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CPI-006 Alone and in Combination With Ciforadenant and With Pembrolizumab for Patients With Advanced Cancers

ABSTRACT: This is a Phase 1/1b open-label, dose escalation and dose expansion study of CPI-006, a humanized monoclonal antibody (mAb) targeting the CD73 cell-surface ectonucleotidase in adult subjects with select advanced cancers. CPI-006 will be evaluated as a single agent, in combination with ciforadenant (an oral adenosine 2A receptor antagonist), in combination with pembrolizumab (an anti-PD1 antibody), and in combination with ciforadenant and pembrolizumab.

DISEASE(S): Endometrial Cancer,Lung Cancer,Metastatic Castration Resistant Prostate Cancer,Sarcoma,Cervical Cancer,Triple Negative Breast Neoplasms,Colorectal Cancer,Bladder Cancer,Triple Negative Breast Cancer,Pancreatic Cancer,Endometrial Neoplasms,Breast Cancer,Non-hodgkin Lymphoma,Ovarian Cancer,Squamous Cell Carcinoma Of Head And Neck,Nsclc,Squamous Cell Carcinoma Of The Head And Neck,Non-small Cell Lung Cancer,Carcinoma, Renal Cell,Renal Cell Cancer

PROVIDER: 2267503 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Background: Ascaris lumbricoides cystatin (Al-CPI) prevents development of allergic airway inflammation and colitis in mice models. It has been suggested that helminth derived cystatins inhibit cathepsins in dendritic cells (DC), but their immunomodulatory mechanisms are unclear. We aimed to analyze the transcriptional profile of human monocyte derived DC (moDC) upon stimulation with Al-CPI to elucidate target genes and pathways of parasite immunomodulation. Methods: moDC were generated from peripheral blood monocytes from six healthy human donors of Denmark, stimulated with 1 μM of Al-CPI and cultured for 5 hours at 37°C. RNA was sequenced using TrueSeq RNA libraries and the NextSeq 550 v2.5 (75 cycles) sequencing kit (Illumina, Inc). After QC, reads were aligned to the human GRCh38 genome using STAR. Differential expression was calculated by DESEq2 and expressed in fold changes (FC). Cell surface markers and cytokine production by moDC were evaluated by flow cytometry. Results: Compared to unstimulated cells, Al‐CPI stimulated moDC showed differential expression of 444 transcripts (|FC| ≥1.3). The top significant differences were in kruppel like factor 10 (KLF10, FC 3.3, PBH = 3 x 10-136 ), palladin (FC 2, PBH = 3 x 10-41 ) and the low-density lipoprotein receptor (LDLR, FC 2.6, PBH = 5 x 10-41 ). Upregulated genes were enriched in regulation of cholesterol biosynthesis by sterol regulatory element-binding proteins (SREBP) signaling pathways. Several genes in the cholesterol biosynthetic pathway showed significantly increased expression upon Al-CPI stimulation, even in the presence of LPS. Regarding the pathway of negative regulation of immune response, we found significant decrease in cell surface expression of CD86, HLA-DR and PD-L1 upon stimulation with 1 μM Al-CPI. Conclusion: Al-CPI modifies the transcriptome of moDC, increasing several transcripts encoding enzymes involved in cholesterol biosynthesis and SREBP signaling. Moreover, Al-CPI target several transcripts in the TNF-alpha signaling pathway influencing cytokine release by moDC. Several SMADs, members of the TGF-beta and the IL-10 families, including KLF10 were also This is a provisional file, not the final typeset article modified by Al-CPI stimulation. The regulation of the mevalonate pathway and cholesterol biosynthesis suggests new mechanisms involved in DC responses to helminth immunomodulatory molecules.

Dataset Information

CPI-006 Alone and in Combination With Ciforadenant and With Pembrolizumab for Patients With Advanced Cancers

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