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Phase I Study of CDX-1307, hCG-B Vaccine, for Patients With Incurable, Locally Advanced or Metastatic Breast, Colorectal, Pancreatic, Bladder or Ovarian Cancer

ABSTRACT: This research study is for individuals who have advanced breast, colon, pancreatic, ovarian or bladder cancer. Celldex Therapeutics, Inc. is testing a form of immune therapy (vaccine) to see if it can be used to make the immune system attack the cancer. The study includes administration of additional treatments, in combination, thought to enhance the immune response effect. This study specifically administers the vaccine systemically to explore whether dendritic cell targeted vaccines can generate more robust effects via intravenous injection. (CDX 1307-02)

DISEASE(S): Ovarian Cancer,Carcinoma, Ovarian Epithelial,Colorectal Cancer,Colorectal Neoplasms,Urinary Bladder Neoplasms,Bladder Cancer,Ovarian Neoplasms,Pancreatic Cancer,Pancreatic Neoplasms,Breast Cancer

PROVIDER: 2053115 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Decrease in Cdx dosage in an allelic series of mouse Cdx mutants leads to progressively more severe posterior vertebral defects. These defects are corrected by posterior gain of function of the Wnt effector Lef1. Precocious expression of Hox paralogous 13 genes also induces vertebral axis truncation by antagonizing Cdx function. We report here that the phenotypic similarity also applies to patterning of the caudal neural tube and uro-rectal tracts in Cdx and Wnt3a mutants, and in embryos precociously expressing Hox13 genes. Cdx2 inactivation after placentation leads to posterior defects including incomplete uro-rectal septation. Compound mutants carrying one active Cdx2 allele in the Cdx4 null background (Cdx2/4), transgenic embryos precociously expressing Hox13 genes, and a novel Wnt3a hypomorph mutant all manifest a comparable phenotype with similar urorectal defects. Phenotype and transcriptome analysis in early Cdx mutants, genetic rescue experiments and gene expression studies lead us to propose that Cdx transcription factors act via Wnt signalling during the laying down of urorectal mesoderm, and that they are operative in an early phase of these events, at the site of tissue progenitors in the posterior growth zone of the embryo. Cdx and Wnt mutations and premature Hox13 expression also cause similar neural dysmorphology including ectopic neural structures sometimes leading to neural tube splitting at caudal axial levels. These findings involve the Cdx genes, canonical Wnt signalling, and the temporal control of posterior Hox gene expression in posterior morphogenesis in the different embryonic germ layers. They shed a new light on the etiology of the Caudal Dysplasia or Caudal Regression range of human congenital defects. We used dissected Cdx2 null mutant versus wild type embryos at the 4/5 somite and 7/8 somite stage. RNA was isolated from the posterior part of the embryos (20 embryos of each genotype and stage), dissected at the same axial levels by using the last somite boundary and the base of the allantois as landmarks. Differentially labelled cRNA from the Cdx2 and control embryos were hybridized on 4X44K Agilent Whole Mouse Genome dual colour Microarrays (G4122F) in two dye swap experiments and two technical replicates, resulting in eight individual arrays.

Project description:Hypermethylation of helicase-like transcription factor (HLTF) in colorectal cancer (CRC) cells occurs more frequently in men than women. Progressive epigenetic silencing of HLTF in tumor cells is accompanied by negligible expression in the tumor microenvironment (TME). Cell line-derived xenografts were established in control (Hltf+/+) and Hltf-deleted male Rag2-/-IL2rg-/- mice by direct orthotopic microinjection of HLTF+/+HCT116 cells into the submucosa of the cecum. Combinatorial induction of IL6 and S100A8/A9 in the Hltf-deleted TME with ICAM-1 and IL8 in the primary tumor activated a positive feedback loop. The proinflammatory niche produced a major shift in CDX metastasis to peritoneal dissemination compared to controls. Inducible nitric oxide (iNOS) gene expression and transactivation of the iNOS-S100A8/A9 signaling complex in Hltf-deleted TME reprogrammed the human S-nitroso-proteome. S-nitroso (SNO) proteins POTEE, TRIM52 and UN45B are S-nitrosylated on the conserved I/L-X-C-X2-D/E motif indicative of iNOS-S100A8/A9-mediated S-nitrosylation. 2D-DIGE and protein identification by MALDI-TOF/TOF mass spectrometry authenticated S-nitrosylation of 53 individual cysteines in half-site motifs (I/L-X-C or C-X-X-D/E) in CDX tumors. POTEE-SNO in CDX tumors is both a general S-nitrosylation target and an iNOS-S100A8/A9 site-specific (Cys638) target in the Hltf-deleted TME. REL is an example of convergence of transcriptomic-S-nitroso-proteomic signaling. The gene is transcriptionally activated in CDX tumors with an Hltf-deleted TME, and REL-SNO (Cys143) is found in primary CDX tumors and all metastatic sites. Primary CDX tumors from Hltf-deleted TME shared 60% of their S-nitroso-proteome with all metastatic sites. Forty percent of SNO-proteins from primary CDX tumors were variably expressed at metastatic sites. Global S-nitrosylation of proteins in pathways related to cytoskeleton and motility is strongly implicated in the metastatic dissemination of CDX tumors. Hltf-deletion from the TME plays a major role in the pathogenesis of inflammation and links protein S-nitrosylation in primary CDX tumors with spatiotemporal continuity in metastatic progression even when the tumor cells express HLTF.

Dataset Information

Phase I Study of CDX-1307, hCG-B Vaccine, for Patients With Incurable, Locally Advanced or Metastatic Breast, Colorectal, Pancreatic, Bladder or Ovarian Cancer

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