Oslo Cancer Cluster Incubator collaborates with partners in Sweden, Norway and Finland to help life science professionals learn from their neighbours.
“Life science is a global business and cross-border collaboration is important, in particular for small countries in the Nordics” says Bjørn Klem, manager at Oslo Cancer Cluster Incubator.
Bjørn Klem, manager of Oslo Cancer Cluster Incubator.
Together with partners from three different professional sectors in three countries, Oslo Cancer Cluster Incubator recently received €75,000 in project funding over two years from the Nordplus Programme.
Digital competences
Nordplus is the Nordic Council of Ministers’ most important programme in the area of lifelong learning. On its webpage, Nordplus writes that more than 10,000 people in the Nordic and Baltic region benefit from the programme every year.
In 2019 and 2020, Nordplus welcomes applications on digital competences and computational thinking.
Innovation and competition
Bjørn Klem hopes that the project will benefit both Nordic innovation and competition.
“The outcome of this project should be to share educational resources to increase competence in the Nordic innovation environments. This will make innovation in life science more competitive in the global market.” Bjørn Klem
The Association of the Pharmaceutical Industry in Norway (LMI), one of the five partners in the project, also stresses the importance of Nordic collaboration for the life science industry. Marie Svendsen Aase, project coordinator LMI, puts it this way:
“We see Nordic cooperation as an essential value to the medical development that is now taking place with both personalised medicine and building a life science industry across the Nordic countries.”
Learning across the region
The project will make continuous learning for life science professionals, specifically in pharmaceuticals and medical devices, easier by facilitating courses and material digitally. At the same time, the project aims to adapt national courses to a Nordic and Baltic audience.
A course plan will be made in 2019.
The five partners in the project are:
Swedish Academy of Pharmaceutical Sciences
Swedish Pharmaceutical Industry Association
Pharmaceutical Information Centre in Finland
The Association of the Pharmaceutical Industry in Norway (LMI)
Made in Oslo by a team of researchers from Oslo University Hospital, the first ever Norwegian CAR T cell is now a fact. A potential treatment based on this result depends on a clinical study.
A new Norwegian study shows a genetically modified cell-line with great potential as treatment for patients that are not responding to established CAR T cell therapies. This form of immuno-therapy for cancer patients has recently been approved in many countries, including Norway.
“We hope that the Norwegian authorities will be interested in transforming this research into benefits for Norwegian patients.” Hakan Köksal
What is a CAR?
Before we go into the research, let us clarify an essential question. What is a CAR? Chimeric antigen receptor (CAR) T cells are T cells that have been genetically engineered to produce an artificialreceptorwhich binds a protein on cancer cells.
How does this work? T cells naturally recognize threats to the body using their T cell receptors, but cancer cells can lock onto those receptors and deactivate them. The new CAR T cell therapies are in fact genetic manipulations used to lure a T cell to make it kill cancer cells. This is what a CAR is doing, indeed CARs replace the natural T-cell receptors in any T cells and give them the power to recognize the defined target – the cancer cell.
CAR-T cell therapy is used as cancer therapy for patients with B-cell malignancies that do not respond to other treatments.
A severe consequence of using CAR T cell therapy is that it effectively wipes out all the B cells in the patient’s body — not only the cancerous leukemia cells or the lymphoma, but the healthy B cells as well. Since B-cells are an important part of the immune system, it goes without saying that the treatment comes with risks.
Micrograph of actin cytoskeleton of T-cells. The cell is about 10µm in diameter. Photo: Pierre Dillard
T cells: T lymphocytes (T cells) have the capacity to kill cancer cells. These T cells are a subtype of white blood cells and play a central role in cell-mediated immunity.
Made in Norway
Now let us move on to the new research. This particular construct was designed from an antibody that was isolated in the 1980’s at the Radium Hospital in Oslo.
The CAR construct was designed, manufactured and validated in two laboratories in the Radium Hospital campus. One is the laboratory of Immunomonitoring and Translational Research of the Department of Cellular Therapy, OUH, located at the Oslo Cancer Cluster Incubator. This laboratory is led by Else Marit Inderberg and Sébastien Wälchli. The other is the laboratory of the Lymphoma biology group of the Department of Cancer Immunology, Institute for Cancer Research, OUH. This laboratory is led by June Helen Myklebust and Erlend B. Smeland.
“Even the mouse was Norwegian.” Hakan Köksal
The pre-clinical work that made the Norwegian CAR was completed in March 2019.
In the research paper “Preclinical development of CD37CAR T-cell therapy for treatment of B-cell lymphoma”, published in the journal Blood Advances, the research team tests an artificially produced construct calledCD37CAR and finds that it is especially promising for patients suffering from multiple types of B-cell lymphoma. This may be treated successfully with novel cell-based therapy.
It now needs to be approved by the authorities and gain financial support to be further tested in a clinical study in order to benefit Norwegian patients.
The first CAR-therapy
CAR-based therapy gained full attention when the common B-cell marker CD19 was targeted and made the basis for the CAR T cell therapy known as Kymriah (tisagenlecleucel) from Novartis.
