Cell-Selective Telomere Damage by Thiopurine-Based Oligonucleotide for Diffuse Large B-cell Lymphoma Immunotherapy
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PROVIDER: PRJNA1301366 | ENA |
REPOSITORIES: ENA
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Project description:Telomerase (TERT) is an enzyme involved in maintaining telomere length in diffuse large B-cell lymphoma (DLBCL). Previous attempts to target TERT+ cancers faced challenges, including the delayed clinical responses and on-target/off-tumor toxicities. Here, we present a DLBCL-targeted oligonucleotide designed to deliver a synthetic TERT substrate, 6-thio-2’-deoxy-guanosine (6tdG), damaging telomeres and triggering apoptosis. In vitro, 6tdG-oligonucleotides (6tdGOs) were selectively cytotoxic to TERT + DLBCL cells without affecting activated T-cells or non-malignant TERT— cells. Repeated intravenous administration of 6tdGO, but not 6tdG nucleoside, had significant antitumor effects against xenotransplanted human DLBCL models and syngeneic E-myc/15A lymphoma in mice. In immunocompetent mice, treatment with 6tdGO induced systemic, lymphoma-specific and CD8 T-cell-mediated antitumor immune responses. The abscopal effects of 6tdGO were abolished in mice lacking expression of Sting1 or Ifnar1 but not Trl9. These findings suggest that 6tdGO-induced lymphoma cell death triggered STING-mediated type-I IFN signaling, thereby promoting recruitment/activation of CD8 T-cells. Importantly, the repeated 6tdGO treatments were well-tolerated in humanized hCD34/NOG mice. Except for the reduced percentage of human B-cells, 6tdGO did not decrease the numbers of hematopoietic stem cells, myeloid cells, or T-cells. Overall, 6tdGO offers an effective and safer strategy against aggressive TERT + DLBCL with potential to activate T-cell based antitumor immunity
2025-08-04 | GSE304480 | GEO
Project description:Remarkable progress has been made in the field of cancer immunotherapy in the past few years. Immunotherapy has become a standard treatment option for patients with various cancers, including melanoma, lymphoma, and carcinomas of the lungs, kidneys, bladder, and head and neck. Promising immunotherapy approaches, such as chimeric antigen receptor (CAR) T cell therapy and therapeutic blockade of immune checkpoints, in particular cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 pathway (PD-1/PD-L1), have boosted the development of new therapeutic regimens for patients with cancer. Immunotherapeutic strategies for diffuse large B-cell lymphoma (DLBCL) include monoclonal anti-CD20 antibody (rituximab), monoclonal anti-PD-1 antibodies (nivolumab and pembrolizumab), monoclonal anti-PD-L1 antibodies (avelumab, durvalumab, and atezolizumab) and chimeric antigen receptor (CAR) T cell therapy. In this review, we outline the latest highlights and progress in using immunotherapy to treat patients with DLBCL, with a focus on the therapeutic blockade of PD-1/PD-L1 and CAR T cell therapy in DLBCL. We also discuss current clinical trials of PD-1/PD-L1 and CAR T cell therapy and review the challenges and opportunities of using immunotherapy for the treatment of DLBCL.
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Project description:RC-DLBCL (Diffuse Large-B Cell Lymphomas)
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Project description:Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin's lymphoma, is clinically heterogeneous: 40% of patients respond well to current therapy and have prolonged survival, whereas the remainder succumb to the disease. We proposed that this variability in natural history reflects unrecognized molecular heterogeneity in the tumors. Using DNA microarrays, we have conducted a systematic characterization of gene expression in B-cell malignancies. Here we show that there is diversity in gene expression among the tumors of DLBCL patients, apparently reflecting the variation in tumor proliferation rate, host response and differentiation state of the tumor. We identified two molecularly distinct forms of DLBCL which had gene expression patterns indicative of different stages of B-cell differentiation. One type expressed genes characteristic of germinal center B cells ('germinal center B-like DLBCL'); the second type expressed genes normally induced during in vitro activation of peripheral blood B cells ('activated B-like DLBCL'). Patients with germinal center B-like DLBCL had a significantly better overall survival than those with activated B-like DLBCL. The molecular classification of tumors on the basis of gene expression can thus identify previously undetected and clinically significant subtypes of cancer. This study is described more fully in Alizadeh AA et al.(2000) Nature 403:503-11
2002-06-27 | E-GEOD-60 | biostudies-arrayexpress
Project description:To investigate the biological differences between HIV-, HIV+/ART-experienced and HIV+/ART-naive diffuse large B-cell lymphoma, we performed whole exome sequencing of 30 pre-treatment formalin-fixed paraffin-embedded (FFPE) whole lymph node biopsies of diffuse large B-cell lymphoma.
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