There are a number of good reasons to assume that combing immunotherapy and radiotherapy can be more effective than each therapy on its own. Radiotherapy can make tumor cells more sensitive to killing by immune cells. In addition radiotherapy can, by killing part of the tumor cells, act like a kind of vaccine and generate a (body-wide) tumor-specific immune response. This can be further enhanced by immunotherapy. When such a response occurs, radio-immunotherapy can potentially eradicate not only the irradiated tumor, but also distant metastases that were not irradiated.
Several preclinical studies do indeed show that immunotherapy can enhance the effect of radiotherapy. But these studies have all been performed in mouse models with transplanted tumor cell lines. The team of Verbrugge and Blank instead decided to use a BRAF-mutant and PTEN deficient mouse model, which more closely resembles de novo human melanomas. The results of their experiments were published in the June 2016 issue of Cancer Immunology, Immunotherapy. The first author is Paula Kroon.
The researchers used different combinations of the most effective immunotherapeutic strategies currently used in the clinic; namely anti-PD-1 and anti-CTLA-4 monoclonal antibodies, interleukin-2 (IL-2 and the clinically promising anti-CD137 antibody. They also combined these drugs with radiotherapy. None of the immunotherapy approaches showed any anti-tumor efficacy. But the combination of anti-PD-1, anti-CD137 and radiotherapy clearly outperformed both radiotherapy by itself and other combinations of immunotherapy with radiotherapy.
"Next to the improved therapy outcome, there were fifty to a hundred times more T-cells present in the tumors of the mice that received this particular combination, compared to other treatment combinations. This suggests that our radio-immunotherapy combination induces an immune response and allows these immune cells to infiltrate into the tumor. Radiotherapy or immunotherapy on its own had no effect on the number of T cells inside the tumors.", says Verbrugge.
She continues: "Our study suggests that a combination of anti-PD-1, anti-CD137 and radiotherapy may be superior to other combinations of immunotherapy and radiotherapy that are currently being tested in human patients. This combination may even work if immunotherapy alone is ineffective in a specific patient. On top of that, it is quite possible this therapeutic strategy will work even better in human patients than in our mouse model. Our mouse model closely resembles human melanomas in terms of the mutations that cause melanomas. But an important difference is that human melanomas are very immunogenic (which means it is easy for the immune system to recognize them). This is the consequence of the high number of UV-induced mutations, caused by the sun. These UV-induced mutations are absent in our mouse model, making these tumors poorly immunogenic. We therefore expect that in human melanomas, with a higher mutational load, our radio-immunotherapy approach will have a bigger effect."
The researchers are currently investigating to which extent other (immune) cells contribute to the observed combined responses. In addition, they are currently determining how an 'abscopal response' (the disappearance of non-irradiated metastases) can be achieved.
This study was financially supported by the Dutch Cancer Society.