Immunotherapy Combination Elicit Waves of Response in Advanced Melanoma

An algorithm has helped researchers determine a combination of immunotherapy that may work best for patients with advanced melanoma.

Cyclone, an algorithm developed to track immune responses and patterns over time among patients with cancer by tracking receptors of individual T cells, has found that new immune cells are enlisted to fight advanced melanoma with every infusion of a pair of checkpoint inhibitor therapies, researchers have announced.

Cyclone was developed by researchers at the University of Pennsylvania Perelman School of Medicine and Penn Medicine’s Abramson Cancer Center, who published their findings in Cancer Cell, according to a news release from the University of Pennsylvania.

Researchers used Cyclone to track the impact of the combination of PD-1 and CTLA-4 checkpoint inhibitors. According to The University of Texas MD Anderson Cancer Center in Houston, immune checkpoint inhibitors are a type of immunotherapy that stops a patient’s immune system from being turned off before cancer is completely eliminated.

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Analyzing the data of 36 patients who were treated with the immune checkpoint inhibitor combination for advanced melanoma, researchers found that each dose of the combination treatment produced a clonal response, or a new wave of T cells.

“We found that after every infusion, you have a new immune response, with a new group of T cells coming in to fight the cancer,” stated senior author Dr. Alexander Huang, an assistant professor of Hematology-Oncology and a research investigator with the Tara Miller Melanoma Center at the Abramson Cancer Center, in the news release. “Think about these T cells like an army: for many cancer patients, even when they have tumors growing, experienced T cell fighters are trying to slow down the advance of the enemy cancer cells. We call them ‘exhausted T cells’ because they’ve been fighting so long, but they’re elite because they’re able to survive in a hostile environment and know how to recognize and fight the cancer cells.”

The source of the “exhausted T cells,” according to the news release, are cells known as progenitor cells. While anti-PD-1 immunotherapy eventually depletes this supply of immune cells, anti-CTLA-4 therapy replenishes the supply of progenitor-exhausted T cells, as explained in the news release.

Researchers used Cyclone to track patients’ immune responses by examining blood samples taken at various points during a nine-week treatment course.

“Checkpoint blockade induces waves of clonal T cell responses that peak at distinct time points,” researchers stated in a summary of their findings in Cancer Cell, noting that combination therapy resulted in greater magnitude of clonal responses after both six and nine weeks of treatment when compared to treatment with single-agent therapies.

Cyclone, according to the news release, is planned to be applied in upcoming clinical trials for new approaches to cancer treatment with immunotherapy, according to the news release.

“We envision that this more precise method of immune monitoring could be applied to clinical trials in several ways,” Huang said in the news release. “For example, it could help researchers better understand how new drugs are impacting the immune system or understand the appropriate dosage needed to produce the necessary biological effect, without having to push to find the ‘maximum tolerated dose’ and potentially expose patients to unnecessary toxicity.”

“These next-generation immune profiling approaches,” researchers wrote in Cancer Cell, “can guide the selection of drugs, schedule and dosing for novel combination strategies.”

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