This article is more than 5 years old. Information may no longer be current.
Patient age influences response to immunotherapy for melanoma
Click Here to Manage Email Alerts
Age should be a consideration when predicting response to immunotherapy for melanoma, according to study results published in Clinical Cancer Research.
Patients aged older than 60 years responded more efficiently to immunotherapy, even in the absence of an involved mutational landscape.
Ashani Weeraratna, PhD, Ira Brind professor and co-program leader of the immunology, microenvironment and metastasis Program at The Wistar Institute, and colleagues assessed the association between age and immunotherapy response among 538 patients with melanoma treated with the anti-PD1 therapy pembrolizumab (Keytruda, Merck).
The likelihood for progression after treatment decreased by 13% with each increasing decade of life.
“Our study shows that age is an important factor to consider when administering immunotherapy to [patients with melanoma],” Weeraratna said in a press release. “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 of this approach.”
HemOnc Today spoke with Weeraratna about the study, the possible explanations for the results, and the clinical implications of the findings.
Question: How did this study come about?
Answer: This study stemmed from work we previously published in 2016 in Nature, in which we showed that the aging microenvironment promotes metastatic progression. When we approached this study, we showed that melanomas in older patients are more resistant to targeted therapy. We then thought about older patients and how they respond to immunotherapy. We thought older patients would respond less to immunotherapy, just as they did with targeted therapy. However, this was not the case.
Q: How did you conduct the study?
A: The first thing we did was gather data from various medical institutions from across the world. Our data came from Australia, Germany, the United Kingdom and across the United States. We took the pooled patient data and asked how well patients responded to immunotherapy and how old they were at diagnosis. We then sought to understand the mechanistic changes that underlined our observation with a confirmatory aspect in younger-aged mice to see if they would respond differently.
Q: What did you find?
A: Contrary to our initial expectation, older patients fared significantly better on immunotherapy than younger patients. In the mice aspect of our study, it was quite striking that the T-regulatory population was increased in young animals but not in the older animals. We wondered if this was true in humans, so we went back to the human data and gathered about 200 samples and stained them for the T-regulatory marker of that population of immune cells, and we found that the T-regulatory cells were much higher among young human patients.
Q: What are the possible explanations for this finding?
A: It is not really clear, but it could be due to the fact that as children and young adults, we are constantly being exposed to new things. If a person did not have some way to regulate this, the immune system would be constantly in overdrive. As we age, our immune system has been exposed to a lot of the things that it is going to be exposed to already, so it will not react as much and we, therefore, do not have to regulate it as intensely. We think this is why the T-regulatory cells decrease in the older population. Having said this, older adults do have chronic inflammation. In some organs, it has been shown during aging that there is an increase in T-regulatory cells, but intratumorally it appears as though this is not happening. Some of our new work shows that the T-regulatory cells have a harder time getting to the tumor microenvironment from their source.
Q: What are the potential implications of the findings?
A: Younger patients may require additional therapies to overcome their ability to regulate the immune response as efficiently as they do. However, one must be extremely cautious about toxicity.
Q: What will subsequent research on this topic address?
A: Although this particular study is exciting in terms of being able to deplete T-regulatory cells using an antibody, we do not know what kind of toxicity this will have in humans, so this needs to be carefully addressed before we can move forward. Second, we need to assess why the immune microenvironment is so different between young and old patients. We had plans to initiate a clinical trial, but the drug that we were going to use was pulled off the market due to brain toxicity. So, we are now looking at another 2 to 5 years for a clinical trial to be initiated.
Q: Is there anything else that you would like to mention?
A: This study is an example of what can be achieved through global collaborations, and through collaboration between clinicians and basic scientists. Our lab-based findings were borne out by the observations of our clinical colleagues across the country, and across the world. – by Jennifer Southall
References:
Kaur A, et al. Nature. 2016;doi:10.1038/nature17392.
Kugel CH III, et al. Clin Cancer Res. 2018;doi:10.1158/1078-0432.CCR-18-1116.
For more information:
Ashani Weeraratna, PhD, can be reached at The Wistar Institute, 3601 Spruce St., Philadelphia, PA 19104; email: aweeraratna@wistar.org.
Disclosure: Weeraratna reports no relevant financial disclosures. The study was supported by NIH grants, as well as a Cancer Institute NSW Fellowship, a Melanoma Research Alliance/L’Oreal Paris-USA Women in Science Team Science Award, and an Established Investigator Award from Melanoma Research Foundation.
Editor’s Note: On Oct. 5, we corrected Weeraratna’s title to Ira Brind professor. The Editors regret this error.