“If you think of the immune system like a bicycle, there are two broad ways of regulating the bike’s speed: pedaling and braking. To go faster, you can either pedal harder or release the brakes. In this case, we’ve attempted to stimulate the immune system both by pedaling faster, using the anti-CD40 antibody, and by cutting the brakes, using the anti-CTLA4 antibody,” said David L. Bajor, MD, an instructor in the Division of Hematology/Oncology at Perelman School of Medicine at the University of Pennsylvania.
“This novel combination of an immunostimulatory molecule and a checkpoint inhibitor was found to be safe. There was real concern that stimulating the immune system while ‘cutting the brakes’ with checkpoint inhibition could lead to increased incidence or severity of immune side effects. We did not see this,” said Bajor. “Secondarily, the clear clinical evidence of response to this combination, even in some patients with highly morbid visceral disease, was striking.”
In this phase I dose-escalation trial, Bajor and colleagues enrolled 24 patients with metastatic melanoma who had never received an anti-CD40 or anti-CTLA4 antibody before and tested four different dose levels of the combination. Patients received tremelimumab every 12 weeks and the anti-CD40 antibody every three weeks until progression, toxicity, or one year of treatment elapsed.
After a median follow-up of 22 months, the overall response rate (ORR) was 27 percent, which included complete responses in two patients and partial responses in four patients. The median progression-free survival (PFS) was 2.5 months and the median overall survival (OS) was 26.1 months.
The side effects were nonoverlapping and similar to those which had been seen when each of these agents was tested independently, according to Bajor.
To see whether there was a correlation between treatment outcomes and changes in the patients’ immune cells to which the two drugs were targeted, the investigators analyzed specific immune cells called CD8-positive T cells isolated from the patients’ blood and found increases in biomarkers that were indicative of immune activation.
“Immunotherapy is not just a single agent or class of agents; there are many targetable molecules to manipulate many facets of the immune responses against cancer. Checkpoint inhibition was just the beginning,” said Bajor. The investigators will next combine anti-CD40 with chemotherapy as a neoadjuvant treatment for pancreatic cancer and study new anti-CD40 compounds. “Our upcoming trials are designed to expand our understanding of CD40 biology and hopefully continue to broaden the spectrum of safe, effective treatments for patients.”
This study was funded by a Penn-Pfizer alliance grant and the National Cancer Institute. Bajor declares no conflicts of interest.
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