A single-arm phase 2 clinical trial conducted by researchers from the University of Pittsburgh, UPMC Hillman Cancer Center and the National Cancer Institute (NCI), tested a new treatment approach for high-risk, resectable melanoma. The trial measured proteins with tests developed by the NCI Clinical Proteomic Tumor Analysis Consortium (CPTAC). The results suggest that combining the drugs vidutolimod and nivolumab (vidu/nivo) could be a promising neoadjuvant treatment option for these patients. Recently published in Cancer Cell, this study reports an enhanced anti-tumor immune response in patients treated with vidu/nivo and describes a number of biomarkers which could be used to measure immunotherapy response in the clinic.
The trial demonstrated a 55% major pathologic response (MPR) rate among patients treated with the vidu/nivo combination and patients who achieved MPR showed higher rates of recurrence-free survival and metastasis-free survival at two years. Patients who responded positively exhibited markers related to macrophage activation, phagocytosis, and tertiary lymphoid structure (TLS) formation within the tumor microenvironment. Gene expression signatures in responders also indicated immune activation, including plasmacytoid dendritic cells (pDCs), phagocytic activity, and macrophage involvement.
Mass spectrometry-based assays developed by study co-author Dr. Amanda Paulovich’s CLIA Laboratory at the Fred Hutchinson Cancer Center, a member of the Clinical Proteomic Tumor Analysis Consortium (CPTAC), were used to measure the results of TLR9 agonist administration in pre-treatment plasma samples. Researchers were able to confirm that TLR9 agonist vidutolimod administration resulted in increases in proteins associated with interferon activity (STAT1, IFIT1, IFIT3, and CXCL10) and lymphocyte activation (CD48), irrespective of response.
“These data suggest the TLR9 administration results in quantifiable changes in key proteins directly linked to the theorized mechanism of action of this class of drug, potentially constituting a pharmacodynamic biomarker of TLR9 activity,” said first and corresponding author Diwakar Davar, M.D.
“The mass spectrometry-based assays provided robust multiplexed protein quantification that can serve to monitor response and potentially identify those patients that would most benefit from the combined therapy,” said co-author Dr. Jeff Whiteaker, Senior Staff Scientist in the Paulovich laboratory.
The study also found that vidutolimod can directly activate pDCs and myeloid cells within the tumor microenvironment. This was verified through spatial and transcriptomic analyses and suggests significant therapeutic value, as these cells produce type I interferons and other immune-activating molecules that play a crucial role in enhancing anti-tumor responses.
Additionally, researchers were able to identify distinct gut microbiome features in patients who responded well to vidu/nivo. Gut microbiome profiles that are typically associated with anti-PD-1 monotherapy feature an abundance of certain Gram-positive bacteria. In contrast, the microbiomes of patients responding to vidu/nivo were enriched in Gram-negative bacteria, including species from the Bacteroidaceae and Enterobacteriaceae families. This observation suggests that the gut microbiome could serve as a valuable biomarker for melanoma and highlights the complex interaction between microbiota and the immune system in cancer patients.
In a press release for the University of Pittsburgh, co-senior author Hassane Zarour, M.D commented, “Our data suggest that the mechanisms by which the gut microbiome modulates responses to cancer immunotherapy may differ depending on the specific therapy… such novel findings highlight the complexity and context-dependency of the gut microbiome’s effects in cancer immunotherapy and have prompted ongoing studies to confirm this observation.”