Hakan Köksal has researched new designs of cells to improve cancer treatment. He defended his PhD via a digital platform from Oslo Cancer Cluster Incubator, due to corona restrictions.

Designing cells to fight cancer

How can new designs of T cells improve cell therapy for cancer patients?

Hakan Köksal defended his PhD digitally from Oslo Cancer Cluster Incubator.

Hakan Köksal defended his PhD digitally from Oslo Cancer Cluster Incubator.

This was the question Hakan Köksal attempted to answer in his PhD thesis, which he defended from the Oslo Cancer Cluster Incubator via a digital platform on Thursday 28 May 2020.

Köksal first arrived at Oslo Cancer Cluster Incubator to begin his PhD in October 2016 for the Department of Cellular Therapy, belonging to Oslo University Hospital. Three and a half years later, he is finally finished and has made a discovery that could potentially help cancer patients that are not responding to standard cell therapies.

“Essentially, what we are doing is called adoptive T cell therapy. We try to manufacture designs of chimeric antigen receptors to redirect T cells against cancer cells,” Köksal explained.

Cell therapy is an exciting, new area in cancer research and is a type of immunotherapy. This means that the patient’s immune system is changed in order to recognise and destroy the cancer cells in the body. CAR T cell therapy (CAR is short for chimeric antigen receptor) specifically involves collecting cells from the patient’s blood and changing them in the laboratory.

“We collect T cells, or lymphocytes, from the patients and engineer them so they can detect cancerous cells. Afterwards, they can be reinfused in the patient to destroy the cancer cells.” Hakan Köksal

Novel designs and new approaches

Current CAR T cell therapies have proved successful against several haematological cancers (blood cancers). However, the long-term clinical effects are quite limited and several barriers remain to cure all cancers with cell therapy. One problem Köksal looked at is when lymphoma patients treated with CD19 CAR T therapy relapse with CD19 negative lymphoma.

“We come up with alternative designs and approaches that may have an improved therapeutic effect, a lowered toxicity and improved survival in the body,” Köksal said. “The study we conducted can potentially be used as a standalone therapy or it can be complementary to reduce relapse.”

Standard CAR T therapies use antibody fragments as recognition units to detect cancer cells. In his thesis, Köksal has used a T cell receptor part, which is a different recognition domain, to increase the number of the targetable markers on cancer cells.

“Usually CAR T therapies can only detect proteins on the surface of the cell, but this new design can technically also recognise proteins inside the cell.” Hakan Köksal

Köksal stresses that we cannot know the clinical efficacy of the study before testing it in humans. The furthest they have tested is in mice, which is still a completely different organism from humans.

Read more about the research in this article: “The first Norwegian CAR”

Presenting during corona

Köksal finished his thesis in August 2019 but has not had the opportunity to defend it until now. Due to the ongoing corona situation, he could not present the trial lecture and defence in a filled auditorium but had to make do with an empty room and a laptop.

“It’s completely different. Normally, I would be standing on a stage and looking the audience in the eyes to see if I do well or bad. Now, I couldn’t see the audience, because they couldn’t share their video screens. I could only see my opponents,” Köksal explained.

In March, the corona pandemic affected the researchers in the Incubator too, because there were difficulties getting the necessary deliveries as companies worldwide had limited personnel. The laboratory had to restrict the number of people coming in and meeting rooms were temporarily converted to offices to avoid shared office space. The Incubator never closed completely and stayed open with extra sanitation procedures in place, so that the important research could go on.

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.

A collaborative effort

Köksal emphasised that the research behind his PhD thesis has been a team effort. He is thankful to his supervisors at Oslo University Hospital, Else Marit Inderberg, Sebastien Wälchli and June Helene Myklebust, for helping him and giving important guidance during his projects.

It has also meant a lot for him to be a part of the Oslo Cancer Cluster Incubator, Innovation Park and the Oslo Cancer Cluster ecosystem.

“It is good to be in such a translational building. You have one part that has an arm in the clinic and at the same time you have pre-clinical research going on side-by-side with the private companies. You have different niches and you can meet a lot of people with different backgrounds and interests. It gives you new perspectives,” Köksal said.

Köksal thinks the Incubator is a calm, relaxing work environment and not super busy like many other research buildings, where there is a lot of competition going on. In the Incubator, the researchers are united by the common goal to accelerate cancer treatments.

