CD40 Activator Plus Chemotherapy Helps Fight Mesothelioma

Long-term mesothelioma survival was experienced by three out of 15 patients who took a CD40-activating antibody along with standard chemotherapy for malignant pleural mesothelioma

This finding hails from Perth, Australia. There, investigators from three research centers conducted a phase 1b clinical trial of the CD40-activating antibody known as CP-870,893.

Most of the 15 patients who took part in that clinical trial fared no better or worse than if they had received chemotherapy alone. That means CP-870,893 might not be a benefit for everyone.

However, for at least some, it could help keep mesothelioma at bay months or years longer than might otherwise be the case.

Waging a Two-Front War on Mesothelioma

The researchers are from Sir Charles Gairdner Hospital, the University of Western Australia, and St. John of God Hospital. They wrote about their phase 1b trial in the Annals of Oncology.

The clinical trial allowed the researchers to test a theory they’d developed about treatment synergy. Synergy is what happens when two or more ordinary ingredients, components or people interact with each other so powerfully that they produce an extraordinary result.

Here, the researchers thought it might be possible to synergistically enhance the effectiveness of the mesothelioma chemotherapy drugs cisplatin and pemetrexed.

The key to achieving this was to trigger a simultaneous immunological attack against the mesothelioma.

The researchers figured chemotherapy coupled with an attack by the immune system would do extra-serious damage to mesothelioma cells. It is sort of like conducting a two-front war against the disease.

The means by which this synergistic assault would be triggered involved giving doses of CP-870,893 right along with the cisplatin and pemetrexed.

What’s special about CP-870,893 is that it activates a costimulatory protein called Cluster of Differentiation 40 — a.k.a CD40.

Normally, CD40 is expressed by cells that have antigens. These include B cells and macrophages — weapons in the arsenal of the immune system.

When CD40 is activated naturally, it causes the immune system to generate big quantities of antibodies. If cancer is present, CD40 should tell the immune system to roll out antibodies specific to mesothelioma.

But that doesn’t happen. Somehow, the mesothelioma jams the CD40 communications system, so the producers of those mesothelioma-specific antibodies never receive the order to start making them.

CP-870,893 makes it possible for the production orders to get through despite the jamming.

Mesothelioma Survival Beyond 30 Months

In the phase 1b trial, the researchers first and foremost needed to establish how much CP-870,893 to give the patients.

Here’s how they did that. They slated the 15 patients to each receive cisplatin and pemetrexed for 21 days. On the eighth day, the researchers started giving the patients CP-870,893.

The patients were divided into three groups. One group received a small amount of CP-870,893. The second group received more. The third group received the most of all.

Using this approach, the researchers determined that the maximum dose of CP-870,893 that a patient could tolerate was 0.15 mg/kg.

Toward the end of the trial, the researchers reported that partial responses could be seen in 40 percent of the patients. Meanwhile, 53 percent were said to be disease-stable.

Median overall mesothelioma survival was pegged at 16.5 months. Three of the patients survived beyond 30 months.

The researchers determined that CD40 activation had been achieved because they noticed a decrease in CD19+ B cell over 6 cycles of chemotherapy with immunotherapy.

This decrease was accompanied by a rise in the proportion of CD27+ memory B cells to activated CD86+CD27+ memory B cells.

All of which led the researchers to conclude that combining CP-870,893 with cisplatin and pemetrexed is safe and — for a few — effective.

The only drawback was that most of the patients experienced cytokine release syndrome. The effect of cytokine release syndrome is that it makes you feel super lousy.

Happily, it’s relieved by taking antihistamines, corticosteroids or acetaminophen.