Immune Analysis of Biopsies Predicts Response to Melanoma Immunotherapy

Immune response measured in tumor biopsies during the course of early treatment predicts which melanoma patients will benefit from specific immune checkpoint blockade drugs.

Immune checkpoint blockade represents a major breakthrough in cancer therapy; however, responses are not universal. Genomic and immune features in pretreatment tumor biopsies have been reported to correlate with response in patients with melanoma and other cancers, but robust biomarkers have not been identified.


A large team of scientists at The University of Texas MD Anderson Cancer Center (Houston, TX, USA) 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 programmed death-1 (PD-1) and PD-L1, the ligand found on tumor and other cells that activates PD-1. They studied a cohort of 53 patients with metastatic melanoma initially treated with cytotoxic T-lymphocyte–associated antigen-4 (CTLA4) blockade followed by 46 patients treated with PD-1 blockade at progression and analyzed immune signatures in longitudinal tissue samples collected at multiple time points during therapy.

Patients were treated with the CTLA-4 inhibitor ipilimumab followed by biopsies, when feasible, after the second or third treatment and at progression. Seven (13%) of 53 patients had a clinical benefit, defined as either absence of disease, tumor shrinkage or stable disease for at least six months. There were no immune biomarker differences between responders and non-responders 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 pembroluzimab and 13 (28%) of the 46 responded. Before treatment, three immune markers were slightly elevated in responders compared to non-responders, but values overlapped the two groups.

As with the immune profiling, the gene expression panel turned up significant differences between responders and non-responders only at the on-treatment biopsy for anti-PD1. 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 the vascular endothelial growth factor (VEGFA), which is involved in the generation of new blood vessels, or angiogenesis.

Jennifer A. Wargo, MD, an associate professor of Genomic Medicine and Surgical Oncology and the senior author of the study, said, “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 non-responders. Therefore we could start by treating with anti-PD1, do an early on-treatment biopsy and, based on that, either continue or add ipilimumab or another agent.” The study was published on August 1, 2016, in the journal Cancer Discovery.

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University of Texas MD Anderson Cancer Center