“I feel happy when I see an announcement that a company has reached a new milestone, because it means someone is making an impact and a difference out there.” Hakan Köksal

Köksal will now begin a postdoctoral position and continue his ongoing research projects. He aims to work on the development of cell therapies and hopes to make new breakthroughs on the treatment of solid cancers in the future.

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From left to right: Peder, Henrik, Isha and Christofer are very happy with the placement at the research group Experimental Cancer Therapy. Photo: Elisabeth Kirkeng Andersen

Advanced microscopy on the timetable

The Ullern students visited the Core Facility for Advanced Light Microscopy at Oslo University Hospital.

This article was first published in Norwegian on our School Collaboration website.

How can we learn more about cancer cells by using advanced microscopes?

A microscope is an important tool for scientists in many different branches of research. In February, four first-year students from the Researcher programme at Ullern Upper Secondary School got to test multiple different microscopes at the Core Facility for Advanced Light Microscopy, The Gaustad node, at Rikshospitalet (Oslo University Hospital).

Isha Mohal, Peder Nerland Hellesylt, Christofer Naranjo Woxholt and Henrik Eidsaae Corneliussen are sitting in a small, rectangular room, which belongs to the research group Experimental Cancer Therapy at Oslo University Hospital.

“If you sit next to me, you can see better what I am doing,” says Emma Lång to the students.

Emma Lång is a researcher at the research group Experimental Cancer Therapy. She explains to Henrik and Isha how the advanced microscope, connected to the computer behind her, can record videos of living cells. Photo: Elisabeth Kirkeng Andersen

Emma Lång is a researcher in the research group Experimental Cancer Therapy. She explains to Henrik and Isha how the advanced microscope, connected to the computer behind her, can record videos of living cells. Photo: Elisabeth Kirkeng Andersen

It is the second day of the work placement for the Ullern students. Lång will show them how she is setting up a very special microscope with the somewhat cryptical name “ImageXpress Micro”.

The microscope is so special that it is the only one in the entire Oslo region and Eastern Norway. The unique thing about the microscope is that it creates videos of thousands of living cells over a long time period. This enables the researchers to understand more about how the cells move.

This is important knowledge in the research on cancer and wound healing, which this research group is working on.

The students sit down beside Lång and follow what she is doing closely. The microscope is entirely automatic, so all the settings are done on a computer. Later the same day, the students will use the microscope themselves to record videos of cells that they have been working on from the day before.

Learning from practical work

This is the first work placement for the students from the Research programme – and they are really enjoying it.

“It is fun to see what the researchers are doing and to try it out ourselves in practice,” says Peder.

“We have done some work with pipettes and worked in the laboratory at school, so we are already familiar with some of the practical handiwork. It is fun to try it out in a real research setting,” says Isha.

She likes that the placement gives some insight into what a career in research and cellular biology can be like.

“I am more interested to work in cellular biology after this placement, but I haven’t decided anything yet. I think we are learning things in an exciting way. It is practical learning and not as theoretical as it is usually in school,” says Peder.

“I absolutely see this as an opportunity to become a researcher. It is great to have so much science subjects as we have on the Researcher programme,” says Henrik and Isha agrees.

“I am very interested in the natural sciences. We have a lot of theory in school and it is fun to come out into the hospital and into companies to see how researchers work – and to try it out ourselves,” says Isha.

Christofer also thinks it is interesting, but he is more interested in data and other general subjects.

“That’s great, Christofer,” Lång says. “Research needs more people with good data knowledge. Do you see the computer over there? It costs NOK 100 000 and it will be used to develop machine learning and a technique called ‘deep learning’ on the data produced from our microscopes. Maybe in a few years time, computers will be analysing the microscope images and videos that we are recording now.”

Images of cells

Yesterday, Isha, Peder, Christofer and Henrik worked on cells in the laboratory. They learned a technique to fixate cells. Then, they coloured the cells with antibodies that turn blue when they bind to the core of the cell and with a protein called actin that turns green. Actin performs several functions in the cell, it is both inside the cell structure and functions as threads of communication between the cells.

Stig Ove Bøe leads the research group was visited by the four students from the Research programme at Ullern Upper Secondary School for two days. Here, he is preparing the images of skin cells that the students worked on the day before. Photo: Elisabeth Kirkeng Andersen

Stig Ove Bøe leads the research group that was visited by the four students from the Research programme at Ullern Upper Secondary School for two days. Here, he is preparing the images of skin cells that the students worked on the day before. Photo: Elisabeth Kirkeng Andersen

Now, the students are looking at the results uploaded to a computer in an advanced image editing software program that can visualise the cells as two- or three-dimensional.

