Close up of melanoma
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New research highlights the different mechanisms of action of two immunotherapy combination therapies for advanced melanoma. An anti-PD-1/LAG-3 drug combination required the presence of CD4 T cells for its anticancer effects, in both cutaneous melanoma and brain metastases melanoma, while the anti-PD-1/CTLA-4 combination did not.

“These observations are of particular interest in the context of melanoma brain metastases, where additional therapeutic strategies are urgently needed,” lead author Keiran Smalley, PhD, tells Inside Precision Medicine. Smalley is director of the Donald A. Adam Melanoma and Skin Cancer Center of Excellence at Moffitt.

The study appears in the Journal for ImmunoTherapy of Cancer.

Checkpoint inhibitors activate the immune system to target cancer cells for destruction. These drugs have revolutionized treatment of many cancers, leading to more options and improved survival. The market is estimated at approximately $34 billion already. However, in advanced melanoma, “Only approximately 40% of patients respond upfront to anti PD-1 therapy, acquired resistance then occurs in approximately 25% of initial responders,” Smalley says.

“Acquired resistance is complex,” he adds. “It can involve loss of immune recognition of the tumor (loss of MHC expression), inhibitory growth factors/cytokines and immune exclusion programs. Other factors can involve metabolic changes in the tumor microenvironment and the accumulation of inhibitory immune cells (e.g. regulatory T cells and myeloid-derived suppressor cells).”

The checkpoint treatments approved for advanced melanoma include PD-1 and PD-L1 inhibitors. More recently, results from clinical trials revealed that these drugs work better in combination with other immune checkpoint inhibitors that target the proteins CTLA-4 or LAG-3. That realization led to the approval of the combination of CTLA-4 inhibitor ipilimumab and PD-1 inhibitor nivolumab (Opdivo), as well as LAG-3 inhibitor relatlimab and nivolumab.

While anti-PD-1/CTLA-4 and anti-PD-1/LAG-3 therapies work in generally similar ways to stimulate the immune system, CTLA-4 and LAG-3 have different cell expression patterns, binding partners, and signaling activity.

The Moffitt researchers wanted to analyze the mechanisms of action of anti-PD-1/CTLA-4 and anti-PD-1/LAG-3 treatments in advanced melanoma and identify the specific subtypes of immune cells that become activated.

The primary mediators of the anticancer effects of immune checkpoint inhibitors are T cells, which include CD8 T cells that kill infected cells or tumor cells and CD4 T cells, which coordinate immune responses between CD8 T cells and other immune cell.

The researchers used single cell RNA-seq, flow cytometry, and IHC analysis to study the mechanism of action of the anti-PD-1+LAG-3 and the anti-PD-1+CTLA-4 combinations. They discovered that the two combinations have different mechanisms of action mediated through different effects on CD4 T cells.

Most research to date, they wrote, has focused on the importance of CD8 T-cell activity to immune checkpoint inhibitor anticancer effects. But this team’s combined observations support the growing evidence that CD4 helper T cells also play an important role in the effects of immune checkpoint inhibitors. These data reveal the key differences that can be used to optimize outcomes for patients with melanoma, particularly among patients who develop drug resistance.

There are plenty of questions left to answer.

“Possible future strategies could include adding additional checkpoint inhibitors to boost CD8+ T cell activity and approaches to limit the accumulation of inhibitory immune cells in the tumor microenvironment,” says Smalley.

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