A new UCLA-led study revealed molecular biomarkers in the blood and tumors of patients with oral-cavity cancer could indicate how likely someone is to respond or not to immunotherapy before surgery — neoadjuvant anti-PD-1 therapy — to remove the tumor. The study also tracked how the cancer has evolved when some patients relapse after treatment.
The research, published online in Cell Reports Medicine, is one of two papers highlighting a collaborative effort between the UCLA Jonsson Comprehensive Cancer Center, MUSC Hollings Cancer Center and Winship Cancer Institute of Emory University, and looks at the clinical benefits and underlying biologic basis of neoadjuvant anti-PD-1 therapy for patients with locally invasive oral-cavity cancer.
“The study opens a new way to help improve precision management of patients with resectable oral-cavity squamous cell carcinoma, a subset of mostly HPV-negative head and neck cancers that tend to have a far worse prognosis compared to HPV-positive head and neck cancers,” said senior author Roger Lo, MD, PhD, a professor of medicine at the David Geffen School of Medicine at UCLA and member of the UCLA Jonsson Comprehensive Cancer Center. “If we can intervene with immunotherapy earlier in the natural history before surgery and when the disease is still amenable to surgery, then we have a chance of improving survival or the prognosis of this disease.”
Head and neck squamous cell carcinoma tend to be highly invasive and are often resistant to therapies. Researchers have looked to anti-PD1 immune checkpoint inhibitors to improve outcomes. This type of immunotherapy has revolutionized the way patients with advanced malignancies are treated, and findings from the co-publications indicate that about one-third of patients with oral-cavity cancer treated in a trial with the anti-PD-1 agent nivolumab before surgery displayed tumor response, indicating the agent might improve their survival.
“Because anti-PD-1 is a therapy that re-energizes the patients’ tumor-killing immune or T cells, it is thought that deploying this therapy may work better before surgery, when most of the tumor cells are still there,” Lo said. “After surgery, the T cells that protect the patients from residual tumor cells may thereby persist in the circulation or body to protect the patient.”
To explore the mechanisms of response patterns, survival, and post-operative recurrence, the researchers analyzed blood and tumor tissue of 12 patients who were enrolled in a single-arm, phase II clinical trial that looked at the effectiveness of nivolumab in patients newly diagnosed with oral-cavity cancer who were about to undergo surgery. The tissues were collected over the course of the clinical trial and during follow-up after the clinical trial, if and when patients relapsed.
The researchers used omic and multi-plex molecular tools to analyze the tissues deeply to discover markers associated with favorable or unfavorable outcomes. By making large-scale measurements in a longitudinal fashion, the team was able to track immune and tumor cell co-evolution.
The team detected biomarkers at three time points: before neoadjuvant anti-PD-1 therapy, after neoadjuvant anti-PD-1 therapy at the time of surgery, and after surgery, if and when patients relapsed. They uncovered potential biomarkers in the blood and in the tumors that involve the types of T cells present and genetic changes present inside the tumors.
Inside the tumors, they identified mutations in specific genes, such as CDKN2A, FLT4, and YAP1, which can explain either initial tumor response patterns or post-surgical relapses. In the blood before treatment, a high ratio of two distinct T cell types (regulatory T cells and Th17 cells) associates with a lack of tumor response. The researchers also found tumor shrinkage elicited by neoadjuvant anti-PD-1 therapy tracks with not only clonal proliferation of T cells after treatment but proliferation of specifically those T cells that were present and abundant before treatment.
“Identifying predictive biomarkers in the blood before treatment raises the possibility of a convenient tool for patient stratification and helps us understand connections between the overall and the local- inside the tumor- immune systems,” said Sixue Liu, PhD, a post-doctoral scholar at the David Geffen School of Medicine at UCLA.
Results from these studies justify larger clinical trials and focus the scientific community on specific pathways that may be therapeutic targets, in addition to PD-1. Treating cancers at earlier stages with precise targets may dramatically change the landscape of survival.
The research was supported in part by the National Institutes of Health, the Melanoma Research Alliance, the V Foundation for Cancer Research, and the UCLA Jonssonn Cancer Center Foundation.