It quickly became known as the first gene therapy allowed in the US when it was approved by the US Food and Drug Administration (FDA) just last year, in 2018, to treat certain children and young adults with B-cell acute lymphoblastic leukemia. Shortly after, the European Commission also approved this CAR T cell therapy for young European patients. The Norwegian Medicines Agency soon followed and approved the treatment in Norway.
“CD19CAR was the first CAR construct ever developed, but nowadays more and more limitations to this treatment have emerged. The development of new CAR strategies targeting different antigens has become a growing need.” Dr. Pierre Dillard
Not effective for all
Although the CD19CAR T cell therapy has shown impressive clinical responses in B-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma, not all patients respond to this CAR T treatment.
In fact, patients can become resistant to CD19CAR. Such relapse has been observed in roughly 30% of the studies of this treatment. Thus, alternative B-cell targets need to be discovered and evaluated. CD37 is one of them.
“You could target any antigen to get a new CAR, but it is always a matter of safety and specificity.” Hakan Köksal said.
Dr. Pierre Dillard and Hakan Köksal are part of the team behind the new study on CD37CAR T-cell therapy for treatment of B-cell lymphoma.
The Norwegian plan B
The novel Norwegian CAR T is the perfect option B to the CD19CAR.
“The more ammunition we have against the tumours, the more likely we are to get better response rates in the patients.” Hakan Köksal
The CD37CAR T cells tested in mouse models in this Norwegian study, show great potential as treatment for patients that are not responding to the established CD19CAR-treatment.
“More and more labs are studying the possibility of using CAR therapy as combination, i.e. CAR treatments targeting different antigens. Such a strategy will significantly lower the probability of patients relapsing.” Dr. Pierre Dillard said.
The CD37CAR still needs to be tested clinically. The scientists at OUS underline the importance of keeping the developed CD37CAR in Norway and having it tested in a clinical trial.
“It is a point to keep it here and potentially save patients here. We would like to see the first CD37CAR clinical study here in Norway.” Hakan Köksal
More from the Translational Research Lab of the Department of Cellular Therapy, OUH:
New research: A new study may potentially enable scientists to provide cancer immunotherapy that is cheaper, faster and more manageable.
New work by researchers with laboratories at Oslo Cancer Cluster Incubator may help to dramatically improve a T cell-based immunotherapy approach so that it can benefit many more patients.
T cell assassins
T cells are the professional killers of the immune system – they have a unique capability to specifically recognize ‘foreign’ material, such as infected cells or cancer cells. This highly specific recognition is achieved through receptors on the surface of T cells, named T cell receptors (TCRs). Once its receptor recognizes foreign material, a T cell becomes activated and triggers the killing of the infected or cancerous cell.
T cell receptors (TCRs): receptors on the surface of T cells, that recognize foreign material and activate the T cell. This triggers the killing of the infected or cancerous cell by the T cell.
Adoptive cell therapy
Unfortunately, many cancers have adapted fiendish ways to avoid recognition and killing by T cells. To combat this issue, an immunotherapy approach known as adoptive cell therapy (ACT) has been developed in recent years. One such ACT approach is based on the injection of modified (or ‘re-directed’) T cells into patients. The approach is further explained in the illustration below.
Illustration from the research paper ‘NK cells specifically TCR-dressed to kill cancer cells’.
The left side of the illustration shows how redirected T-cell therapy involves:
1) Harvesting T cells from a cancer patient
2) Genetic manipulation of T cells to make them express an ideal receptor for recognizing the patient’s cancer cells
3) Growing T cells in culture to produce high cell numbers
4) Treating patients with large quantities of redirected T cells, which will now recognize and kill cancer cells more effectively
An alternative approach
Adoptive T cell therapy has delivered very encouraging results for some cancer patients, but its application on a larger scale has been limited by the time consuming and costly nature of this approach. In addition, the quality of T cells isolated from patients who have already been through multiple rounds of therapy can sometimes be poor.
Researchers have long searched for a more automated form of adoptive cell therapy that would facilitate faster and more cost-effective T cell-based cancer immunotherapy.
One approach that has seen some success involves the use of different immune cells called Natural Killer cells – NK cells in brief.
Despite their great potential, NK cells have unfortunately not yet been proven to provide a successful alternative to standard T cell-based cancer immunotherapy. One major reason for this may be that, because NK cells do not possess T cell receptors, they are not very effective at specifically detecting and killing cancer cells.
NK cell lines: Natural Killer cells (NK cells) have the ability to recognise and kill infected or cancerous cells. Scientists have been able to manipulate human NK cells so that they grow without restriction in the lab. This is called a cell line. It enables a continuous and unlimited source of NK cells that could be used to treat cancer patients.
Cells dressed to kill
The group led by Dr. Sébastien Wälchli and Dr. Else Marit Inderberg at the Department of Cellular Therapy aimed to address this issue and improve NK cell-based therapies.
They reasoned that by editing NK cells to display anti-cancer TCRs on their cell surface they could combine the practical benefits of NK cells with the potent cancer killing capabilities of T cells. This is shown in the right hand side of the illustration above.
