Patient age appears to correlate with response to immunotherapy for melanoma, and depleting regulatory T cells in younger patients may potentially be a method of improving treatment response in younger patients, according to a paper published online ahead of print in Clinical Cancer Research (June 13, 2018).
Prior research from the authors had shown that older patients were at higher risk of melanoma metastasis, and that targeted therapies were less effective in this population.
“We have shown that the characteristics of the aged tumor microenvironment in older patients promote resistance to melanoma targeted therapies, highlighting the importance of considering patient age when predicting response to therapy,” said corresponding author Ashani Weeraratna, Ph.D., in a press release. Dr. Weeraratna is the Ira Brind Professor and co-program leader of the immunology, microenvironment and metastasis program at the Wistar Institute in Philadelphia.
These findings led Dr. Weeraratna and colleagues to investigate the impact of age on response to immunotherapy. “We were initially surprised to find that older patients fare better on immune checkpoint blockade therapy,” she said.
The researchers analyzed a multi-national, multi-institutional cohort of almost 500 melanoma patients who were treated with pembrolizumab, an anti-programmed cell death receptor-1 (PD1) checkpoint therapy. A significant difference in response to this treatment by age was observed. In particular, older patients had a decreased chance of disease progression after therapy, irrespective of gender and prior treatment with targeted therapies.
Investigators then confirmed the observation in mouse models of melanoma. They found that genetically identical tumours responded more to anti-PD1 treatment when transplanted in old mice than they did in young mice, which the authors say suggests that the difference in response can be attributed to the environment in which the tumour develops.
In both the human and animal models, the researchers found a significant decrease in tumor infiltration of regulatory T cells (Treg) with age. Treg cells suppress the anti-tumor immune response and reduce response to anticancer immunotherapy.
Older age also correlated with increased presence of killer CD8 T cells, which are the primary cells involved in the response to immune checkpoint blockade therapy.
Based on these observations, the researchers depleted Treg cells in the young mouse model by targeting them with an antibody against the protein CD25, which is predominantly expressed at high levels on Treg cells. They found that combining anti-PD1 and anti-CD25 treatment was significantly more effective than anti-PD1 therapy alone, and they obtained response rates similar to those seen in aged mice. These findings suggest that overcoming the immune suppression observed in the young microenvironment helps to restore sensitivity to immunotherapy.
“Our study shows that age is an important factor to consider when administering immunotherapy to melanoma patients,” said Dr. Weeraratna. “A combination approach to deplete immune suppressive cells in combination with checkpoint blockade therapy might benefit younger patients, although further studies will be required to evaluate more broadly the potential immune toxicities in this approach.”