3 years ago

Older melanoma patients may respond better to anti‐PD1 immunotherapy

A study published in Clinical Cancer Research found that with each decade of life, the likelihood of melanoma progression after anti–programmed cell death 1 (anti‐PD1) immunotherapy treatment decreased by 13%.1

Researchers wanted to study how the aging microenvironment affected immunotherapy response, and they learned to their surprise that the effect was exactly the opposite of what they had found with targeted therapy according to Ashani Weeraratna, PhD, professor and coprogram leader of the Immunology, Microenvironment, and Metastasis Program at the Wistar Institute in Philadelphia, Pennsylvania.

Previously, Dr. Weeraratna and her colleagues had demonstrated that the tumor microenvironment in older patients actually promoted melanoma metastasis and resistance to targeted therapy with a BRAF inhibitor. Their current study, however, found the opposite effect in older patients after anti‐PD1 immunotherapy.

The multinational study involved data from 538 patients with melanoma treated with the anti‐PD1 therapy pembrolizumab (Keytruda). Among the patients, 238 were younger than 62 years. Researchers found that 50% of the patients younger than 62 years but only 37% of the patients 62 years old or older had a poor response to the treatment. The finding was independent of sex or prior treatment with mitogen‐activated protein kinase inhibitor (MAPKi) therapies.

In addition, the team conducted experiments using mice with melanoma to understand the relation between the aging microenvironment and the response to anti‐PD1 immunotherapy. Results from the mouse studies corresponded with those from human patients. These results were independent of the tumor mutational burden because both young and old mice were implanted with genetically identical tumors. In the mouse studies, researchers also found that the immune microenvironment differed between young and old mice. Specifically, a subpopulation of T cells known to be immunosuppressive, forkhead box P3 (FOXP3)–positive regulatory T cells, was smaller in older mice in comparison with younger ones.

Investigators also analyzed primary and metastatic melanoma samples from another cohort of 268 patients for the presence of the protein FOXP3 in T cells. They found that the FOXP3 positivity of intratumoral T cells decreased in patients older than 50 years. They also observed age‐related differences in T‐cell subpopulations within the patients’ tumors.

Dr. Weeraratna and her colleagues discovered that in young mice, combining anti‐PD1 therapy with an anti‐CD25 antibody therapy, which depletes regulatory T cells, led to response rates comparable to those observed in older mice. They concluded that when therapies are being designed for melanoma, age should be considered a factor in both preclinical and clinical models.

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