Radiation as a Tool to Induce Responses in Immunological Cold GI Tumors

Overcoming resistance to immunotherapy for MSS colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) remains challenging. We conducted a single-arm, non-randomized, phase 2 trial combining radiation, ipilimumab and nivolumab to treat patients with metastatic MSS CRC and PDAC.

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Overcoming intrinsic resistance to immune checkpoint blockade for microsatellite stable (MSS) colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) remains challenging. There are many strategies being explored to make this historically "cold" tumors "hot." Radiation is emerging as one such strategy, radiation can potentially can increase susceptibility of tumor cells to immune mediated killing, as it has been shown that radiation can increase negative feedback mechanisms such as checkpoints that can hinder the immune response while also promoting release of tumor-specific antigens and may act as "in situ vaccine." 

We conducted a single-arm, non-randomized, phase 2 trial (NCT03104439) combining radiation, ipilimumab and nivolumab to treat patients with metastatic MSS CRC (n = 40) and PDAC (n = 25) with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The primary endpoint was disease control rate (DCR) by intention to treat. DCRs were 25% for CRC (ten of 40; 95% confidence interval (CI), 13–41%) and 20% for PDAC (five of 25; 95% CI, 7–41%). In the per-protocol analysis, defined as receipt of radiation, DCR was 37% (ten of 27; 95% CI, 19–58%) in CRC and 29% (five of 17; 95% CI, 10–56%) in PDAC. Pretreatment biopsies revealed low tumor mutational burden for all samples but higher numbers of natural killer (NK) cells and expression of the HERVK repeat RNA in patients with disease control. This study provides proof of concept of combining radiation with immune checkpoint blockade in immunotherapy-resistant cancers. We showed that the combination is safe, has some efficacy and demonstrated the emergence of a possible biomarker, namely higher repetitive RNA transcription that correlates with benefit.