Combination Immunotherapy: Finding the Right Sequence and Timing

The sequence and timing of many events in life are critical, including cancer treatments. Many cancers, including mesothelioma, are often treated with a multimodal approach. This can consist of two different treatments, like chemotherapy and surgery, or the same type of therapy with different drugs, like the standard chemotherapy combination for mesothelioma of pemetrexed and platinol.

For these standard treatments, researchers and doctors are already aware of the best sequence and timing for patients to receive these therapies. But when researching new drugs or new combinations of therapies, it’s important to step back and consider the biology of how these treatments will work together. Understanding how the drugs’ effects will differ when given before or after another, as well as how much time apart they are administered, can have a vast difference on the treatment’s efficacy and the patient’s survival.

A recent study tested the efficacy of two types of immunotherapy on a mice model, with differing sequence and timing between treatment application. Their results showed great disparities, and highlight the importance of finding the right order and spacing between treatments.

A Look at the Study

In the study, investigators wanted to show the need for controlled clinical trials around immunotherapy combinations to make better progress in finding effective treatments for patients with all kinds of cancer. Researchers examined two types of immunotherapy specifically in their study using mice: a PD-1 inhibitor and an OX40 agonist.

PD-1 inhibitors have also been used in mesothelioma treatment, like the drug Keytruda®. PD-1 itself is a checkpoint protein on T cells, a type of immune cell that attacks cancerous cells. PD-1 acts as an off switch, prohibiting the T cell from attacking normal cells by binding to their corresponding PD-L1 proteins. Many cancer cells present high quantities of PD-L1, thus tricking the T cell into not attacking them. Checkpoint inhibitors block these signals so the cancerous cells can be properly identified and attacked.

OX40 agonists have the opposite effect. This newer type of immunotherapy works by enhancing the T cell’s ability to attack. The agonists bind to OX40, one of the co-stimulatory tumor necrosis factor superfamily receptors (TNFRs) that’s present on activated T cells. In essence, these receptors can have a big effect on tumor regression. OX40 agonists work by potentially ramping up this T cell activity and hopefully having an even stronger effect on fighting the cancer cells.

Researchers have found certain kinds of cancer don’t really respond to immunotherapy. The researchers wanted to find if those who don’t see results from PD-1 alone could see positive change with the introduction of another immunotherapy, like the OX40 agonist. They tested these therapies alone and together in different orders and timing of administration to get a sense of the tumor response in every scenario.

As solo treatments, the researchers found the PD-1 inhibitor had no impact on slowing tumor growth in these untreated mice, while the OX40 agonist slowed growth and improved overall survival. They next tested the two treatments together, applying the PD-1 inhibitor first. They were surprised to find the combination had less of an effect than the OX40 alone, diminished the length of survival, and led to bad side effects.

After such unexpected results, the researchers decided to change the sequence of treatment, theorizing that the OX40 agonist could boost the initial antitumor effect of the T cells and then extend the effect with the checkpoint inhibitor. Applying the agonist first and waiting 2 days for the PD-1 treatment, researchers found delayed tumor growth and the best survival outcomes.

In general, they concluded that the sequence and timing of cancer drugs like this can have a profound influence on their impact together, and should be considered throughout the clinical trial process and on a case-by-case basis. By better understanding an individual’s unique biomarkers in their tumors, doctors will be able to determine which immunotherapies will have the best antitumor response for that individual case.

Immunotherapy Combinations for Mesothelioma

In the majority of clinical trials so far, immunotherapy has been used in mesothelioma treatment as an individual treatment or in combination with another therapy, like following chemotherapy or a more novel approach before surgery. More recently, a few recruiting clinical trials are testing the combination of a few immunotherapy drugs in the treatment of malignant mesothelioma.

One of these studies will test the application of cancer vaccine CRS-207 with pembrolizumab (Keytruda) for patients with malignant pleural mesothelioma that have seen disease progression after receiving other therapies like chemotherapy. The study will be testing different applications of the immunotherapy drugs for up to 24 months, as long as they can identify sufficient clinical benefit, and safety for the patients.

The study will begin with a cycle of pembrolizumab administered on day 1, and CRS-207 applied the following day. If the treatment is well tolerated, researchers will then try administering the therapies on the same day for the next cycle. Over time, this will switch to one cycle of pembrolizumab every three weeks and one treatment of CRS-207 every six weeks to monitor their overall impact together in tumor growth and survival with various timing.

Several other studies are also emerging looking at the effects of two immunotherapy drugs used in combination. With several of these drugs showing promise in mesothelioma patients already, hopefully this research will lead to the development of more effective treatments.

More Research in Immunotherapy

Overall, these studies show the continued importance in studying and developing these immunotherapy drugs for all kinds of cancer. Understanding how the drugs work individually and together can have a big impact on their effectiveness and patient survival.

Fortunately, this research will soon be getting even more attention through the Cancer Moonshot Initiative. Earlier this month, the National Institutes of Health announced a collaboration with 11 pharmaceutical companies in the so-called Partnership for Accelerating Cancer Therapies (PACT). The collaboration brings a budget of $215 million dedicated to the study and advancement of immunotherapy specifically. The PACT’s main focus is around why immunotherapy hasn’t worked for everyone and how they can overcome that.

The PACT plans on first prioritizing the study of biomarkers across many clinical trials to understand how and why cancers respond to immunotherapy positively or negatively. They expect this data sharing will allow researchers to more easily decide what drugs to use in combination for certain types of cancer.

Hopefully with the efforts of this partnership along with the clinical trials already in motion, more patients will see the benefits of immunotherapy and we can continue to take steps toward a future without cancer.