On-treatment Biomarkers Predict Immune Checkpoint Blockade Responses in Melanoma

August 17, 2016

Immune response markers from on-treatment-but not pretreatment-melanoma biopsies predict responses to immune checkpoint blockade.

Immune response markers from on-treatment-but not pretreatment-melanoma biopsies predict responses to immune checkpoint blockade, according to a preliminary longitudinal study, published in Cancer Discovery.

“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,” said senior study author Jennifer Wargo, MD, an associate professor of Genomic Medicine and Surgical Oncology at MD Anderson Cancer Center, Houston, in a press release.

“On treatment, there were night-and-day differences between responders and non-responders,” Dr. Wargo said. The numbers of killer T cells were significantly higher in tumors that later responded to immune checkpoint blockade, for example.

Analysis of tumor samples early in immune checkpoint blockade treatment might be more informative than those using pretreatment biopsies, her team concluded.

More research is needed, but if the findings are confirmed, then such analyses might allow early detection of patients who will not benefit from therapy, and who should not be subjected to potential treatment toxicities.

“Overall, these data suggest that assessment of adaptive immune responses via early on-treatment biopsies should be considered as well as, or in place of, pretreatment biopsies to predict patients who will respond to anti-PD-1 treatment,” wrote Michele WL Teng, MD, Rajiv Khanna, and Mark Smyth of the QIMR Berghofer Medical Research Institute in Queensland, Australia, in a commentary published alongside the study in Cancer Discovery.

The study included a cohort of 53 patients with metastatic melanoma who underwent cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) blockade with ipilimumab (Yervoy, Bristol-Myers Squibb) and 46 patients who were subsequently administered pembrolizumab (Keytruda, Merck), a programmed death-1 (PD-1) blockade therapy, after tumor progression.

Significant differences were reported between PD-1 blockade responders and nonresponders for several immune markers measured from early on-treatment biopsies, including CD8, CD3, and CD4-helper T-cell densities within tumors. The presence of PD-1, PD-ligand 1 (PD-L1) and Lymphocyte Activation Gene-3 (LAG-3) protein also predicted tumor responses to checkpoint blockade.

“Importantly, these changes were observed as early as 2 to 3 doses following initiation of anti-PD-1 therapy,” Dr. Teng and coauthors noted. “Similarly, analysis of early on-treatment tumor biopsies identified a significantly higher density of CD8+ T cells in responders versus nonresponders to CTLA4 blockade, though the sample sizes were very small (n=2 for responders vs n=3 for nonresponders).”

The study also offered gene expression data that might yield new insights into gene pathway mechanisms of tumor resistance to immune checkpoint therapy, identifying more than 400 genes that were differentially expressed in treatment-responsive tumors.

In most cases, immune response-associated genes were upregulated in responsive tumors; another six genes were downregulated in responders, including the vascular endothelial growth factor (VEGFA) gene, which is involved in tumors’ recruitment of new blood vessels. The authors are now analyzing tumor-genome correlations with altered interferon signaling and antigen processing and presentation, which might be involved in tumors’ PD-1 blockade resistance.

The study was part of MD Anderson’s Melanoma Moon Shot program, which employs serial biopsies and molecular analyses to study treatment responses.