A team of scientists from the United Kingdom and the United States has discovered that the activity of macrophages may prove to be useful in predicting whether or not a patient with melanoma will respond to immunotherapy. Their findings, published in JCO Oncology Advances, may help clinicians to select treatments that are most likely to be effective for their patients.
Researchers from the Universities of Bath (United Kingdom) and Stanford University (California), have examined novel biomarkers that may identify patients with melanoma more likely to respond to the immunotherapy known as T-VEC (talimogene laherparepvec). This modified oncolytic virus is injected into melanoma directly to stimulate an immune response. Although it previously has been used in advanced melanoma, this study is reportedly the first to examine its potential to treat high-risk stage II melanoma in the upfront setting.
It was conventionally thought that T-VEC worked by activating T cells. However, the team found that preexisting and posttreatment T-cell populations did not have association with treatment responses. Instead, they found that changes in the macrophages seemed to correlate to which patients responded to the treatment and which did not.
Additionally, previous research has monitored the amounts of protein indicators such as PD-L1 and at the genes involved in T cells to assess whether immunotherapy is effective. However, this latest study showed these techniques did not accurately predict which patients would respond to treatment.
Key Findings
In their study, the researchers used a method called iFRET (immune time-resolved Förster resonance energy transfer), which monitors protein activation instead of simply measuring the amounts of protein present. They found that T-cell presence showed no consistent trends to viral stimulation or tumor response before and after treatment. However, there was a heavy infiltration of macrophages after treatment in responding patients, associated with activation across immune checkpoint regulators.
The researchers plan to use the findings to develop clinically predictive tests of which patients will respond to the therapy. This may enable clinicians to tailor a personalized treatment and potentially reduce the use of costly treatments that do not work.
Professor Banafshé Larijani, PhD, of the Department of Life Sciences and Director of the Centre for Therapeutic Innovation at the University of Bath, co-led the study. She shared these comments: “We know that people respond to immunotherapy very differently; in some cases, the tumors shrink, and in others, sadly the patients do not survive. Our findings show that it’s not enough to simply look at T-cell activity; instead, it’s imperative to look at the whole immune response environment in detail to predict how a patient will respond to different treatments.”
Prof. Larijani continued: “Our results suggest that, in nonresponding patients, we should be targeting these macrophages to reprogram the tumor immune environment. We hope our research will enable clinicians to make important decisions over which patients would be better served by surgery or immune checkpoint blockade by immunotherapy.”
Amanda R. Kirane, MD, PhD, Director of Cutaneous Surgical Oncology Department at Stanford University School of Medicine, who led the clinical part of the study, commented: “This study is highly informative in establishing a connection between preexisting innate immune functions and ability to respond to immune-stimulating drugs. It extends new and important context to the disconnect between measuring PD-L1 protein values as a clinical biomarker and protein activity in the tumor. The added information of iFRET-based immune activity measurements may offer the critical missing link of why current biomarkers have failed to yield a usable test to aid patients in treatment decision-making.”
Disclosure: For full disclosures of the study authors, visit ascopubs.org.
