Project description:Increasing evidence across malignancies suggests that infiltrating T cells at the site of disease are crucial to tumor control. We hypothesized that marrow-infiltrating immune populations play a critical role in response to donor lymphocyte infusion (DLI), an established and potentially curative immune therapy whose precise mechanism remains unknown. We therefore analyzed marrow-infiltrating immune populations in 29 patients (22 responders, 7 nonresponders) with relapsed chronic myelogenous leukemia who received CD4+ DLI in the pre-tyrosine kinase inhibitor era. We used microarrays to detail the global programme of gene expression underlying T cell infiltration into bone marrow of responders and nonresponders to DLI. mRNA expression profiling of marrow-infiltrating CD3+ positively selected T cells of 4 responders compared to 2 non-responders, before and after DLI, was performed on Affymetrix microarrays.
Project description:Increasing evidence across malignancies suggests that infiltrating T cells at the site of disease are crucial to tumor control. We hypothesized that marrow-infiltrating immune populations play a critical role in response to donor lymphocyte infusion (DLI), an established and potentially curative immune therapy whose precise mechanism remains unknown. We therefore analyzed marrow-infiltrating immune populations in 29 patients (22 responders, 7 nonresponders) with relapsed chronic myelogenous leukemia who received CD4+ DLI in the pre-tyrosine kinase inhibitor era. We used microarrays to detail the global programme of gene expression underlying T cell infiltration into bone marrow of responders and nonresponders to DLI.
Project description:Newly diagnosed chronic phase chronic myeloid leukemia (CML) patients with a major cytogenetic response (MCyR) after 12 months of imatinib therapy have an excellent long-term outcome, while patients without MCyR have a high progression risk. Since patients with primary cytogenetic resistance may benefit from more intensive therapy up-front, we sought to identify biomarkers to predict MCyR. Keywords: Two group comparison to identify trasncriptomic signature that predicts response to therapy CD34+ cells were isolated from cryopreserved mononuclear cells of chronic phase CML patients with a complete cytogenetic response (CCyR) or >65% Ph-positive metaphases after 12 months of imatinib therapy (training set N=36). Gene expression profiles generated on amplified RNA using Affymetrix HG-U133 Plus 2.0 arrays were compared between responders and non-responders, using the criteria ANOVA p<0.1 and fold difference >I1.5I. A minimal response classifier derived from the comparison was used to predict response in a prospectively collected validation set using same criteria for responders/nonresponders (N=23).
Project description:This is a class prediction experiment, where the class is the response status to imatinib (also called Gleevec), a drug used to treat patients with chronic myelogenous leukemia (CML). There are two data sets, a training set (from Leipzig, 8 Responders and 5 Non-Responders) and a validation set (from Mannheim, 8 Responders and 7 Non-Responders). The objective is to identify differentially regulated genes between CML patients who respond and those who do not respond to imatinib and confirm the results in the validation data set. The samples from blood or bone marrow of CML patients were hybridized to Affymetrix HG-U95Av2 chip and RMA was used to generate the normalized signal values.
Project description:Biopsy specimens were collected from rectal cancer before starting preoperative radiotherapy.The expression profiles were determined using Affymetrix Human Genome U95 version 2 arrays.Comparison between the sample groups allow to identify a set of discriminating genes that can be used for characterization of responders and nonresponders to preoperative radiotherapy in rectal cancer. Keywords: repeat
Project description:Biopsy specimens were collected from rectal cancer before starting preoperative radiotherapy.The expression profiles were determined using Affymetrix Human Genome U95 version 2 arrays.Comparison between the sample groups allow to identify a set of discriminating genes that can be used for characterization of responders and nonresponders to preoperative radiotherapy in rectal cancer. Experiment Overall Design: 35-training and 11-test samples were analyzed
Project description:This is a class prediction experiment, where the class is the response status to imatinib (also called Gleevec), a drug used to treat patients with chronic myelogenous leukemia (CML). There are two data sets, a training set (from Leipzig, 8 Responders and 5 Non-Responders) and a validation set (from Mannheim, 8 Responders and 7 Non-Responders). The objective is to identify differentially regulated genes between CML patients who respond and those who do not respond to imatinib and confirm the results in the validation data set. The samples from blood or bone marrow of CML patients were hybridized to Affymetrix HG-U95Av2 chip and RMA was used to generate the normalized signal values. Keywords = chronic myelogenous leukemia Keywords = imatinib Keywords = cytogenetic responses Keywords = Gleevec Keywords = Affymetrix Keywords: other
Project description:We conducted a phase I trial (NCT04628338) of IFN-γ combined with donor leukocyte infusions (DLI) in myeloblastic malignancies that relapsed post-HLA-matched allogeneic stem cell transplantation (alloSCT). Patients self-administered IFN-γ for 1-4 weeks, followed by DLI and concurrent IFN-γ for 12 weeks. IFN-γ monotherapy was well tolerated by all subjects (n=7). Four of 6 DLI recipients achieved minimal residual disease-negative complete remissions and full donor hematopoietic recovery. Median overall survival was 579 days (range, 97-906) in responders. Single cell RNA sequencing (scRNAseq) was performed on bone marrow (BM) samples collected before IFN-γ treatment and 48-60 hours after the 1st or 2nd dose of IFN-γ from three patients: one responder (Patient 1) and two non-responders (Patients 5 and 7). Recipient-derived cells were distinguished from donor-derived cells based on single nucleotide polymorphisms (SNP) in expressed genes. As expected, most immature pluripotent and myeloid lineage cells (HSC, myeloid progenitor cells, early erythroid cells) at relapse were of recipient genotypic origin, while lymphoid progenitors were mainly donor derived. Genomic copy number in single cells showed that most HSCs or myeloid progenitor cells harbored recurrent chromosome abnormalities known to each patient. To investigate the effects of in vivo IFN-γ within the major lineage clusters, we performed single-cell pathway analyses (SCPA). Transcription changes in the post-IFN-γ specimens were predominantly found in the non-lymphoid subsets (HSC-like cells, myeloid progenitors, CD14 or CD16 monocytes, and erythroid cells). IFN-γ response pathway was activated in HSC-like cells (Patients 1 and 7) and myeloid progenitor cells (Patients 1, 5, 7) in the post-IFN-γ samples. Post-IFN-γ samples also had evidence of activation of “TNF-alpha signaling via NFkb” in HSC-like and myeloid progenitor cell populations. “IL2 STAT5 signaling” and “inflammatory response” pathways were also engaged in post-IFN-γ myeloid populations. These scRNAseq analysis confirmed in vivo IFN-γ action on the dominant malignant myeloid population.
Project description:Gene signatures were derived to separate responders from nonresponders by tipifarnib treatment. Experiment Overall Design: 58 samples from 58 patients
