From the left: Hakan Köksal, PhD student, and Pierre Dillard, scientist, are splitting cells in the lab at Oslo Cancer Cluster Incubator. They are two of the scientists behind the new Norwegian study described in this article.

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.

 

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: 

 

Encouraging news from BerGenBio

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A second group of patients have been added to an ongoing phase II clinical study of a drug combination to treat lung cancer.

 

The ongoing trial is a collaborative effort between two members of Oslo Cancer Cluster: Norwegian biopharmaceutical company BerGenBio and US-based pharmaceutical company Merck (known as MSD in Europe). It involves an kinase inhibitor called bemcentinib, developed by BerGenBio, in combination with an immunotherapy drug called Keytruda (also known as pembrolizumab) from MSD.

 

“Throughout 2018, we reported encouraging updates from our ongoing proof-of-concept phase II clinical trial assessing bemcentinib in combination with Keytruda in advanced lung cancer patients post chemotherapy.”
Richard Godfrey, Chief Executive Officer, BerGenBio

 

The second group will involve patients that have been treated with immunotherapy before, but that have experienced a progression of the disease. There are various treatments available for patients with non-small cell lung cancer, but patients often acquire resistance to treatment. New treatments that can overcome these resistance mechanisms are therefore urgently needed.

 

“I am pleased that we are now extending the ongoing trial to test our hypothesis also in patients showing disease progression on checkpoint inhibitors.”
Richard Godfrey, Chief Executive Officer, BerGenBio

 

The aim is to evaluate the anti-tumour activity of this new drug combination. Preliminary results from the second patient group of the study are expected later this year. BerGenBio is in parallel also developing diagnostic tools to see which patients are most likely to benefit from their drug.

 

The decision to extend the trial was based on new positive results from pre-clinical studies, which were presented at the American Association of Cancer Research (AACR) earlier this week. The results open for the possibility to use bemcentinib both as a monotherapy and in combination with other cancer treatments on a broad spectrum of cancers.

 

 

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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

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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.

 

 

 

 

Promising start for expansion group of Targovax clinical trial

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Doctor examining the birthmark of a female patient

Targovax, one of the members of Oslo Cancer Cluster, has begun an expansion patient group in the clinical trial of a drug to treat skin cancer.

The company Targovax is developing immune activators to target solid tumours that are difficult to treat. The drug in question, called ONCOS-102, is aimed at patients with malignant melanoma (skin cancer) who have either been through chemotherapy, biological therapy or surgery and experienced a recurrence or progression of the cancer.

 

How does it work?

The immune activators work by activating the patient’s own immune system to attack the cancer cells. The drug that is now being tested is a genetically modified oncolytic adenovirus, a type of virus that has been designed to infect in the cancer cells and then replicate.

 

Initial positive results

Targovax, a member of the Oslo Cancer Cluster, are developing a treatment for skin cancer.

In September 2018, the first six patients had been treated with 3 injections of the drug and all of them showed a strong activation of their immune systems – one patient even had a complete response. The results suggested that the patients could benefit from more injections of the drug.

“The results seen to date with only three injections of ONCOS-102 are promising, and we are confident that by increasing to twelve injections we will release the full potential of ONCOS-102 to reactivate these patients to respond to Keytruda treatment,” said Magnus Jäderberg, CMO of Targovax.

 

Expansion patient group

On 11 February 2019, the first patient in the expansion group of the phase I trial was injected with ONCOS-102. The patient will be treated in combination with pembrolizumab, also known as Keytruda, an immunotherapy drug that works as an immune checkpoint inhibitor. This means that the drug involves antibodies, which “unlock” the protective mechanisms of the cancer cells so the immune system then can destroy them.

 

For more information, read the full press release from Targovax.