Quadruple therapy improves anti-tumor immunity

Immunotherapy is a promising new cancer therapy. It stimulates the patient's own immune cells to recognize and kill tumor cells. Unfortunately, not all patients respond to immunotherapy and scientists are looking for ways to change this. Researcher Inge Verbrugge and her colleagues at the Netherlands Cancer Institute discovered that a specific combination of immunotherapy, radiotherapy and chemotherapy is very effective against tumors that do not respond to immunotherapy alone. They describe their findings in the scientific journal Cancer Immunology Research.

Attract and activate

The scientists were looking for a way to boost the immune cells. When immune cells encounter something foreign, such as a virus or a tumor, they will usually proliferate and kill it. Immunotherapy with checkpoint inhibitors can help the immune cells to kill cancer cells (this video explains how these drugs work). However, this treatment is not effective in all patients, partly because not every tumor attracts and activates many immune cells.

Sensitive

Under supervision of Inge Verbrugge and Jannie Borst researchers Paula Kroon, Elselien Frijlink and colleagues investigated a strategy for inducing an effective immune response against these tumors as well. In mice with cancer they combined a checkpoint inhibitor with a different form of immunotherapy (anti-CD137 antibody) and added radio- and/or low-dose chemotherapy on top of this (see illustration). The second form of immunotherapy was able to help induce an immune response, however this was not sufficient to kill the tumor. The idea behind adding radiotherapy is that the cells that die because of it can help induce an immune response, and the surviving cells are more sensitive to the immune attack. A low-dose of chemotherapy can also make tumor cells more sensitive to elimination by immune cells.

In tumor cells that are resistant to immunotherapy with checkpoint inhibitors, radiotherapy and chemotherapy can synergize with a specific immunotherapy combination to induce tumor cell death. The checkpoint inhibitor (red Y) 'removes the brake' on the immune cells (T cells) and the other form of immunotherapy (an antibody to CD137, green Y) 'presses the gas pedal' on the immune cell. Radiotherapy and chemotherapy enable the activated immune cells to kill the tumor cells (shriveled purple cells).

Chemo-radio-immunotherapy

Indeed, the combination of these four treatment modalities proved to be very efficient in mice. The newly raised immune cells did a better job and the mice survived longer. The immune cells even cleared tumor cells that resided outside the irradiated tissue. In the future, chemo-radio-immunotherapy may contribute to improving the survival of patients with tumors that do not respond well to immunotherapy with checkpoint inhibitors.

Researchers of the Netherlands Cancer Institute are already studying this concept in several patient cohorts. The PEMBRO-RT trial combines radiotherapy with checkpoint inhibition in patients with lung cancer. The TONIC-trial investigates to what extend radiotherapy and chemotherapy can improve the efficacy of checkpoint inhibitors in breast cancer patients.

Read the scientific article here.

This research was financed by the Dutch Cancer Society and Health Holland.