Identifying and Targeting Mechanisms of Resistance to Immunotherapy

Rizwan Haq, MD, PhD

Dr. Haq is an assistant professor in the Melanoma Treatment Center at Dana-Farber Cancer Institute in Boston. His SU2C Innovative Research Grant project, awarded in 2017, is titled “Identifying and Targeting Mechanisms of Resistance to Immunotherapy.”

A form of immunotherapy called immune checkpoint blockade therapy has revolutionized the treatment of metastatic melanoma. However, not all patients respond to this kind of therapy, and some who respond initially will later have progression in their disease. Understanding the mechanism of these varied responses could improve patient care for two reasons. First, patients who are more likely to respond favorably to the treatment could be identified before embarking on a treatment. Second, novel drug targets could be identified that have the potential to overcome resistance to the therapy. By analyzing samples from melanoma patients treated with immunotherapies, Dr. Haq and his team uncovered mutations in genes associated with treatment outcome. In some non-responding patients, mutations that hindered the ability of the patient’s immune system to destroy tumor cells led to treatment resistance. In other cases, mutations in genes without known function were identified that predicted beneficial response to immunotherapies. To understand better the role of genes associated with resistance or response to immunotherapy, Dr. Haq will use a unique tool developed in his lab to recreate resistance mutations in a mouse model. This platform will also be used to evaluate whether a drug currently in clinical trials can overcome immunotherapy resistance. Altogether, this approach could transform the way we understand and treat resistance to immunotherapy.