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Differences in Anti-PD-1/CTLA-4 and Anti-PD-1/LAG-3 Reported in Recent Study


The study examined the mechanisms of action associated with immune checkpoint inhibitor combination therapies.

WavebreakmediaMicro/Adobe Stock
WavebreakmediaMicro/Adobe Stock

New research published in the Journal for ImmunoTherapy of Cancer reveals differences in the mechanisms of action of 2 FDA-approved immune checkpoint inhibitor combination therapies for advanced melanoma. In patients with advanced melanoma, checkpoint inhibitors that activate the immune system to target cancer cells for destruction have led to more options for patients and improved survival; however, according to the study authors, the anticancer effects of immune checkpoint inhibitor regimens that treat melanoma are still somewhat unknown despite the FDA approvals.

Including drugs that target the proteins programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1), multiple types of immune checkpoint inhibitors have been approved to treat advanced melanoma. In addition, results from clinical trials demonstrated that in combination with other immune checkpoint inhibitors that target the proteins CTLA-4 or LAG-3, PD-1/PD-L1 inhibitors result in better patient outcomes than when used alone, leading to their approvals to treat advanced melanoma. Further, anti-PD-1/CTLA-4 and anti-PD-1/LAG-3 therapies work in similar ways to stimulate the immune system, but mechanistic differences are likely due to the different cell expression patterns, binding partners, and signaling activity between CTLA-4 and LAG-3.

The study examined the mechanisms of action of anti-PD-1/CTLA-4 and anti-PD-1/LAG-3 treatments in advanced melanoma and identified the subtypes of immune cells that become activated during treatment. The immune system is made up of different types of immune cells that work in collaboration to promote and inhibit immune responses: the primary mediators of the anticancer effects of immune checkpoint inhibitors are T cells, including CD8 cells (cytotoxic T cells that kill tumor or infected cells), CD4 cells (helper T cells that coordinate immune responses between CD8 T cells and other immune cells), and regulatory cells called Tregs (cells that can suppress immune responses).

Using mouse models of melanoma and melanoma brain metastases, the study authors identified the exact immune cells that become activated during treatment and discovered that the 2 immune checkpoint inhibitors combination regimens have different mechanisms of action mediated through different effects on CD4 T cells.

The investigators found that the anti-PD-1/LAG-3 drug combination needed the presence of CD4 T-cells for its anticancer effects in both cutaneous melanoma and brain metastases melanoma, whereas the anti-PD-1/CTLA-4 combination did not require their presence. Further, the anti-PD-1/LAG-3 regimen decreased Treg cell activity and increased CD4 helper T cell activity that led to CD8 T-cell activation, whereas the anti-PD-1/CTLA-4 regimen resulted in the accumulation and the direct activation of more cytotoxic CD8 T cells.

“Many patients exhibit upfront or acquired resistance to standard of care anti-PD-1 or the anti-PD-1+CTLA-4 combination, suggesting there could still be responses to a second line immune checkpoint inhibitor therapy with a different mechanism of action. These observations are of particular interest in the context of melanoma brain metastases, where additional therapeutic strategies are urgently needed,” said study author Keiran Smalley, PhD, director of the Donald A. Adam Melanoma and Skin Cancer Center of Excellence at Moffitt, in a press release.

Although most research has focused on the significance of CD8 T cell activity to immune checkpoint inhibitor anticancer effects, the current study’s observations support the evidence that CD4 helper T cells also have an important influence on the effects of immune checkpoint inhibitors. According to the study authors, these data show the key differences that can be used to further optimize outcomes for patients with melanoma, most notably for those who develop drug resistance.


H. Lee Moffitt Cancer Center & Research Institute. Moffitt researchers identify key mechanisms of action differences in 2 immune checkpoint inhibitor combination therapies for advanced melanoma. News release. December 6, 2023. Accessed December 13, 2023. https://www.eurekalert.org/news-releases/1010331

[This article was originally published by our sister publication, Pharmacy Times.]

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