Almost 4000 people are diagnosed with malignant melanoma in Sweden every year. Although the tumor can usually be surgically removed, in more than 15 percent of cases it will spread through the body by metastasis. The prognosis for patients in which the cancer has spread has long been very bad. Thanks to basic genetic and immunological research, we now know how melanoma starts and how the disease can remain hidden from the immune system, which has led to new treatments being found – either in the form of new targeted drugs or in the form of treatments that stimulate the immune system, which activates immune cells in the tumors.
“The remarkable thing about the new treatments is the fact that patients respond in such different ways to them. The targeted treatments shrink the tumors in almost all patients with a mutation in the BRAF gene, but the tumor develops resistance and returns within one year. For some patients, the immunotherapy works so well that they are cured by and large, but for some tumors, these drugs do not work at all,” says Professor Jonas Nilsson.
Jonas Nilsson heads a multidisciplinary group of researchers at the Sahlgrenska Cancer Center, at the University of Gothenburg. Via their two studies, which have been published in Nature Medicine and Nature Communications, the group is now taking important steps toward improving the treatment for metastatic malignant melanoma.
After several years of work, the group has managed to further develop an advanced research tool that may provide answers as to why patients respond so differently to the cancer treatments currently available, which in turn is likely to give more patients the opportunity to recover.
They have discovered how a new type of laboratory animal, known as “avatar mice”, can help in this area. The mice are genetically modified so that they have no immune system, which makes it possible to transplant the tumor samples from patients to the mice. Although these avatar mice represent a step forward for cancer research, for a long time their lack of immune system meant that they could not be used to study immunotherapies.
Jonas Nilsson and his group managed to solve this problem by upgrading the mouse model so that it can support the tumor and immune cells of the same patient. This upgrade meant, among other things, that a further change was made to the mouse’s genes so that they produce a special factor that human immune cells require to be able to survive in the mice.
Trials in which avatar mice with both tumors and immune cells from a number of Danish patients treated with the form of immunotherapy known as “adoptive cell therapy” (ACT) proved successful.
“The tumor disappeared and the mice were cured,” says Mattias Lindberg, who until recently was a post-doctoral fellow in the group and one of the article’s main authors.
Henrik Jespersen, a resident physician of oncology and a doctoral candidate in the research group at the Sahlgrenska Cancer Center, shared the first authorship with Mattias.
“The robust response only occurred when the tumor and immune cells were taken from patients from Herlev in Denmark who had also responded well to the ACT treatment. The fact that not all tumors respond to their immune cells in the avatar mice gives us a platform on which to pursue further research”, says Henrik Jespersen.
In other words, the upgraded avatar mice provide a model for immunotherapies, and will now be used to investigate reasons why certain patients respond so poorly to the treatment. The group is going to use tumors from patients who did not respond to the treatment and try to influence these so that they will respond just as well to the immunotherapy.
“We are also going to have the opportunity to study how to combine targeted treatment with immunotherapy, which we are yet to really master in a clinical setting,” says associate professor Lars Ny (right), who is head of the melanoma team at Sahlgrenska University Hospital’s ‘Jubileumklinik’, and also main supervisor to Henrik Jespersen.
The avatar mice are also helping the researchers to investigate the problem of resistance to targeted treatment. Researchers at Memorial Sloan Kettering Cancer Center in New York discovered that mice with lung cancer from patients did not respond to treatment with BRAF inhibitors even though the tumor had a mutation in the BRAF gene. The American team of researchers discovered that this was due to the cancer cells changing during the treatment, and beginning to create more copies of the BRAF gene; in the end, they were able to stop the tumor from growing in the mice by combining the treatment with three different signal inhibitors for enzymes BRAF, MEK and ERK. The triple combination treatment was, in other words, effective at treating lung cancer and, in order to investigate whether it was also effective at treating malignant melanoma, they contacted the group of researchers at Sahlgrenska Cancer Center:
“The idea is to inhibit the signalling enough in the tumors so that they cannot return and cause a relapse simply due to an increase in their signalling,” says Jonas Nilsson, before continuing:
“The triple combination treatment also seems to work for melanoma. We used tumor samples from six patients, with the tumors disappearing completely in the mice for five of the human tumors. We almost never see that if we treat them with just one of the drugs.”
Titles: An approach to suppress the evolution of resistance in BRAFV600E-mutant cancer and Clinical responses to adoptive T-cell transfer can be modeled in an autologous immune-humanized mouse model
