powerful effectors to eradicate cancer, a prime motivation behind the work of the NATURIMMUN project, an EU-backed initiative which combines basic and applied research into NK cells. “We have assembled a combination of labs with different competencies from several countries that have contributed to NK cell research. This includes basic research, such as delineating the function of certain receptors on the surface of NK cells, and more clinicallyoriented research,” says Professor Hofer. “Indeed, we and others could demonstrate safety and feasibility when infusing donor NK cells to leukemia patients after stem cell transplantation. However, limitations due to low cell numbers and tumor immune escape mechanisms still exist,” adds Professor Ulrike Köhl, the current coordinator of the project.

The combination of basic and applied research is designed to help bridge the gap between academia and the commercial sector, and in turn to help translate research advances into improved treatment in the clinic. The foundation of the NATURIMMUN

NK cells are effective against cancer and NK cells prepared for infusions have

been classified as ‘Advanced Therapy Medicinal products’

work is a deep understanding of both the immune system and the function of NK cells. “It is intriguing that viruses and tumor cells have developed mechanisms to subvert the immune system in order to avoid the NK cell response and we can learn counter-strategies from these,” says Professor Hofer.

Activating NK cells

Standard leukemia therapy is to use chemotherapy or radiation treatment, which kills the tumour cells and the normal immune cells – after which patients receive a stem cell transplant from a donor. “These cells re-constitute a new immune system for the patient, that can then target leukemia cells,” explains Professor Hofer. “It has been shown that NK cells are an important component of the new immune system formed by the donor transplant, and are active in rejecting the leukemia cells.”

Further, a number of clinical trials have been performed where donor NK cells,

expanded and activated ex vivo, have been directly infused into patients, with promising anti-leukemia effects. The sideeffects have been found to be far less severe than with conventional treatment methods. Using an infusion of NK cells after a transplant also reduces the risk of graft versus host disease, a complication where the transplant itself reacts against the normal cells, which in severe cases can even lead to the death of the patient. “With NK cells adverse effects are very much less

Patients receiving infusion therapies..

pronounced, and therapies undertaken by infusion of activated NK cells have so far been shown to be safe,” explains Professor Köhl. “However, we still need to learn more about how we can activate NK cells and use them effectively against tumour cells.”

While NK cells can be activated through exposure to cytokines, a type of signalling molecule, partners in the NATURIMMUN project are developing novel antibody reagents. “One arm of these reagents would bind to a specific surface structure, a socalled antigen, on the tumour cell, and the other arm to a specific surface receptor on the NK cell. By cross-linking the NK cells directly to the tumour cell, that enhances the reactivity of the NK cells to the tumour target,” Professor Hofer explains.

Chimeric Antigen Receptors

A major research priority now is to investigate how NK cells can be activated against specific tumour cells through the use of additional reagents in order to overcome a tumour’s immune escape capacity. One area of interest to Professor Köhl is the use of Chimeric Antigen Receptors (CARs), a type of engineered receptor that has already clinically been used on T-lymphocytes, another class of lymphocyte distinct from NK cells. “We are very interested in using CARs with NK cells, because NK cells have specific advantages in comparison to T lymphocytes,” she outlines. “T lymphocytes from donors are really reactive and can destroy healthy tissue. To avoid this, patients’ own T lymphocytes are used for CAR therapy. Unfortunately, due to the previous heavy treatment of the patients with chemotherapy, in some cases these T lymphocytes are of low quality. Therefore we are focused on using healthy NK cells from donors, a procedure which has been shown to be safe in our clinical studies, and in combination with CARs we might really get promising new treatments.”

Large therapeutic cell numbers

Researchers are also looking to bring these technologies to the commercial sector, especially to achieve the large cell numbers required. A small biotechnology company called Glycostem has been established in the Netherlands, with proprietary technology to generate large quantities of NK cells from blood stem cell samples. “These NK cells have been tested in a phase 1 trial, in elderly acute myeloid leukemia patients. The results so far have shown the safety of the procedure,” continues Professor Hofer. The number of patients in this particular trial was too small and the time period since then too short to get reliable clinical data on survival rates. Another partner in the project is Miltenyi, a major supplier of equipment and reagents for the generation of cellular therapeutic products, which has developed technology to generate large numbers of NK cells from peripheral blood. “In future, we will look together towards clinical research and company-supported clinical trials,” Professor Köhl adds.

There are plans to establish a follow-up project to NATURIMMUN, in which the therapeutic procedure will be more fully developed, paving the way for an eventual clinical trial. One major priority will be to further develop the CAR technology in NK cells, which Professor Hofer and Professor Köhl believe is a highly promising procedure. “We want to collaborate with companies that already have clinical trials ongoing with certain aspects of this procedure,” Professor Köhl says. This combination of fundamental and applied research is central to translating research into improved treatment. “In NATURIMMUN we had a combination of basic and translational research labs, and together we have developed a couple of interesting findings and technologies that will support the follow-up project,” says Professor Hofer.

Full Project Title

NATURAL KILLER CELL-BASED ANTI-CANCER IMMUNOTHERAPIES: (NATURIMMUN)

Project Objectives

The main objective of this project was to study within an European research network novel molecular mechanisms of innate immune responses mediated by natural killer cells towards hematopoietic cancers and herpes viruses. Based on obtained insights NK cell-based technologies and products for the therapy of cancer are now being developed.

Additional Project Partners

Prof. James P. Di Santo, Institut Pasteur, Paris, FR; Prof. Ofer Mandelboim, Hebrew University of Jerusalem, IL; Prof. Miguel López Botet, University Pompeu Fabra, Barcelona, ES; Prof. John Trowsdale, University of Cambridge, UK; Prof. Arndt von Haeseler, Medical University of Vienna, AT; Prof. Amit Nathwani, UCL London, UK; Volker Huppert, Miltenyi Biotec GmbH, Bergisch Gladbach, DE; Dr. Jan Spanholtz; Glycostem Therapeutics BV, ‘s Hertogenbosch, NL; Dr. Martin Treder, Affimed Therapeutics AG, Heidelberg, DE.

Project Funding

Research training in molecular medicine and biotechnology business / Project acronym: NATURIMMUN / Call identifier: FP7-PEOPLE2012-ITN / Grant agreement for: Initial Training Networks / Implementation mode: Multi-ITN / Grant agreement no.: 317013

Contact Details

Professor Erhard Hofer Medizinische Universität Wien Schwarzspanierstrasse 17 A-1090 Wien, Austria E: erhard.hofer@meduniwien.ac.at W: www.naturimmun.eu W: https://www.meduniwien.ac.at/web/

Prof. Erhard Hofer Prof. Ulrike Köhl

Professor Erhard Hofer has a focus of research in molecular immunology and vascular biology. He has been a professor at the Medical University of Vienna (MUW) since 1997. In 2014 he retired and is since then involved in the management of the NATURIMMUN project and the planning of follow-up projects in NK cell-based cancer immunotherapies. Ulrike Köhl, is a full professor for Stem Cell Transplantation and director of the Institute of Cellular Therapeutics at Medical School Hannover since 2012. She studied both, biology and medicine, worked at MD-Anderson-Cancer-Centre (Houston/ USA) and at the University Hospital Frankfurt. Her goals are focused on both, development and manufacturing of cell-based therapies.

http://www.mh-hannover.de/zelltherapeutika.html