NEW STUDY. Immunotherapy often does wonders for many patients with malignant melanoma, a form of skin cancer, after it has spread to other parts of the body. For some patients, however, this new treatment is totally ineffective against the tumors. A new study from Sahlgrenska Academy shows that an advanced animal model in which mice become carriers of patients’ tumors may be used to find out in advance which tumors will respond to the treatment. This animal model can, accordingly, be applied to testing of new treatments against malignant melanoma.
Malignant melanoma is an aggressive disease that arises when uncontrolled division of pigment cells, mainly in the skin, begins. This cancer used to be incurable after spreading (metastasizing), but new drugs based on greater knowledge of the genes of tumor cells and how the immune system works have now been available for a few years. Current research indicates that almost half of all patients with metastatic melanoma can now live free from cancer for several years. One of the latest forms of immunotherapy involves using what are known as PD-1 checkpoint inhibitors. This treatment, which releases the “brakes” on the T cells in the immune system, is based on the discovery for which the Nobel Prize was awarded in 2018.
Mice carry patients’ tumors
Although immunotherapy has revolutionized the treatment of metastatic melanoma, there are many cases in which it is entirely ineffective. Half of the patients do not respond to this treatment, and scientists all over the world are now working to understand why.
“Our research group has long been using a special mouse model with the mouse acting as a kind of ‘avatar’ for patients’ tumors. It enables us to investigate, outside the patient’s body, which treatment is best for a particular tumor. In practice, the method involves letting a small piece of the patient’s tumor grow under the skin of a mouse, which then becomes a patient-specific mouse model. The tumor can then be transferred further to more mice, in which various drugs can be tested against the tumor,” says Professor Jonas Nilsson, who heads the research group.
The group has previously used other cancer therapies in this advanced mouse model. Not until now, however, have the researchers been able to show that this model can also be used to predict treatment outcomes when using the new PD-1 checkpoint inhibitors.
Testing the immune system
The scientists’ hypothesis was that, for the PD-1 checkpoint inhibitor to work, the T cells in the tumor must be of high quality. To determine whether tumors had good immunity, the research team implanted small tumor samples (biopsies) from patients in, first, an ordinary mouse and, second, a mouse that had been genetically modified so that its cells produced the protein interleukin-2 (IL-2), a factor that stimulates T cells. Of tumors from 20 patients, only half proved capable of growing in the mice that produced this IL-2. The IL-2 thus activated the T cells in the tumor, and these then destroyed tumor cells, preventing tumor growth.
Some of the patients who provided tumor biopsies for the study had been treated with PD-1 checkpoint inhibitors.
“When we compared the results from the mice with the patients’ treatment responses, it turned out that the patients who, in the mouse experiment, had good immune responses to their tumors also responded better to the drug treatment,” Nilsson relates.
Mouse study helped patient
The researchers followed up the patients’ records and noted that in one of the patients, whose tumor exhibited activated T cells in the mice with interleukin-2, there had not yet been a follow-up of the clinical chemical examination. This patient underwent an X-ray examination, which showed that the surgically removed tumor had returned.
Oncologist Lars Ny comments: “At that stage, we had more data from the mouse experiment indicating that the tumor would be troublesome to treat with immunotherapy if it was too large. Fortunately, the tumor wasn’t that big, so I felt comfortable prescribing a PD-1 checkpoint inhibitor. This patient’s tumors also responded well to the treatment, by clearly decreasing in size and then disappearing completely. One may, of course, wonder what would have happened if we hadn’t had this mouse study underway.”
Importance of correct order
Another of Lars Ny’s patients, while receiving treatment for tumors, provided tissue samples from them for the mouse study.
“That patient’s tumor was interesting, since it had hardly any T cells. Instead, it was able to create an acid tumor environment, which makes the tumor more resistant to immune cells,” relates Lisa Nilsson, senior researcher and tissue coordinator at the laboratory.
In the mouse study, this tumor grew equally fast in the untreated mouse and in the one with the IL-2 factor. Since the patient’s tumor had metastasized extensively in the body, other drugs were tested. These were BRAF and MEK inhibitors, which stop tumor signaling, kill melanoma cells, and cause metabolism to slow down. This treatment worked well and tumors throughout the body shrank and disappeared. When only a few tumors were left, the patient received immunotherapy instead, with a favorable outcome.
Subsequently, the research team was able to repeat the entire course of treatment in the mouse and compare it with how the tumors would have responded if the treatment had been carried out differently. The mouse study clarified how important it had been to administer the treatment in the particular order in which it had been given.
“If immunotherapy had been prescribed as an initial treatment, the outcome for the patient — who has been tumor-free for two years to date — would probably not have been as good,” says Ny.
Relevant clinical model
Although some of the patients included in the study were able to benefit directly from the results of the mouse model, the mice are probably not going to be used for clinical purposes, to find the right treatments for individual patients. The primary reason is that the animal ethical permit covers scientific research only, and stipulates that the mice must be bred specially for research purposes. However, the mouse model is clinically relevant, the study shows, so is therefore suitable for translational and clinical research. It has recently, for example, been possible to use this mouse model to develop a treatment for melanoma known as “CAR-T- cells. These results were published by the group in the journal Cancer Research in 2019. Currently, the group is engaged in further work to enable patients to access this treatment.
The new study has been published in the clinical journal Annals of Oncology. Besides Lars Ny, Lisa Nilsson, and Jonas Nilsson, much of the work was carried out by postdoctoral researcher Larissa Rizzo, who is the joint first author with Lars Ny. Four nationwide Swedish funders — the Knut and Alice Wallenberg Foundation, the Swedish Cancer Society, the Sjöberg Foundation and the Erling-Persson Family Foundation — and a regional cancer fund, Lions Cancer Research Fund of Western Sweden, provided financial support for the study.
- Read the article at https://www.annalsofoncology.org/article/S0923-7534(19)39083-0/fulltext
- An editorial commenting on the study is also available in the journal Annals of Oncology: https://www.annalsofoncology.org/article/S0923-7534(19)39095-7/fulltext
- The CAR-T study is accessible at https://cancerres.aacrjournals.org/content/79/5/899.
TEXT: ELIN LINDSTRÖM
PHOTO: ANNA REHNBERG