The first Norwegian CAR

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: 

 

Researcher testing lab sample.

New research: 3D structure tumors in immunotherapy

New work from cancer researchers at the Department of Cellular Therapy could help to streamline the development of exciting new immunotherapy approaches for treating cancer.

Cancer treatments that aim to switch on a patient’s immune system to kill tumor cells – so-called immunotherapy approaches – have received much attention and encouraging results in recent years. Now, the immunomonitoring unit of the Department of Cellular Therapy at Oslo University Hospital has devised a new experimental approach that could improve early stages of the immunotherapy development pipeline.

The unit is present in Oslo Cancer Cluster Incubator with a translational research lab, led by Drs. Else Marit Inderberg and Sébastien Wälchli.

 

Researchers in laboratory.

Dr. Sébastien Wälchli and colleagues in the translational research lab in Oslo Cancer Cluster Incubator. Photo: Christopher Olssøn

 

CAR T cells drive new successes

Our immune systems are generally very good at recognizing foreign infectious agents and disposing of them appropriately. However, although our immune systems are capable of recognizing tumors as a threat, cancer cells have adapted mechanisms that enable them to evade the immune response. Immunotherapy is the name given to a range of different approaches that aim to overcome this problem by improving the immune system’s ability to target cancer cells.

One relatively new example of an immunotherapy approach comes from CAR T cells. These 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. The modified T cells are then placed back into the patient so that they can ‘home in’ on the tumor and kill the cancer cells.

Read about related research: T-cells and the Nobel Price

 

Difficult for solid cancers

Current models for testing new CAR T cells aren’t always optimal. Although CAR T cells have shown encouraging results in treating some cancers, particularly the blood cancers leukemia and lymphoma, the development of CAR T cells for non-blood, or ‘solid’, cancers has been more difficult.

In part, this is due to the fact that tumor models currently used in early stages of testing involve two-dimensional monolayers of cancer cells, which do not reflect the complex three-dimensional structure and organization of solid tumors found in patients.

Consequently, CAR T cells that show encouraging results using these two-dimensional models often produce less effective results at later stages of the development pipeline, meaning time, effort and resources are wasted.

 

3D tumor spheroids

To improve the early stages of testing new CAR T cells, Dr. Wälchli’s group has developed a new approach that enables researchers to grow three-dimensional cancer cell structures, or ‘spheroids’, in the lab, and to test the effect that CAR T cells have on killing off these spheroids.

Compared to current two-dimensional methods, the spheroids are more similar in complexity and structure to tumors found in patients.

In a recent publication in the Journal of Visualized Experiments, this group demonstrated for the first time that their spheroid approach has the potential to provide a useful new tool for developing CAR T cells.

They generated spheroids using colorectal cancer cells – a type of cancer for which there is currently no effective CAR T cell therapy available. These cancer cells were modified so that they possessed a molecule on their cell surface called CD19, which is known to be recognized by certain CAR T cells. The researchers then incubated these spheroids with CD19-targeting CAR T cells and used advanced live imaging techniques to track the effect on cancer spheroids.

To help other research groups who would like to start using the spheroid technique, Dr. Wälchli’s publication is accompanied by this video which introduces the approach and provides a basic overview of how it works. The Journal of Visualized Experiments requires a subscription to see the entire video. You can also read a PDF of the article “A Spheroid Killing Assay by CAR T Cells” without a subscription.

 

Successful approach

As expected, shortly after adding CAR T cells, the researchers could detect that spheroids were shrinking due to cancer cell death, proving that their approach successfully measures CAR T cell-induced tumor clearance in a quantitative manner.

Discussing the work, Dr. Wälchli says, “We believe this method can help to answer key questions about using 3D structure tumors as a suitable alternative for testing new immunotherapy approaches.”

The approach now opens the door for testing a range of different target molecules in combination with new CAR T cells targeting those molecules.

 

Fast, affordable and straightforward

Dr. Wälchli believes many researchers could benefit from the spheroid technique. He continues,

“A major advantage to our approach is that it is fast, affordable and straightforward, meaning any research group with the right equipment can test the effect of their immunotherapy on 3D tumors before moving to animal models”.