“These are the skin cells you coloured yesterday. Can you see that the cells make up one close network? The reason for this is that it is skin and it is supposed to be impenetrable. Can you also see that the single cells act differently at the edge than closer inside? It is our job to explain why and how,” Bøe explains to the students.

The students look and nod with interest.

After the placement, researchers at Rikshospitalet (Oslo University Hospital) have worked more on the images and videos that the students created.

These have been delivered to the students and will be used when they make a presentation of the placement and everything they learned to the rest of the students at the Research programme.

You can see the cell image below.

A three-dimensional image of the skin cells that the students have coloured. Photo: Emma Lång

A three-dimensional image of the skin cells that the students have coloured. Photo: Emma Lång

What is cell migration?

The research group “Experimental Cancer Therapy” led by Dr Stig Ove Bøe at Rikshospitalet are researching how cells move, which is called cell migration in scientific terms.

Cell migration plays a central role in many of the body’s physiological functions, such as the immune system and wound healing. Cell migration is also essential for cancer, since cancer cells can spread from the location of the tumour to other organs of the body.

Cells use different mechanisms to migrate. They can move as single cells or they can move collectively. Thousands of cells can, for example, cooperate so they can move in the same direction.

The research group uses many different microscopy-based methods to research cell migration. They are also developing new video methods to study living cells in microscopes.

The research group is also responsibly for the daily running of the Core Facility for Advanced Light Microscopy at Oslo University Hospital. The facility gives other research groups in the Oslo region access to and guidance of the use of advanced microscopy equipment.

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Torbjørn Furuseth, Chief Financial Officer, Targovax, is delighted to announce that the company's second part of the clinical trial for skin cancer patients will be held at Oslo University Hospital.

New clinical trial at Oslo University Hospital

Torbjörn Furuseth, Targovax

Our member Targovax has announced a new clinical trial for skin cancer patients at Oslo University Hospital.

The second part of a clinical trial for patients with refractory advanced melanoma (a type of skin cancer) will take place at Oslo University Hospital.

“We are excited that we can offer this treatment alternative to patients in our home country, and hopefully it will help us to recruit more patients faster,” said Torbjørn Furuseth, Chief Financial Officer, Targovax.

Targovax is a Norwegian biotech company that develops oncolytic viruses called ONCOS-102 to destroy cancer cells. The treatment is targeted towards solid tumours that are especially hard to treat. The ultimate goal is to activate the patient’s immune system to fight cancer.

Promising results

“The trial is until now conducted at three top hospitals in the US, where competition for patients to clinical trials is high. Oslo University Hospital is also a great cancer center, and currently there are no trials offered to this patient population,” said Furuseth.

Three out of nine patients responded to the treatment during the first part of the clinical trial. This included one complete response and two partial responses.

Dr. Magnus Jäderberg, CMO of Targovax, said: “It is promising to see this level of clinical responses after only three ONCOS-102 injections, including a complete response, which is rare in this heavily pre-treated patient population.”

A forceful combination

The treatment involves a combination of an oncolytic virus and an anti-PD1 checkpoint inhibitor.

The oncolytic virus is a modified virus that has been developed to selectively attack and kill cancer cells. You can read more about the oncolytic viruses on Targovax’s official website.

The anti-PD1 checkpoint inhibitor disrupts the interaction between proteins on the surface of cancer cells. This stops the cancer from evading the immune system.

“Earlier this year, we decided to expand the trial to test a more intensified schedule of ONCOS-102, and it will be interesting to see whether this regimen can generate more and deeper clinical responses,” said Dr. Alexander Shoushtari, Principal Investigator, Memorial Sloan Kettering Cancer Centre, New York.

The second part of the clinical trial is currently enrolling new patients.

 

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Dr. Jon Amund Kyte is the new Head at the Department of Experimental Cancer Treatment at OUH.

Attracting clinical trials to Norway

Dr. Jon Amund Kyte at Oslo University Hospital (OUH) and Oslo Cancer Cluster share the common goal of bringing more clinical trials to Norway.

