Significant medical research is focused on immunotherapy for the treatment of malignancies, including deadly melanomas. Rather than using toxic chemotherapy drugs, immunotherapy works by stimulating the body’s immune system to fight the cancer. UCLA researchers have gained understanding regarding how immunotherapy attacks cancerous cells. The findings are a promising step toward personalized medicine using this treatment. The findings were published online on March 17 in the journal Cell.
The study authors note that using anti-PD-1 antibodies has revolutionized the treatment of advanced melanoma and many other malignancies; however, 60-70% percent of patients’ melanoma tumors are resistant to the anti-PD-1 antibodies. Thus, there is an urgent need to determine how to identify patients who will and will not respond to this therapy and ultimately improve the response rates.
The researchers explain that Anti-PD-1 antibodies (e.g., pembrolizumab/Keytruda®, and nivolumab/Opdivo®) target the protein PD-1, which is a negative receptor expressed by immune cells that turn them off. Some tumors evade an immune response by expressing the ligand to PD-1 (called PD-L1). (A ligand is a molecule that binds to another (usually larger) molecule.) When PD-1 binds to PD-L1, it protects the cancer cells from immune cell attack. Therefore, by blocking the interaction between PD-1 and PD-L1, anti-PD-1 antibodies unleash the patient’s immune system to attack the cancer.
A team led by lead author Roger Lo, MD, PhD, a UCLA Jonsson Comprehensive Cancer Center member, analyzed melanoma tumors from patients before anti-PD-1 therapy. The samples were then divided into two groups, based on whether those patients responded or failed to respond to treatment. The researchers then sought to assess the “on” or “off” status of a tumor cell’s genes by detecting their mutational rates and/or gene expression levels.
Dr. Lo explained that the degree to which genes and groups of genes are turned on or off has a major influence on whether a tumor will respond to or resist a drug. He said, “Once we observed how groups of genes were expressed at different levels between the responding versus non-responding tumors, we could compute the biological processes these genes likely participate in to promote resistance. This anti-PD-1 resistance-associated gene expression pattern defined a signature which was also detected across other common cancers of the lung, colon, kidney and pancreas.”
“We are rapidly advancing our knowledge on why some patients respond to anti-PD-1 immunotherapies and other do not,” explained co-investigator Antoni Ribas, MD, professor of medicine and director of the tumor immunology program at the Jonsson Cancer Center. He added, “Anti-PD-1 therapies are arguably the most impacting advance in cancer treatment in the past years as they have activity in 15 different types of cancers leading to long lasting tumor responses, but they only work in a subgroup of patients. Understanding who is likely to respond or not will allow developing personalized immunotherapy to decide which patients can be treated with anti-PD-1 or require a combination strategy.”
From other computational experiments, the researchers also found that tumors with more mutations were associated with longer patient survival after anti-PD-1 therapy. Furthermore, in a surprise discovery, the investigators found that another common therapy for advanced melanoma that utilizes small molecules to turn off a specific pathway activated by the BRAF mutation can induce processes inside a tumor similar to those associated with anti-PD-1 resistance.
Dr. Lo noted that the discovery suggests that, despite the potential of BRAF and PD-1 targeted combination therapies to deliver further improvements in patient survival, future development of this approach should consider the altered immune microenvironment brought on by BRAF targeted therapy. He and his colleagues are hopeful that the overall study findings have the potential to help explain why people battling the disease respond differently to or derive different degrees of long-term benefit from this type of treatment. These findings will certainly open up new research into ways to improve response rates to PD-1 antibodies. The researchers plan to begin validating significant associations discovered in this group of patients, and design predictive analyses to help physicians stratify patients for PD-1 antibody therapy.