A new study was recently published in the journal Nature showing an effective combination therapy for metastatic melanoma treatment along with the resistance mechanism underlying combined radiation therapy and ipilimumab in both patients and mice. The study is entitled “Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer.”
Melanoma is the most dangerous form of skin cancer and is caused by damage to skin cells (usually by ultraviolet radiation), triggering mutations that are not repaired and allowing skin cells to rapidly multiply and generate malignant tumors. Melanoma is curable when detected and treated early; if it goes undetected or if it recurs, the cancer can proliferate and spread (metastasize) to other parts of the body, becoming more difficult to treat.
The research team had previously concluded, based on a phase I clinical trial (“RadVax” trial), that the combination of radiation with ipilimumab (an antibody against CTLA4 [cytotoxic T-lymphocyte-associated protein 4], known to inhibit the immune system) was safe and capable of shrinking metastatic melanoma tumors in patients.
“These new immunotherapies are potent treatment options that have generated a lot of excitement in the past few years, but we know that many patients fail to respond, underscoring the need to further improve the drugs’ abilities,” said one of the study’s senior authors Dr. Andy Minn in a news release. “Anecdotally, we know that combining radiation with immunotherapy can be powerful, so we were very motivated to move forward with both a clinical trial to demonstrate that this combination is a promising route to pursue and with laboratory studies to understand why response happens and why it does not.”
Researchers recruited 22 stage IV melanoma patients previously treated and untreated to assess different therapeutic approaches. Patients received stereotactic body radiation therapy (SBRT) to a single tumor; ipilimumab was given three to five days later and then every three weeks for four cycles. The team found that 18% of the patients had a partial response in unirradiated tumors, another 18% had a stable disease and the remaining 64% had a progressive disease. The overall survival rate of the group was 35%, whereas a previous trial with ipilimumab treatment alone had an overall survival rate of 20%. Similar results were obtained in experimental mouse models, where 17% of the mice were responsive to the combined treatment of radiation therapy and ipilimumab.
Although the combined treatment was to some extent effective, resistance was common. Using mice models, the researchers showed that resistance to cancer treatment was developed through the upregulation of a molecular pathway linked to PD-L1 (programmed death-ligand 1), which is thought to suppress the immune system by inhibiting the activation of important immune T cells.
Researchers hypothesized that an antibody against PD-L1 could be a perfect third approach to improve immunity. To test it, they inhibited PD-L1 in mice and found it could restore both T cell function and cancer response to the combined treatment of radiation and anti-CTLA4, resulting in an increased survival rate of 60%. In agreement with these observations, melanoma patients who had high PD-L1 levels failed to respond to radiation plus anti-CTLA4 treatment and had impaired T cells, while patients with low PD-L1 had a 50% survival.
The research team concluded that PD-L1 on tumor cells can play a key role in the resistance mechanism to radiation therapy and ipilimumab treatment. “Understanding resistance is very important. Although outcome can be improved when more therapies are combined, risk of side effects can increase. Precision medicine requires knowing when to give more and what to give,” noted Dr. Minn.
Researchers have now found that treating metastatic melanoma with a triple therapy based on radiation and two immunotherapies targeting the CTLA4 and PD-L1 pathways can induce an optimal response in patients. “These results are extremely encouraging and will allow us to propel the work further, into bigger clinical studies investigating the triple threat,” concluded one of the study’s senior authors Dr. Robert Vonderheide. “Once again, we are extending the reach of the immune system, and breaking the ceiling on what these drugs can do for our patients.” The team plans to start clinical trials for other tumors such as lung, breast and pancreatic.