Older melanoma patients respond better to anti-PD1 therapy than younger patients

According to a study published in Clinical Cancer Research, older patients with melanoma responded more efficiently to pembrolizumab, an anti-programmed-death-receptor-1 (PD-1) antibody, when compared with younger patients. This may be due to age-related differences in regulatory T cells (Treg) and CD8+ T cells.

Multiple factors—including differences in immune function—are responsible for the increased incidence of most cancers, such as melanoma, in older people.

The study, led by Curtis H. Kugel III, from the Wistar Institute in Philadelphia, PA, analyzed melanoma patients treated with pembrolizumab to determine the role of age-mediated differences in intra-tumor immune populations in patient response to immunotherapy.

Tissue samples were collected from 538 melanoma patients treated with pembrolizumab from centers in the US, Australia, and Germany. A total of 238 patients were under the age of 62; 300 patients were 62 years of age or older.

Results showed a significant difference in response to pembrolizumab by age. The odds of progressing during therapy decreased 13% for every decade of patient age at initiation of treatment. The results were not dependent on sex or prior treatment with targeted therapies.

The investigators confirmed the observation in mouse models of melanoma. In mice transplanted with genetically identical tumors, treatment with anti-PD1 had a significant benefit in controlling tumor growth in older mice, but had no effect in younger mice.

Both patient-derived tissues and mouse models revealed a significant decrease in tumor infiltration of Treg cells with age, which skewed the CD8+:Treg ratio.

Based on these observations, the researchers depleted Treg cells in young mice model by targeting them with an antibody against CD25, which is predominantly expressed at high levels on Treg cells. Combining anti-PD1 and anti-CD25 treatment was significantly more effective than anti-PD1 alone. The young mice had response rates similar to the older mice and the combination was not toxic (ie, there was no change in body weight or distress in the mice).

The authors acknowledge that the study had some limitations. Performing a meta-analysis was not possible because there are no clinical trials with the same parameters. In addition, investigators did not know possible confounders so a multivariate analyses could not be performed.

“These data reveal the unexpected finding that older patients fare better on anti-PD1, and suggest that treating refractory patients with antibodies that deplete Tregs may increase their chance of response to anti-PD1,” the authors concluded.

In an editorial accompanying the study, Graham Pawelec, PhD, University Hospital Tuebingen, Germany, suggested that the results of the study “provide evidence that not only should clinicians not hesitate to treat older melanoma patients with anti-PD1 antibodies, but that such patients might even experience greater benefit than younger patients, and no worse side effects.”

To read more about this study, click here.