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 first Norwegian CAR

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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

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.

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: 

 

Oslo, Norway, 26.04.2017. Photographs from Oslo Cancer Cluster (OCC), an oncology research and industry cluster dedicated to improving the lives of cancer patients by accelerating the development of new cancer diagnostics and medicines. Photographs by Christopher Olssøn

Natural killer cells dressed to kill cancer cells

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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'.

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.
  • Read more about research from this research group in this article from January.
  • Read more about Natural Killer cells in this Wikipedia article.

 

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One of the tenants in the Oslo Cancer Cluster Incubator.

The Incubator Labs are expanding

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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

 

Office plan of the OCC Incubator

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

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.

 

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Why a Nordic mentor network is a good idea 

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The Nordic Mentor Network of Entrepreneurship (NOME) is the first pan-Nordic mentor network for lifescience start-ups. Why is it a good idea for start-ups working in cancer?

 

Bjørn Klem has an answer. He is the General Manager of Oslo Cancer Cluster Incubator and point of contact for start-ups within the cancer field in Norway.

“Start-ups working in cancer need to access commercialisation expertise and investor networks. When looking for this, it is an advantage to seek in other Nordic countries where investors are experienced with cancer and biotech in general. Participating in NOME will also take you into their global network.” Bjørn Klem

 

Connecting with a mentor team

NOME is based on the mentoring principals of MIT’s Venture Mentoring Service. The fundamental principle is to connect first time entrepreneurs with a team of three to four experienced and skilled mentors to help them reach their goals and technology milestones. 

From Boston to the Nordics, this is the first mentor network within life sciences that spans across all the Nordic countries. 

In Norway, Oslo Cancer Cluster Incubator og the health incubator Aleap are coordinating start-ups with suitable mentors.

“Team mentorship, where mentees have a group of mentors, rather than single one-on-one mentorship, encourages more diverse thinking, cross-disciplinary approaches to ideas and problem solving, and it allows the access to professionals from different fields.”  NOME Magazine Issue 1 2018

 

Norwegian mentors and start-ups

One of the Norwegian NOME mentors is Kari Grønås. She has extensive experience in drug development and commercialisation within the pharmaceutical industry.

You can listen to her (in Norwegian) in this video that was made by Oslo Cancer Cluster Incubator as the programme was just starting in Norway in 2017.

One of the Oslo Cancer Cluster members that have taken advantage of the NOME opportunity and mentors, is Nacamed.

Nacamed is a Norwegian spin-off company of Dynatec AS. The Nacamed technology is based on 10 years of research on silicon done by Dynatec engineering. According to the company webpage, this enables a production that can tailor particles with the desired physical attributes. With this, Nacamed aims to create a new generation of treatment methods.

 

Best in class-network

This video, made by Accelerate, explains the concept of NOME and the value it adds to the Nordic startup ecosystem.

The mentors are volunteering to share their knowledge and experience with new entrepreneurs within fields such as digital health, immuno-oncology and AI in healthcare. NOME mentors can give unbiased advice, provide strategic guidance, open their network and possible collaboration partners, as well as assisting in reaching key milestones.

The start-ups have to be best in class too. The local NOME partners evaluate the companies on the novelty of the science or technology, their high commercial potential as well as the strength and commitment of the founding team. Furthermore, strong IP or alternative protection strategies, market differentiation, and the impact NOME potentially can have on the company’s development are also taken into consideration.

Participation is free of charge and funded by the Novo Nordisk Foundation.

Infographic from NOME magazine.

Source: The NOME Magazine, Issue 01, 2018

 

20 start-ups since 2016

Since 2016, 20 start-ups have joined NOME and of these two have graduated from the program. Graduation usually means the start-up has successfully raised funds for the coming few years and has engaged a formal board and therefore has less need for the NOME mentors.

The mentors either move on to work with other emerging companies or have been so excited about the potential of the company they have been working with that they have taken a seat on the board.

By the end of 2018, NOME had 50 mentors and 18 enrolled start-ups.

 

Mentors in immuno-oncology

In the NOME Magazine first edition, released in October, Carl Borrebaeck, professor at Department of Immuno-technology at Lund University in Sweden, is interviewed about his field of expertise, immuno-oncology and creating companies from his research. Borrebaeck is a founding mentor in NOME and has been part of the network for the past two years. 

“People tend to think, that innovation just happens and that it will reach patients without any commercial drive. That is simply untrue.” Prof. Carl Borrebaeck 

He continues to explain what is really needed to make health innovations happen:

“A combination of companies and academia is needed. Big pharma is always looking for the newest discoveries and ways they can collaborate in order to stay at the forefront of innovative research. The Nordics are highly innovative and they have a strong reputation globally. However, there are too few big pharma companies commercializing the science at the very early stages. This is often a major challenge for emerging companies who then have to seek funding not only in the Nordics but across Europe and the US to cover this funding gap.”

 

Mentors in artificial intelligence

NOME has mentors in several interesting life science fields. Lars Staal Wegner, the CEO of Evaxion Biotech, is another mentor. He started a company dedicated to using artificial intelligence, supercomputers, and big data to fight cancer and infectious diseases. In the NOME Magazine Wegner says: 

“It is no longer the pharma industry or the companies producing the off-the-shelf drugs. It is the ones who own the data and know how to convert it to effect, the cloud-based giants that are half life science half tech. This is maybe 30-40 years into the future, but it is important already now to know that the tech evolution is not linear. It is exponential. We have reached an inflection point in tech. The industry doesn’t have five or ten years to toe the line. It is exploding.” 

Artificial intelligence and machine learning are expected to have an unprecedented impact on how drugs are developed, their cost, and time to market, according to Wegner. 

 

Nordic partnership

NOME is operated by Accelerace and funded by the Novo Nordisk Foundation. The initiative is represented in the Nordic region through partnerships in Sweden, Norway and Finland. In Norway, Oslo Cancer Cluster Incubator og the health incubator Aleap are coordinating start-ups with suitable mentors.

In the US, the California Life Sciences Institute (CLSI) is a new partner for NOME. In fact it is too new to have entered the overview below. CLSI is a non-profit organization which supports entrepreneurship, STEM education and workforce development for the life science industry in California. It is located in the San Francisco Bay Area.

Infographic from NOME magazine.

Source: The NOME Magazine, Issue 01, 2018