Immune response measured in tumor biopsies during the course of early treatment predicts which melanoma patients will benefit from specific immune checkpoint blockade drugs, researchers at The University of Texas MD Anderson Cancer Center found in a report published by Chen et al in Cancer Discovery.1
Analysis of biopsies before treatment did not indicate who would respond in this unique longitudinal study of 53 melanoma patients treated with two immune checkpoint inhibitors between October 2011 and March 2015.
Jennifer Wargo, MD
“Before treatment, analyzing samples with a 12-marker immune panel or a 795-gene–expression panel, you can’t tell who will respond with any degree of certainty. On treatment, there were night-and-day differences between responders and nonresponders,” said senior author Jennifer Wargo, MD, Associate Professor of Genomic Medicine and Surgical Oncology.
Their findings, if confirmed in larger studies, could help guide treatment with drugs that block PD-1 (programmed cell death protein 1) and CTLA-4 (cytotoxic T-lymphocyte antigen 4). Identifying biomarkers to help determine who should receive these drugs has been the subject of much research, but the team noted that biomarkers have not strongly or exclusively predicted response.
Their research suggests that assessment of adaptive immune responses should be considered in early on-treatment biopsies after initiating therapy, Dr. Wargo said, and may provide far more value than analysis of pretreatment samples, at least until better pretreatment biomarkers are identified.
Serial Biopsies Performed
The researchers assembled a cohort of longitudinal tumor samples from patients and analyzed each biopsy for gene expression and the presence of certain types of T cell and protein markers such as expression of PD-1 and PD-L1 (programmed cell death ligand 1).
Patients were treated with the CTLA-4 inhibitor ipilimumab (Yervoy). Biopsies followed, when feasible, after the second or third treatment and at disease progression. Of 53 patients, 7 (13%) had a clinical benefit, defined as absence of disease, tumor shrinkage, or stable disease for at least 6 months. There were no immune biomarker differences between responders and nonresponders before treatment. After treatment began, the presence of killer T cells was significantly higher in the tumors of responders.
The remaining 46 patients proceeded to treatment with the PD-1 inhibitor pembrolizumab (Keytruda). Of them, 13 (28%) responded. Before treatment, three immune markers were slightly elevated in responders compared to nonresponders, but values overlapped the two groups. “Profound and highly statistically significant” differences between responders and nonresponders were found in nearly all of the 12 immune markers in the early anti–PD-1 on-treatment biopsies. .
The team’s findings have implications for treatment and further research to understand how melanoma responds to or resists treatment. “We could start by treating with anti–PD-1, do an early on-treatment biopsy and, based on that, either continue or add ipilimumab or another agent,” Dr. Wargo said. Such a strategy has the potential to more accurately apply these drugs to patients who will benefit and avoid the cost and potential side effects for those who won’t.
Gene Profiling Identifies Resistance Mechanisms
The gene-expression panel turned up significant differences between responders and nonresponders only at the on-treatment biopsy for anti–PD-1. Significant differences were found in 411 differentially expressed genes in responders.
Most differences involved increased expression in the responding patients of genes involved in immune response. Only six genes were lower in responders, including vascular endothelial growth factor (VEGF). This suggests a targetable mechanism for resistance to treatment, Dr. Wargo said. Anti–PD-1 therapy is being tested with VEGF inhibitors in clinical trials now.
Potential mechanisms of therapeutic resistance to PD-1–based therapy were also identified through defects in interferon signaling and altered antigen processing and presentation. ■