The researchers found that by simply switching on the production of a protein complex called CD3, which associates with the TCR and is required for T cell activation, they could indeed induce NK cells to display active TCRs. These ‘TCR-NK cells’ acted just like normal T cells, including their ability to form functional connections to cancer cells and subsequently mount an appropriate T cell-like response to kill cancer cells.
This was a surprising and important finding, as it was not previously known that NK cells could accommodate TCR signaling.
This video shows TCR-NK cell-mediated killing of cancer cells in culture. The tumour cells are marked in green. Tumour cells that start dying become blue. The overlapping colours show dead tumour cells.
The researchers went on to show that TCR-NK cells not only targeted isolated cancer cells, but also whole tumours.
The method was proven to be effective in preclinical studies of human colorectal cancer cells in the lab and in an animal model. This demonstrates its potential as an effective new form of cancer immunotherapy.
Paving the way
Lead researcher Dr. Nadia Mensali said:
“These findings pave the way to the development of a less expensive, ready-to-use universal TCR-based cell therapy. By producing an expansive ‘biobank’ of TCR-NK cells that detect common mutations found in human cancers, doctors could select suitable TCR-NK cells for each patient and apply them rapidly to treatment regimens”.
Whilst further studies are needed to confirm the suitability of TCR-NK cells for widespread treatment of cancer patients, the researchers hope that these findings will be the first step on the road towards off-the-shelf immunotherapy drugs.
Read the whole research paper at Science Direct. The paper is called “NK cells specifically TCR-dressed to kill cancer cells”.
The researchers behind the publication consists of Nadia Mensali, Pierre Dillard, Michael Hebeisen, Susanne Lorenz, Theodossis Theodossiou, Marit Renée Myhre, Anne Fåne, Gustav Gaudernack, Gunnar Kvalheim, June Helen Myklebust, Else Marit Inderberg, Sébastien Wälchli.
The laboratories at Oslo Cancer Cluster Incubator are expanding to meet increasing demand from members.
Oslo Cancer Cluster Incubator has recently converted three offices into new laboratories to accommodate the rising demand from their members.
From the opening in 2015, the laboratories in the Incubator have been a great success. Several of the start-ups have expanded their work force and require more offices and lab space.
The new laboratory is jointly occupied by Zelluna Immunotherapy and the Department of Cellular Therapy (Oslo University Hospital). The Institute for Energy Technology and Arctic Pharma have also expanded their laboratories with an extra room each.
The laboratories are now running at full capacity, but there is some space available in the shared labs. Some of the members of the Incubator offer their services to outside companies who are in need of getting lab work done.
“Our ambition is to grow the Incubator Labs further into the new Innovation Park next door.” Bjørn Klem, General Manager
The Incubator occupies over 550 square meters. Offices have been converted into labs to meet the growing interest from the members.
A unique model
The Incubator Labs follow a unique model, which offers both private laboratories and fully equipped shared laboratories. The private laboratories are leased with furniture, water supply, electricity and ventilation. The companies bring their own equipment depending on their needs.
Shared laboratories, including a bacteria lab, a cell lab and wet lab, are leased including basic equipment with the opportunity for companies to bring their own if shared by all tenants. All laboratories share the common support facilities including a cold room for storage, a laundry room, and storage room including cell tanks and nitrogen gas.
“This model of a shared laboratory is very unusual,” said Janne Nestvold, Laboratory Manager at the Oslo Cancer Cluster Incubator.
The advantage of working in a shared lab is that companies can avoid the costs and limitations associated with setting up and managing a laboratory. A broad range of general equipment, including more advanced, analytical instruments, are provided by the Incubator.
”It would be too expensive for a small company to buy all this equipment themselves.” Janne Nestvold, Laboratory Manager
The Department of Cellular Therapy (Oslo University Hospital) are one of the members using the shared lab. Photograph by Christopher Olssøn
Open atmosphere
The laboratories have an open and light atmosphere. Large windows provide ample lighting and all spaces are kept clean and tidy. The halls are neatly lined with closets and plastic containers for extra storage.
The general mood is calm and friendly. Nestvold communicates daily with the users about changes, updates and improvements, which sets an informal tone. Thanks to monthly lab meetings, the users are also involved in the decision-making process. The companies often work side-by-side or in teams, fostering collaboration rather than competition. There is therefore a strong workplace culture based upon flexibility and mutual respect.
The companies often work side-by-side or in teams, fostering collaboration rather than competition.
Nestvold also ensures that the high demands on the infrastructure of the laboratory are met. She has put agreements in place to facilitate the members’ needs, such as the washing of lab coats, pipette service and shipping packages on dry ice. With all these services included, the Incubator Labs are attractive for researchers and companies to carry out their cancer research.
Over the years, Nordic Nanovector, OncoInvent, Targovax, Intersint, OncoImmunity have conducted research in the laboratories. Now, Arctic Pharma, the Department of Cellular Therapy (Oslo University Hospital), GE Healthcare, the Institute for Energy Technology, Lytix BioPharma, NorGenotech, Ultimovacs and Zelluna Immunotherapy are using the Incubator Labs to develop their cancer treatments.
For more information about the Incubator Lab, get in touch with Janne Nestvold.
