Project description:The aim of the study is to identify differentially expressed genes between chronic lymphocytic leukemia (CLL) patients who will respond to lenalidomide treatment and non responsive patients. We performed a whole genome gene-expression analysis of pre-treatment samples collected from 16 CLL patients included in a phase II clinical trial. The pre-treatment sample comprises purified CD19 cells from peripheral blood. Ten (37%) patients achieved partial responses (PR) and were classified as responders (R), 2 (7%) stable diseases (SD) and 4 (15%) progressive diseases (PD) and were classified as non responders (NR). Supervised analysis identified 78 genes up-regulated and 119 genes down-regulated in R compared with NR (Fold change [FC]≥2, p<0.01, Figure 4). Different expression levels of genes involved in interferon (INF) and Wnt signaling pathways characterized patients who will respond to lenalidomide. In particular, R showed a 23-fold increase in Wnt inhibitor Shisa homolog 3 (SHISA3), whereas a decrease of WISP3, CDH4, HOXB7 and WNT10A. Moreover, leukemic cells collected from R down-regulated interferon-induced proteins (IFI44, -6.6; IFI44L, -9.3; IFIT2, -2) and STAT1 (-2.4 fold change). NR group up-regulated lipoprotein lipase (LPL, +7.5). The baseline expression levels of cereblon (CRBN) were not dissimilar between R and NR subsets
Project description:Tasquinimod is a new immunomodulatory treatment for MM that is in phase I/II clinical evaluation in patients with relapsed/refractory MM. In the present study, we evaluated the effect of tasquinimod on MM cells using RNA sequencing to provide more mechanistic insights into the observed tasquinimod-mediated anti-tumor effects.
Project description:We conducted a phase I-II clinical trial at our institution that was designed to assess the safety and efficacy of escalating doses of CAR19/IL-15 CB-NK cells as treatment for relapsed/refractory CD19-positive malignancies. NK cells from these optimal CBs were highly functional and enriched in effector-related genes. In contrast, NK cells from suboptimal CBs had upregulation of inflammation, cellular stress and apoptosis programs. Finally, using multiple mouse models, we confirmed the superior anti-tumor activity of CAR-NK cells from optimal CBs.
Project description:Acquired resistance of chronic lymphocytic leukemia (CLL) to chemotherapy is an important clinical problem and is often caused by cytogenetic aberrations or gene mutations affecting the ATM-p53 DNA damage response pathway or other pathways. However, there are also a lot of resistant cases without detectable mutations and we decided to check whether there are specific epigenetic changes at the level of DNA methylation that might underlie resistance development in CLL. We used Illumina Infinium HumanMethylation450 BeadChips to obtain DNA methylation profiles of 71 CLL patients with different responses to chemotherapy. Fifty-one patients were subjects of the CLL2O clinical trial and 36 of them were categorized as relapsed/refractory after treatment with fludarabine- or bendamustine-containing regimens, whereas the other 15 patients as well as 20 additional patients not on the trial were untreated at the time of sampling. Although we could not correlate chemoresistance with epigenetic changes, we believe that the dataset is valuable and can be used by researchers to test other hypotheses, especially as the patients are well characterized regarding different prognostic and molecular markers (IGHV mutation status, chromosome aberrations, TP53 mutation status, etc.).
Project description:MicroRNA profiling was performed on baseline bloods using the NanoString nCounter platform in a serial liquid biopsies obtained at baseline in chemo-refractory mCRC patients treated with regorafenib in a phase II clinical trial (PROSPECT-R n=40; NCT03010722).
Project description:This phase II trial studies how well giving lenalidomide with or without rituximab works in treating patients with progressive or relapsed chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), prolymphocytic leukemia (PLL), or non-Hodgkin lymphoma (NHL). Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving lenalidomide together with or without rituximab may kill more cancer cells.
Project description:Immune stimulation contributes to lenalidomide’s anti-tumor activity. Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of mature, autoreactive B cells in secondary lymphoid tissues, blood and bone marrow and progressive immune dysfunction. Previous studies in CLL indicated that lenalidomide can repair defective T-cell function in vitro. Whether T-cell activation is required for clinical response to lenalidomide remains unclear. Here we report changes in the immune microenvironment in patients with CLL treated with single-agent lenalidomide and associate the immunologic effects of lenalidomide with anti-tumor response. Within days of starting lenalidomide, CD3+ cells increased in the tumor microenvironment and showed Th1-type polarization. Gene expression profiling of pre-treatment and on-treatment lymph node biopsies revealed upregulation of IFN and many of its target genes in response to lenalidomide. The IFNγ-mediated Th1 response was limited to patients achieving a clinical response defined by a reduction in lymphadenopathy. Deep sequencing of T-cell receptor genes revealed decreasing diversity of the T-cell repertoire and an expansion of select clonotypes in responders. To validate our observations, we stimulated T cells and CLL cells with lenalidomide in culture and detected lenalidomide-dependent increases in T-cell proliferation. Taken together, our data demonstrate that lenalidomide induced Th1 immunity in the lymph node that is associated with clinical response.
Project description:To identify genomic alterations contributing to the pathogenesis of high‑risk chronic lymphocytic leukemia (CLL) beyond the well‑established role of TP53 aberrations, we comprehensively analyzed 146 high‑risk CLL cases by single‑nucleotide polymorphism (SNP)‑arrays and targeted next‑generation sequencing including 75 relapsed/refractory and 71 treatment‑naïve high‑risk cases from prospective clinical trials. Increased genomic complexity was a hallmark of relapsed/refractory and treatment‑naïve high‑risk CLL, and was associated with TP53 and ATM dysfunction. In relapsed/refractory cases previously exposed to the selective pressure of chemo(immuno)therapy, gain(8)(q24.21) and del(9)(p21.3) were found particularly enriched. Both of these copy number alterations (CNAs) affected key regulators of cell cycle progression, namely c‑MYC and CDKN2A/B. Gains in 8q24.21 were either focal gains in a c‑MYC enhancer region or larger gains directly affecting the c‑MYC locus, but only the latter type was highly enriched in relapsed/refractory CLL (17%). Loss of CDKN2A/B was found frequently to co‑occur with gain of c‑MYC and in this combination it was likely associated with Richter transformation. In addition to a high frequency of NOTCH1 mutations (23%), we found recurrent genetic alterations in SPEN (4% mutated), RBPJ (8% deleted) and SNW1 (8% deleted), all affecting a protein complex that represses transcription of NOTCH1 target genes. We investigated the functional impact of these alterations on HES1, DTX1 and c‑MYC gene transcription and found de‑repression of these NOTCH1 target genes particularly with SPEN mutations. In summary, we provide new insights into the pathogenesis of high‑risk CLL by defining novel recurrent CNAs and identifying alterations that likely contribute to disease refractoriness.
