Abstract 528: Radioembolization followed by durvalumab and tremelimumab does not induce immune responses against liver-metastasized MSS colorectal cancer
Authors: Wang Chongkai , Park John , Ouyang Ching , Pillai Raju , Longmate Jeffrey , Yin Holly , Avalos Christian , Gozo Maricel , Egelston Colt , Lee Peter P. , Fakih Marwan G. 
Published: August 2019

Abstract
Introduction: PD-1 inhibitors have been ineffective in microsatellite stable (MSS) metastatic colorectal cancer (mCRC). Preclinical models suggest that radiation therapy may sensitize MSS CRC to PD-1 blockade. This constitutes the rationale for combining radioembolization to the liver in patients (pts) with MSS CRC with liver metastasis.
Methods: Pts with MSS mCRC with liver predominant disease who progressed following at least 1 prior line of treatment, were eligible for study treatment. Treatment consisted of Y90 radioembolization to the liver (SIRTEX®) followed 2-3 weeks later by the intravenous (IV) combination of durvalumab (D) at 1500 mg and tremelimumab (T) at 75 mg Q4W for 4 months, followed by D 1500 mg Q4W x 8 cycles, or until disease progression (PD). Tumor biopsies were obtained at baseline, 1-2 weeks post SIR-Spheres®, and 2-3 weeks after D+T. A Simon 2-stage design was implemented, with a planned expansion to 18 patients if at least 1 response is noted in the 1st 9 pts. Correlative studies included tumor and peripheral blood flow cytometry, serum cytokine assays, and tumor IHC multiplex assay for CD8, CD4, CD68 and Cytokeratin20 expression. Immune and cancer related gene expression of the tumor microenvironment was analyzed via NanoString.
Results: 9 pts enrolled in the 1st stage of the study, all with PD within or after their first 2 cycles of treatment. Per pre-planned design, the study was closed for futility. Here we report our correlative study for this trial. Based on IHC, intratumoral TILs (CD4 and CD8 T cells) were not detectable on any of the serial tumor biopsies (pre-Y90, post-Y90, and post D+T), while heavy CD68+ macrophage infiltration was consistently observed. Such observations were statistically validated by comparing paired serial samples using NanoString. Increased expression of collagen genes, such as COL1A1, COL1A2, and COL3A1, following Y90 was noted, as reported in literatures for cases with chemo and radiation resistance. MDM2, known to associate with resistance to PD-1/PD-L1 inhibitors, was also upregulated following Y90. Furthermore, flow cytometry results showed no difference in CD4+ T cells, CD8+T cells, CD20+B cells, CD33+HLA-DR-MDSCs, and CD4+Foxp3+ regulatory T cells based on paired serial PBMC samples. However, we observed a significant increase in PD-1+CD4+ and PD-1+CD8+ T cell subpopulations in PBMC following D+T, which agrees with other reports that PD-1/PD-L1 targeting leads to the expansion of PD-1+ T cells. In addition, CD3-CD56+ NK cell population was increased following D+T when compared with Y90.
Conclusion: Y90 radioembolization can be added safely to D+T but did not promote tumor-directed immune responses against liver-metastasized MSS CRC. The associated correlative studies do not support a role for Y90 radioembolization to convert immunologically ‘cold’ tumors into ‘hot’ tumors.
Citation Format: Chongkai Wang, John Park, Ching Ouyang, Raju Pillai, Jeffrey Longmate, Holly Yin, Christian Avalos, Maricel Gozo, Colt Egelston, Peter P. Lee, Marwan G. Fakih. Radioembolization followed by durvalumab and tremelimumab does not induce immune responses against liver-metastasized MSS colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 528.