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Translational analysis from SCALOP trial: CCL5 as a prognostic biomarker and a potentially actionable target in locally advanced pancreatic cancer (LAPC).


Abstract

Background: SCALOP was a multi-centre phase II RCT where 114 patients with LAPC were received 3 cycles of Gemcitabine and Capecitabine (GEMCAP) and those with stable/responding disease (n = 74) were randomised to Gem-RT or Cap-RT. The trial showed superiority of Cap-RT. Baseline blood samples of randomised patients were analysed for 35 circulating biomarkers. In vivo study was undertaken with candidate biomarker (CCL5) to test actionability. Methods: Patient bloods were tested using R&D multiplexed magnetic Luminex assays and IGF-1, TGF-b1 and b-NGF DuoSet ELISA. Orthotropic KrasG12D;P53R172H;PDXcre (KPC) tumors were implanted in Bl6-mice and treated with Gem, CCR5-inhibitor (CCR5i) maraviroc (MV), PD1 inhibitor (PD1i), PD1i+MV alone and in combination with MRI guided small animal Radiotherapy (RT). Immunophenotyping was performed by IHC and Aurora Cytek spectral flow cytometry. Results: Baseline biomarker data was available on 63/74 randomised patients. Of the 35 biomarkers tested, only CCL5 was found to be significantly associated with OS with a median OS of 18.5 (95% CI: 11.76-21.32) vs 11.3 (9.86-15.51) months (low vs high), and HR 1.37 (95% CI:1.04-3.65; p = 0.037) in the Cox multivariable model. Treatment of orthotopic KPC tumors revealed that combination of MV+PD1i+RT resulted in tumour growth inhibition and a switch of tumour macrophages from M2 to M1 accompanied by increase in infiltration of cytotoxic CD8+ Tcells and NK cells. Conclusions: Previous pre-clinical studies reported CCL5-CCR5 axis as a poor prognostic marker and a possible cause of immune-resistance in pancreatic cancer. Herein we have demonstrated in prospectively collected clinical trial blood samples that high circulating CCL5 is associated with poor prognosis in LAPC. CCR5 inhibitor in combination with RT+PD1i may overcome immune-resistance, and should be tested in clinical trials. Clinical trial information: 96169987.

© 2020 American Society of Clinical Oncology

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