Identification of predictive markers of toxicity to immunotherapy

Identification of key immune escape mechanisms of cancers led to the development of drugs that target these escape mechanisms (immune checkpoints) which have produced durable clinical responses in various malignancies, including lung cancer. Because these drugs (immune checkpoint inhibitors) only benefit a fraction of patients, efforts are now focused on combination treatment strategies to increase responses with the cost of increased toxicities, some of which can be life threatening. Immune checkpoint inhibitors have a unique side effect profile and generally it is due to inflammatory tissue damage, named immune related adverse effects (irAE). Unlike the anticipated side effects of chemotherapies, the onset, duration and severity of side effects of immune checkpoint inhibitors are unpredictable. irAEs share some clinical features with autoimmune conditions. Recent studies suggest 8-9% of the US population carries autoimmune diseases and a quarter of healthy individuals have circulating proteins (auto-reactive antibodies) that are directed against individual's own body. We consider, pre-existing or increasing levels of auto-reactive antibodies and changes in some immune cells caused by immune checkpoint inhibition and radiation therapy, can be predictive markers for toxicity. For this study we plan to use blood samples from patients who are in a clinical trial that combines two immune checkpoint inhibitors with/without radiation therapy. In blood, we plan to measure baseline and subsequent levels of auto-reactive antibodies, and a subgroup of immune cells during therapy. Our goal is to identify a predictive marker set for irAEs and we will also correlate these markers with the response to therapy.