Timing, Sequencing of Immunotherapy Combination May Improve Mesothelioma Response

In September, Mesothelioma Help reported on researchers taking a closer look at immune cells to help identify those patients who may respond best to immunotherapy. Since not every patient responds to the latest mesothelioma treatment options, researchers continue to look for ways to enhance the treatment. Now, researchers report that the right combination of immunotherapy treatments could increase effectiveness and safety of a two-drug combo.

Researchers paired a PD-L1 inhibitor, a type of  immunotherapy found effective when fighting pleural mesothelioma in some patients, with a new class of immunotherapy, known as OX40 agonists-drugs, to determine if two treatments were better than one, according to an Oct. 3 article from the National Cancer Institute (http://www.cancer.org/cancer/news/features/when-a-friend-has-cancer). In short, the answer is “yes,” however, the researchers also found that the timing and order in which the treatments were administered are important.

“This study prompts us to take a step back and say, let’s not just haphazardly combine immunotherapies,” said James Gulley, M.D., Ph.D., head of the immunotherapy section of NCI’s Center for Cancer Research, who was not involved in the study. “Let’s understand the biology of what we’re doing before we do clinical trials.”

Keytruda is an FDA-approved PD-L1 inhibitor immunotherapy drug that helps the body’s immune system fight the cancer cells. It is used in the treatment of lung cancer and has shown to be effective in controlling mesothelioma tumors in various clinical trials. Opdivo is also a PD-L1 inhibitor approved for advanced non-small cell lung cancer patients. It is unclear what PD-1 drug was used in the study.

In a mouse model of human breast cancer cells, the team tested the effectiveness of a PD-1 inhibitor, an OX40 agonist-drug, and both immunotherapy agents at the same time. The OX-40 agent alone slowed tumor growth and improved survival, but the PD-1 inhibitor had no impact. Surprisingly, when the two drugs were combined, the survival benefits of OX-40 were lost.

Not convinced this was the best they could do, the team tried sequential treatments. When OX40 was given first, followed two days later by the PD-1 inhibitor, they saw delayed tumor growth and an extended survival better than with the OX40 agonist alone. The researchers report that this combination actually resulted in complete tumor regression in 30% of the mice and nearly doubled the group’s survival time compared with the initial combination treatment.

When the team tried the reverse treatment protocol, administering the PD-1 inhibitor followed by the OX40 agonist, there was no slowed tumor growth.

“The most striking thing was the fact that we could get such long-term survival and apparent cure in some mice if we sequence the therapies,” said Bernard A. Fox, Ph.D., of the Earle A. Chiles Research Institute, Robert W. Franz Cancer Center.

Doctors and researchers have long touted the benefits of personalized medicine – establishing a treatment plan based on a patient’s specific disease characteristics and needs – for mesothelioma patients. In fact, the researchers believe that the use of combination immunotherapies, as tested in their study, may be even more effective if physicians look to biomarkers in their patients tumors to direct them towards the best drugs to use.

“We’re not there yet, but the idea is that we’ll be able to tailor therapy to each individual,” said Bernard A. Fox, Ph.D., of the Earle A. Chiles Research Institute, Robert W. Franz Cancer Center.

Read the full study in the Aug. 28 issue of Clinical Cancer Research (http://clincancerres.aacrjournals.org/content/early/2017/08/23/1078-0432.CCR-16-2677).