Background BXCL701 (talabostat), an oral innate immune activator is currently in a Phase 2 trial in combination with PD-1 checkpoint inhibitor in metastatic castration-resistant prostate cancer patients. In solid tumors, preclinical data suggest that BXCL701 inhibition of dipeptidyl peptidases (DPPs) enhances antitumor immune responses via two mechanisms: (1) DPP4 inhibition increases tumor content of CXCL9/10, which recruits CXCR3+ NK and T cells, and (2) DPP8/9 inhibition activates the inflammasome resulting in immune cell pyroptosis followed by Th1 proinflammatory cytokine release, and dendritic cells (DCs) activation which further enhances the CXCL9/10-CXCR3 axis1. Recent studies show that BXCL701 exhibits single agent cytotoxicity against human AML cells through a similar pyroptotic mechanism2. Here, we report the identification of potential predictive biomarkers by using BXCL701-responsive and -nonresponsive human leukemic cell lines.
Methods The cytotoxic activity of BXCL701 was evaluated in a panel of 170 hematological and non-hematological cell lines and confirmed that mostly but not all the leukemic cells were responsive to BXCL701. Four responding cell lines (KG1, MV4–11, THP1 and EOL-1, IC50 = 100 – 700 nM) and 2 non-responding cell lines (K562 and Kasumi1, IC50 >60 µM) were selected based on the cytotoxicity data and their gene expression profiles were compared to identify predictive biomarkers for BXCL701. Nanostring analysis was performed followed by qRT-PCR using cDNA from the cell lines.
Results The analysis identified 20 genes as potential predictive biomarkers. These, include 5?genes (DPP9, DPP8, caspase 1, CARD8 and PYCARD) involved in the inflammasome – pyroptosis pathway that is activated by BXCL701 and correlate with the BXCL701 cytotoxic activity. Most of the genes have 2-to-1,000-fold higher expression in at least 3 responding cell lines in comparison to non-responding cell lines. On the other hand, EPCAM gene has 7,000-fold higher expression in non-responding cell lines vs responding cell lines. Further, copy number was evaluated for BXCL701 target genes (DPP8, DPP9, DPP4 and FAP) by RT-PCR in 11?responding leukemic cell lines and 6 non-responding cell lines. The DPP9 copy number variation (CNV) was found to be directly correlated with BXCL701 cytotoxicity in BXCL701-responding human leukemic cell lines with correlation coefficient (R2) of 0.813.
Conclusions A gene panel consisting of genes involved in BXCL701 mechanism of action has been identified as a potential predictive biomarker for BXCL701 in leukemia, which can help in selecting patients susceptible to respond to BXCL701 treatment.
Fitzgerald AA, Wang S, Agarwal V, et al. DPP inhibition alters the CXCR3 axis and enhances NK and CD8+ T cell infiltration to improve anti-PD1 efficacy in murine models of pancreatic ductal adenocarcinoma. J Immunother. Can 2021, 9(11): e002837
Johnson DC, Taabazuin CY, Okondo MAC, et al. DPP8/DPP9 inhibitor-induced pyroptosis for treatment of acute myeloid leukemia. Nat Med. 2018; 24:1151–1156.
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