Dataset Information

CPI-613, Bendamustine Hydrochloride, and Rituximab in Treating Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

ABSTRACT: This phase I trial studies the side effects and best dose of CPI-613 (6,8-bis[benzylthio]octanoic acid) when given together with bendamustine hydrochloride and rituximab in treating patients with B-cell non-Hodgkin lymphoma that has come back or has not responded to treatment. Drugs used in chemotherapy, such as 6,8-bis(benzylthio)octanoic acid and bendamustine hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as rituximab, may find cancer cells and help kill them. Giving 6,8-bis(benzylthio)octanoic acid with bendamustine hydrochloride and rituximab may kill more cancer cells.

DISEASE(S): Extranodal Marginal Zone B-cell Lymphoma Of Mucosa-associated Lymphoid Tissue,Recurrent Grade 3 Follicular Lymphoma,Recurrent Adult Acute Lymphoblastic Leukemia,Lymphoma, Large B-cell, Diffuse,Lymphoma, Large-cell, Immunoblastic,Leukemia,Mycoses,Waldenström Macroglobulinemia,Recurrent Adult Lymphoblastic Lymphoma,Small Intestine Lymphoma,Recurrent Grade 1 Follicular Lymphoma,Refractory Hairy Cell Leukemia,Sezary Syndrome,Testicular Lymphoma,Splenic Marginal Zone Lymphoma,Leukemia, Hairy Cell,Refractory Chronic Lymphocytic Leukemia,Mycosis Fungoides,Lymphoma, Mantle-cell,Recurrent Adult Immunoblastic Large Cell Lymphoma,Recurrent Adult Burkitt Lymphoma,Lymphomatoid Granulomatosis,Leukemia, Lymphoid,Plasmablastic Lymphoma,Precursor Cell Lymphoblastic Leukemia-lymphoma,Lymphoma, B-cell, Marginal Zone,Burkitt Lymphoma,B-cell Chronic Lymphocytic Leukemia,Lymphoma,Recurrent Adult Diffuse Small Cleaved Cell Lymphoma,Recurrent Mycosis Fungoides/sezary Syndrome,Nodal Marginal Zone B-cell Lymphoma,Recurrent Small Lymphocytic Lymphoma,Recurrent Adult Diffuse Mixed Cell Lymphoma,Recurrent Marginal Zone Lymphoma,Recurrent Grade 2 Follicular Lymphoma,Lymphoma, Follicular,Waldenstrom Macroglobulinemia,Recurrent Adult Grade Iii Lymphomatoid Granulomatosis,B-cell Adult Acute Lymphoblastic Leukemia,Lymphoma, Non-hodgkin,Recurrent Adult Diffuse Large Cell Lymphoma,Lymphoma, B-cell,Intraocular Lymphoma,Leukemia, Lymphocytic, Chronic, B-cell,Cutaneous B-cell Non-hodgkin Lymphoma,Recurrent Mantle Cell Lymphoma

PROVIDER: 2168930 | 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-613, Bendamustine Hydrochloride, and Rituximab in Treating Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

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