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Arming the body's own immune system
There are more and more cancer treatment options in health care. The arsenal of heavy weapons available in the fight against tumours has grown and become more effective. Research now focuses largely on developing treatments in which the patient's own immune system kills the cancer cells.
text ÅSA MALMBERG photo MIKAEL WALLERSTEDT
Arming the body's own immune system to fi ght cancer
Angelica Loskog’s research group focuses on the use of viruses to destroy cancer cells. From left: Jessica Wenthe, Ahmed Calandigary, Angelica Loskog and Tanja Lövgren.
Angelica Loskog is one of the pioneers who, as early as the 1990s, studied methods to stimulate the immune system to fight against tumours. CANCER CELLS ARE HIGHLY SKILLED at tricking the body's defence mechanisms to avoid being attacked. However, it is medically possible to activate the immune system so that it kills the cancer. This discovery led to the 2018 Nobel Prize in Medicine.
At Uppsala University, researchers began to study different methods of stimulating the immune system to fight tumours back in the 1990s. One of the pioneers was Angelica Loskog. Her research group focuses on the use of viruses to destroy cancer cells.
“In 1999, I started working on a project with viruses that then became the focus of my PhD. It was serendipitous that on my birthday, April 5, I entered the animal lab to
discover that the mice that had been given the virus were completely tumourfree while there were no changes in the control group. I thought that we were now going to be able to cure cancer,” says Loskog.
However, it proved not to be quite that simple. It was not until 2006 that the new method was given the green light to be tested on cancer patients for the first time.
“It was in Uppsala that the virus was first injected in patients. There were eight patients with bladder cancer where the cancer had begun invading the surrounding tissue, resulting in the need to operate to remove the bladder. Prior to the surgery, we treated the patients with virus therapy three times. In several patients, there were no tumour cells left in the bladder when it was removed,” says Angelica Loskog.
THE VIRUS WORKS BEST in the treatment of what are known as solid tumours, i.e., those that grow in tissues, such as bladder cancer, prostate cancer and breast cancer.
“Our virus is injected directly into the tumour where it infects the cells and tricks them into producing human immunostimulatory genes that we inserted into the DNA of the virus. The tumour cannot protect itself from the virus, which forces the tumour to start producing proteins from the genes in the DNA of the virus, which activates the immune system. It results in a vaccine effect. The viruses we are working on now are also able to replicate, although only in cancer cells. In the end, there is so much virus in the cell that it causes it to burst, releasing new viruses,” says Loskog.
The virus that her research team is working on is a common cold virus that they genetically modify for this purpose. At Lokon Pharma, Loskog is currently evaluating a virus that would be able to attack pancreatic cancer.
“It is a type of cancer with a very poor prognosis, but in patients who have received the treatment, the tumours have reduced in size, and it seems the survival rate
has improved. We are now hoping to carry out a Phase 3 study,” says Loskog.
A Phase 3 study is the final step before a drug can be approved for market and involves testing the drug on a large group of patients that is compared with a control group receiving standard treatment. To be granted approval, the drug must demonstrate the desired result, i.e., that it is better than the standard treatment, and researchers must also be able to demonstrate that there is readiness for full-scale, highquality production.
“What is very exciting is that the pharmaceutical company Roche now wants to test our virus on colorectal cancer,” she says.
Meanwhile, she continues to work tirelessly on developing the method with new viruses.
“We have a new virus in the pipeline that we hope will be akin to throwing a bomb into the tumour. It is a really cool new variant; however, it will take a few years, at least three or four years before it can be clinically tested,” she says.
ANGELICA LOSKOG'S CANCER research has focused not only on virus therapy but also on another powerful form of immunotherapy called CAR T-cell therapy. In a study together with fellow researchers Gunilla Enblad and Magnus Essand, among others, she treated the first cancer patient in Europe with CAR T-cells in 2014.
T-CELLS ARE A FORM OF white blood cell that circulate throughout the blood and lymphatic system, attacking infectious agents that have entered the body. T-cells also have the ability to recognise cancer cells because they have mutations that distinguish them from healthy cells. However, this ability is not on par with its ability to identify, for example, viruses and bacteria. To enable T-cells to effectively identify cancer cells they can be equipped with a special receptor on their surface called CAR.
“CAR stands for chimeric antigen receptor and is a synthetic molecule. The therapy is a treatment that involves removing the cancer patient’s own T-cells and genetically modifying them in the lab. CAR T-cells are then multiplied before being put back into the patient,” says Magnus Essand.
