Cells that become cancerous due to mutations — genetic changes — typically develop telltale “markers” on their surface signaling that they are abnormal. When the immune system detects such biomarkers, that can trigger an immune response to fight the cancer.
Medical researchers measure the number of genetic changes within cells using “tumor mutation burden” (TMB) as an indicator. Cancer cells containing numerous genetic changes are said to exhibit a high TMB. But cells with a low TMB may not produce any surface markers, thereby escaping detection by the immune system.
A team led by David Gandara, codirector of the Center for Experimental Therapeutics in Cancer and senior adviser to the director of UC Davis Comprehensive Cancer, confirmed through a recent research study that high TMB can be used as a reliable biomarker for immunotherapy treatment of cancer.
Advancing immunotherapy
Immunotherapy cancer drugs bind with receptor sites on tumors, helping the immune system recognize and destroy cancers. While some biomarkers previously had proven effective in predicting efficacy of targeted therapies, biomarkers to identify which types of cancer patients could benefit from immunotherapy remained elusive.
In 2020, the U.S. Food and Drug Administration (FDA) approved the use of a specific biomarker TMB to guide treatment decisions for the checkpoint immunotherapy drug pembrolizumab (also known as Keytruda). The FDA allows the use of the drug in patients whose TMB has 10 or more mutations per megabase of tumor DNA. Foundation Medicine, a Massachusetts company that performs molecular profiling for cancer, has developed the only FDA-approved TMB biomarker test.
Gandara and his research collaborators supported the FDA’s decision. Their study confirmed that a high TMB triggering an effective immune response increased overall survival for 24 types of tumors among a large group of cancer patients.
The human immune system, through the coordination of innate and adaptive immune cells, is able to combat cancerous cells once they’re identified. However, cancer cells can create mechanisms that shield them from immune system attacks. For example, tumors can use checkpoint PD-L1 — a protein that “masks” the tumor — to hide and grow within the body. Checkpoint proteins can either initiate or suppress an immune response.
Checkpoint immunotherapy doesn’t directly kill cancer cells.
“Pembrolizumab binds to PD-1/PD-L1 and removes the ‘mask’ from the tumor,” explained Gandara, a UC Davis professor of medicine emeritus. “When a checkpoint inhibitor is given, your immune system realizes there’s a problem, wakes up and goes after the cancer. Patients love it when you tell them immunotherapy helps their own bodies fight the tumor.”
Before Gandara and his colleagues presented their research findings, practicing oncologists were uncertain how closely they could rely upon TMB in initiating immunotherapy for differing types of tumors. Previous studies showed variable results for TMB as a predictive biomarker for immunotherapy treatment, especially when paired with chemotherapy. Additionally, immunotherapy can have harmful side effects for patients who are prone to autoimmune disorders, and it isn’t effective with every cancer type.
To clarify the role of TMB as a justification for treatment with pembrolizumab across various tumor types, Gandara and his colleagues turned to the combined clinical genomic database of Foundation Medicine and health technology company Flatiron Health.
Gandara and his team studied more than 8,000 patients who had advanced stage cancer of numerous types and who had received the Foundation Medicine TMB test and been treated with single-agent immunotherapy. The researchers found that TMB ≥ 10 (TMB with 10 or more mutations per megabase of tumor DNA) is an effective biomarker for immunotherapy use and is associated with improved survival in almost all tumor types. The more mutations that a tumor had, the more likely it would respond to immunotherapy.
“The consistency of the data exceeded my expectations,” Gandara said.
Previous studies of TMB efficacy were limited because they investigated it only in conjunction with chemotherapy.
“That’s because TMB is a biomarker associated almost entirely with immunotherapy efficacy. When you give a combination of immunotherapy and chemotherapy, it tends to dilute the predictive value of TMB,” Gandara explained.
He plans to analyze the database records of 6,000 patients to discover more about how combination therapy affects the predictive value of TMB.