 

Jon Amund Kyte is the new Head at the Department of Experimental Cancer Treatment at OUH. He also runs three separate clinical trials and is the leader of a research group at the Department of Cancer Immunology, where he develops novel CAR T cell therapy and conducts translational studies.

Kyte aims to increase the number of and improve the quality of clinical trials in Norway. He says this will contribute to more patients gaining access to novel cancer treatments and to improving the efficacy of cancer therapies.

“The only way to improve cancer treatment is to have clinical trials,” said Kyte.

Oslo Cancer Cluster also wants to bring more clinical trials to Norway to develop innovative cancer medicines. The ambition is to enable faster patient recruitment from across the Nordic region, so that many more can benefit from new treatments, such as immunotherapy.

 

CAR T cells are produced by isolating specific cells of the immune system (T cells) from a cancer patient and modifying them so that they become more effective at recognizing and killing cancer cells.

 

Promising advances

Immunotherapy represents a new type of cancer treatment, which activates the patient’s immune-system to fight off the cancer cells. It gives doctors the opportunity to help patients that previously had limited treatment options. Most types of immunotherapy also cause less side effects than traditional cancer treatments.

“The important point is that immunotherapy can have a long-term effect,” said Kyte.

“Most patients that experience a recurrence or progression of the disease cannot be cured. The traditional treatments only have a limited, short-term effect on them. But immunotherapy may have a long-term effect on the patient – and, in some cases, even cure the disease.”

 

Two big challenges

Immunotherapy may sound like a miracle drug, but researchers still have a long way to go to perfect the treatment for all cancer patients. Kyte highlights two of the biggest barriers that remain.

“One challenge is to develop immunotherapy so that it works efficiently on all types of cancer. The other challenge is to learn how to choose personalised treatment plans: to identify an individual’s biomarkers and find out which treatment will be effective for that specific patient.”

A biomarker is a biological molecule in the patient’s body and these may be used to see how well a patient will respond to a certain treatment. Kyte said that to develop immunotherapy, there needs to be more clinical trials. It is the only way for researchers to find out how to activate an immune response in the patient’s body.

“A big potential for development lies in trying different possible combinations of cancer treatments. In my clinical trials, for example, we combine immunotherapy with immunogenic chemotherapy or radiation therapy,” Kyte explained.

 

Jon Amund Kyte presenting the Clinical Trial Unit.

The Clinical Trial Unit are experts in assisting companies and researchers to conduct clinical trials in Norway.

 

Welcome, companies

OUH has a long history of conducting clinical trials and is an appealing option for both researchers, doctors and companies that wish to initiate their own trials. Kyte welcomes more companies to conduct clinical trials at OUH:

“The more clinical trials that are conducted here by companies, the stronger our clinical research environment becomes and our ability to run our own studies is also strengthened.”

The Clinical Trial Unit in Kyte’s department offers its services to companies that want to run a clinical trial at OUH. They have extensive background knowledge of how the hospital is organised and which approvals are needed to conduct a clinical trial in Norway. They can step in as project coordinator for companies that need help to get their clinical trials up and running.

“We are highly experienced in applying for approvals in Norway. When you run a clinical trial, there are regulations from the Norwegian Medicines Agency and the ethical committee and other governmental agencies. A clinical trial also involves many different parts of the hospital – the departments of pathology and radiology, the laboratories, the infusion unit, the hospital wards and out-patient clinic and the administrative offices that oversee different agreements, data management and biobanking.”

 

Nordic clinical trials

All these administrative obstacles may appear discouraging, but there are many convincing reasons to conduct a clinical trial in Norway.

“The Oslo University Hospital is a good place to run a clinical trial, because in terms of the number of cancer patients, it is one of the largest hospitals in Europe. Norwegian healthcare is also extremely well-organised. Patients are rarely lost to follow-up, because there are no private healthcare alternatives and patients rarely move out of the country,” Kyte explained.

The Clinical Trial Unit is also taking part in the development Nordic Nect, a collaboration to recruit patients from the entire Nordic region to clinical trials. The plan is to have one hospital where the clinical study is conducted and to involve patients from Sweden, Denmark, Finland and Norway. There will then be a population of 25 million people from which to recruit patients, which opens the possibility for larger clinical trials.

“This is a good thing for the companies that want to run clinical trials in Norway. It is also good for the researchers. But most of all, it is good for the patients – who have the opportunity to take part in more novel cancer treatments,” said Kyte.