Biopsy immune analysis during immunotherapy may predict response in melanoma patients

By Liz Meszaros, MDLinx
Published August 11, 2016

Key Takeaways

During early treatment—but not before—immune responses measured in tumor biopsies may allow researchers a glimpse at which melanoma patients will benefit from therapy with immune checkpoint blockade inhibitors, according to researchers from The University of Texas MD Anderson Cancer Center, who published their results in Cancer Discovery.

For this study, part of MD Anderson’s Cancer Moon Shots Program, researchers included 53 metastatic melanoma patients initially treated with cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) blockade, followed by programmed death-1 (PD-1) blockade at progression in 46 patients.

In all, 13% of patients had a clinical benefit, which they defined as the absence of disease, tumor shrinkage, or stable disease for at least 6 months.

At numerous times during therapy, researchers collected longitudinal tissue samples, in which they analyzed immune signatures. Before treatment, there were no differences in immune biomarkers between patients who responded and those who did not. After treatment initiation, however, researchers found significantly higher levels of killer T cells within the tumors of patients who responded.

“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,” said senior author Jennifer Wargo, MD, associate professor, genomic medicine, surgical oncology, University of Texas MD Anderson Cancer Center, Houston, TX.

Among the 46 patients who continued on to treatment with pembrolizumab, a PD-1 inhibitor, 28% responded. In these patients, researchers found higher pre-treatment levels of three immune markers in responders compared with non-responders, as well as significant differences in the levels of 12 immune markers—including killer CD8 T cells, CD4 helper T cells, CD3 T cells, PD-1, PD-L1, and LAG-3—between responders versus non-responders.

Upon analysis of the gene expression panel, significant differences were also seen in 411 differentially expressed genes in responders, but these differed only in the on-treatment biopsy for anti-PD1. The majority of these differences centered around the increased expression of genes involved in immune responses in responders.

These results may inform future approaches to treatment, and lead to a better understanding of why certain melanoma patients respond to treatment while others do not.

“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,” Dr. Wargo noted.

“These studies demonstrate that adaptive immune signatures in early on-treatment tumor biopsies are predictive of response to checkpoint blockade and yield insight into mechanisms of therapeutic resistance. These concepts have far-reaching implications in this age of precision medicine and should be explored in immune checkpoint blockade treatment across cancer types,” the authors concluded.

This research was funded by grants from the National Cancer Institute of the National Institutes of Health; Melanoma Research Alliance Team Science Award; the Kennedy Memorial Foundation; STARS award of the University of Texas System Board of Regents; the Cancer Prevention and Research Institute of Texas; Conquer Cancer Foundation ASCO Young Investigator Award, the Robert Welch Distinguished University Chair and philanthropic contributions to MD Anderson’s Melanoma Moon Shot. Research also was provided by Merck, Bristol-Myers Squibb, GlaxoSmithKline, MedImmune and Novartis/Array.

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