Study Links Persistent Tumor Mutation with Therapeutic Response to Immunotherapy Schedule

Investigators at the Johns Hopkins Kimmel Cancer Center and its Bloomberg~Kimmel Institute for Cancer Immunotherapy have found that a subset of mutations within the overall tumor mutation burden (TMB), termed “persistent mutations,” are less likely to be edited out as cancer evolves, rendering tumors continuously visible to the immune system and predisposing them to respond to immunotherapy. This persistent mutation load may help clinicians more accurately select patients for clinical trials of novel immunotherapies or predict a patient’s clinical outcome with immune checkpoint blockade, a type of immunotherapy.

In the study, the investigators hypothesized that tumors with a high persistent TMB (pTMB) would be most visible to the immune system and, therefore, would regress after exposure to immunotherapy. They evaluated the potential of pTMB, multicopy and single-copy mutations to predict response to immune checkpoint blockade among 542 patients with melanoma, nonsmall cell lung cancer, mesothelioma and head and neck cancer, and discovered that tumors with a high pTMB attained higher rates of therapeutic responses to the immunotherapy, while TMB, the number of loss-prone mutations, or tumor aneuploidy, less optimally distinguished tumors that responded from those that did not respond. In addition, when comparing tumor samples prior to immunotherapy and at the time of acquired resistance, the team observed a more than 60-fold lower probability of loss for persistent mutations. Persistent mutation load showed promising performance in predicting immunotherapy response when pTMB was computed from targeted next-generation sequencing, which is the testing modality routinely used in clinical practice.

According to the researchers, future steps include additional large-scale validation of the findings, as well as prospective analyses to evaluate the role of persistent mutation load to select patients for cancer immunotherapy.