2021 VA Research Scholar Award Michael Green, MD University of Michigan/Veterans Affairs Ann Arbor Healthcare System Ann Arbor MI Research Summary Immune checkpoint blockades are a new cancer treatment which can cure Veterans with metastatic cancer. Unfortunately, it does not work in most patients. We have found that if a Veteran’s cancer has spread from his lungs to his liver, immunotherapy does not work. We have studied this problem in the lab. We think that cancer spreading to the liver causes the immunotherapy to not work. In the lab, we discovered that getting rid of the cancer within the liver with radiotherapy can help immunotherapy work better. We now want to test the idea that combining immunotherapy and radiotherapy to the cancer in the liver is safe and effective. If we find this, we can use this information to make help Veterans with cancer live longer. Technical Abstract Immune checkpoint inhibitors have revolutionized the care of patients with metastatic non-small cell lung cancer (NSCLC). Unfortunately, not all patients benefit from this therapy, and rational combinatorial strategies to enhance immune checkpoint inhibitors (ICI) efficacy in therapy non-responders are needed. We and others have shown that patients with liver metastases derive limited clinical benefit from ICI across a wide variety of disease types. In preclinical models, we discovered that liver metastases cause anti-PD-L1 resistance by siphoning tumor-specific T cells from systemic circulation. Within the liver, activated antigen-specific CD8+ T cells undergo apoptosis. Consequently, liver metastases create a systemic immune desert in preclinical models. Similarly, patients with liver metastases have reduced peripheral T cell numbers and diminished tumoral T cell diversity and function. In preclinical models, liver-directed radiotherapy eliminates immunosuppressive hepatic macrophages, increases hepatic T cell survival, and reduces hepatic siphoning of T cells. The central hypothesis of this proposal is that liver SBRT can enhance CPP therapy non-responders in NSCLC patients with liver metastases. In Aim 1, we will conduct a Phase IB clinical trial establishing the feasibility of delivering multi-target liver SBRT following the first cycle of carboplatin, pembrolizumab, and pemetrexed (CPP) in metastatic NSCLC patients with liver metastases. Up to four liver metastases will be targeted. In Aim 2, we will determine whether liver SBRT combined with ipilimumab and nivolumab modulates the hepatic and systemic immune microenvironment in NSCLC patients with liver metastases. The completion of these aims will assess the feasibility of ablating liver metastases with SBRT in combination with chemoimmunotherapy and deepen our understanding of the contribution of hepatic immune tolerance mechanisms in patients. The ultimate goal of this work is to test rationally-developed combinatorial treatment approaches in hopes of improving the care of NSCLC patients.