In 2018, the first drugs with CAR T-cells were approved in the US and the EU and the number of preparations has since increased to five. Two of these have started to be used in Swedish health care. Currently, only the blood cancers leukaemia and lymphoma are able to be treated with CAR T-cells, but researchers are working to find ways for the method to fight other cancers as well.
“However, this is more difficult. If you imagine a cancer cell in your blood, it is very easy for the CAR T-cells, which are put into the bloodstream, to find it and kill it. However, if the tumour is sitting in tissue, the CAR T-cells must exit the bloodstream and penetrate the tumour tissue. The tumour creates a very hostile environment for T-cells. The second major problem with solid tumours is that there is no ideal target like there is in blood cancer cells,” says Essand.
In 2018, the first drugs with CAR T-cells were approved in the US and the EU. BY TARGET, HE IS REFERRING to the antigen on the surface of tumour cells that allows the CAR T-cell to identify them. Tumours located out in tissues have a much more varied antigen expression, resulting in the CAR T-cell missing certain tumour cells, which often leads to recurrence.
Essand and his research team are now working on equipping CAR T-cells to become even more effective as well as able to kill the tumour cells that lead to recurrence.
“We ensure that our CAR T-cells carry extra ammunition, you could say, and that ammunition is not fired against the tumour cells but against the immune system. The immune system is further activated, on the one hand, by changing the micro-environment to ensure it does not become so immunosuppressive and, on the other, by educating the other T-cells in the immune system to recognise tumour cells that the CAR T-cells cannot detect,” he explains.
THE RESULTS FROM THE STUDIES that his research group have completed so far have been promising and early next year they hope to take the next step and start a new clinical study on lymphoma patients. A couple of years down the track, they hope to launch a clinical study on glioblastoma patients. Glioblastomas are the most common form of malignant brain tumours and are currently incurable. A functioning drug would therefore have a great impact on this patient group.
In the not too distance future, Essand and his colleagues hope it will be possible to include CAR T-cells in early stages of cancer
Magnus Essand and his research team are now working on equipping CAR T-cells to become even more effective as well as able to kill the tumour cells that lead to recurrence. Sara Mangsbo is hoping that hoping that cancer vaccines will function better by combining cancer vaccines with checkpoint inhibitors. Angelica Loskog´s research is focused both on virus therapy and CAR T-cell therapy.
treatment. And it looks to be on the way.
“Yescarta, one of the approved drugs, has now been approved in the US as secondline treatment for lymphoma. So as soon as the patient relapses, you now have the option to introduce Yescarta, and it is already being trialled as a first-line treatment, i.e., the treatment that is given to lymphoma patients first,” he says.
Another field of cancer research where there is a lot happening is cancer vaccines. Sara Mangsbo is a researcher who currently has several such studies in progress.
“At one company, we are developing a vaccine that will teach the immune system to recognise the protein telomerase, which cancer cells use to grow unhindered. In order to prevent tumour cells from dying when they divide so often, the cancer cells put a machinery in motion to produce more and more telomerase. This is necessary for the tumour cell to be able to protect its genetic code, but it also makes the tumour visible to the immune system. With the vaccine, we train the immune system to recognise small pieces of the protein telomerase, so that our immune cells can specifically search for and control tumour growth,” says Mangsbo.
The aim of these studies is to analyse the effectiveness of the vaccine in combination with the checkpoint inhibitors. These are antibodies that target and neutralise the ‘brakes’ on our immune response, she explains.
“Many researchers around the world are hoping that combining cancer vaccines with checkpoint inhibitors will enable cancer vaccines to function better than previous studies have shown. The checkpoint inhibitors are the result of the research that was awarded the Nobel Prize in 2018.”
TELOMERE ELONGATION is a protective mechanism used by the vast majority of cancer cells. Therefore, vaccine treatment could be effective against most forms of cancer.
“Right now, studies are ongoing in five different stages, carried out on ovarian cancer, skin cancer (malignant melanoma), lung cancer, head and neck cancer and last but not least mesothelioma, which is usually caused by asbestos exposure,” she says.
Unlike most other vaccines that are administered for prevention in order to avoid disease, the cancer vaccine is intended to be administered when a patient has already been diagnosed with cancer.
Future cancer care is set to undergo major changes. That is something Angelica Loskog, Magnus Essand and Sara Mangsbo are certain about. In 10-15 years' time, they believe that virus therapy, CAR T-cells and vaccines will be available at early stages of treatment and will be able to be combined with each other, and that more and improved drugs will enable us to treat forms of cancer that are currently incurable.
“We have to use all the means available to us if we want to fight cancer,” says Angelica Loskog. ●
