Hepatopulmonary Radio-sterilization With Immunotherapy

A number of recent reports have noted the relative resistance of liver metastases to immunotherapy across a range of cancer types1,2, including mCRC. In two studies of MSS mCRC using a combination of PD-1 and CTLA-4 inhibitors there was a marked difference in response rate between subjects with and without liver metastases, 0% vs 42% in the study of Bullock et al3, and 0% versus 36% in the study by Fakih et al4. The proposed mechanism is a macrophage-induced T cell death occurring within hepatic metastases, leading to systemic imunosupression5. Furthermore, these investigators demonstrated that in preclinical models of MSS mCRC, liver-metastasis directed radiotherapy eliminates immunosuppressive hepatic macrophages, increases hepatic T cell survival and reduces hepatic siphoning of T cells, thereby abolishing the immunotherapy resistance induced by liver metastasis5. Conversely, liver irradiation in the absence of metastases was ineffective5. Similarly, in microsatellite instability high mCRC the presence of liver metastases is associated with a poor response to immunotherapy6. In a retrospective analysis of 161 MSI High mCRC patients treated with immunotherapy, pooling data from MD Anderson and Sheba, the presence of liver and lung metastases was associated with a reduced PFS, with a HR of 2.6 and 2.4, respectively (submitted for publication). In this protocol the investigators aim to overcome hepatic-pulmonary metastases-induced resistance to immunotherapy through high dose radiation therapy (SBRT) targeted to the metastases themselves, aiming, when possible, to ablate all macroscopic disease in these organs.