There are many reasons different cancer treatments don't have the intended consequences and the disease is able to prosper despite our best efforts. One example is a tumor that contains barely any immune cells, which renders immunotherapy cancer treatments largely ineffective. A new study has shown how these tumors that have gone "cold" can be heated up through a carefully managed dose of radiation, drawing in fresh immune cells that can take up the fight from within.
The study was carried out by scientists at the Ludwig Institute for Cancer Research and follows some other interesting advances in the area, including research published last year seeking to strategically inflame these so-called "cold" tumors. These tumors are often unable to be detected by the immune system and go on causing harm to the body, but by deliberately inflaming them, the study showed how they could be made "hot" and trigger an immune response.
This type of treatment falls under what's known as immunotherapy, which seeks to supercharge the body's immune system so that it can better fight off cancer. Immunotherapy meets a dead end when it encounters a cold tumor that is nearly devoid of immune cells, though researchers have had some success in using high-dose radiation to both target the cancer cells and pull other immune cells into the mix. But for cancers that have spread into the abdomen, like ovarian or gastrointestinal, these high doses of radiation would cause serious harm to vital organs.
“We came up with this idea of stressing the tumor using levels of radiation that wouldn’t kill its cells, but still apply enough pressure to make it send out signals telling the immune system, ‘come to me because something bad is happening here,’” says study author Fernanda Herrera.
This technique was first explored in mice with advanced ovarian cancer, in which it was combined with a cocktail of immunotherapy drugs to effectively destroy their tumors. This treatment actually cured 20 percent of the mice, and analysis showed that the tumor response was driven by complementary immune cells that took on the role of T cells, the primary hunters of diseased cells, and other atypical immune responses.
“We began by interrogating in mice what happens to the microenvironment of advanced ovarian tumors if you apply low doses of radiation and showed there was a massive uptick in the expression of druggable targets,” says study author Melita Irving. “It was a rational approach to the therapy.”
At the same time, the scientists explored the technique's potential in human subjects through a clinical study involving eight patients with metastatic prostate, ovarian and gastrointestinal cancers devoid of key immune cells. These subjects were given a cocktail of immunotherapy drugs, and their abdominal tumors were exposed to very low doses of radiation every two weeks. Some side effects linked to the immunotherapy had to be managed, but the tumors successfully targeted with the radiation did indeed regress, while those that were missed did not. Halting the treatment led to a rapid tumor recurrence.
“The human studies recapitulated our findings in the mice,” says study author George Coukos.
The scientists are continuing to study the technique through this clinical trial, and investigating why some tumors were able to avoid the therapy. Another trial is now in the works involving more advanced immunotherapy drugs and the use of low-dose radiation in combination with experimental T cell therapies, in which a patient's immune cells are engineered specifically to target cancer.
“We’ve really shown here that low dose irradiation can make tumors that were previously unresponsive to immunotherapy responsive, and that both adaptive and innate immunity need to work together for tumor control,” says Coukos. “It’s a whole environment you need to create in the tumor to support the killer T cells, and in this case, the helper T cells that were killers.”
The research was published in the journal Cancer Discovery.