Myeloid cell-selective, oligonucleotide-based STAT3 inhibition combined with total marrow and lymphoid irradiation for immunotherapy of acute myeloid leukemia

骨髓细胞选择性、基于寡核苷酸的 STAT3 抑制联合全骨髓和淋巴照射用于急性髓系白血病的免疫治疗

• 批准号: 10752538
• 负责人: Susanta K Hui
• 金额: $ 71.13万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-19 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10752538
• 关键词: Acute Myelocytic Leukemia; Adverse effects; Aftercare; Allogenic; Biopsy; Blood Vessels; Bone Marrow; Bone marrow biopsy; CD8-Positive T-Lymphocytes; CD8B1 gene; Cause of Death; Cell Death; Cell Death Induction; Cell Differentiation process; Cell Survival; Cell Transplantation; Cells; Clinical; Clinical Research; Clinical Trials; Combined Modality Therapy; DNA; DNMT3a; Development; Effector Cell; Epigenetic Process; FDA approved; Feedback; Flow Cytometry; Gene Expression; Gene Silencing; Generations; Genetic Transcription; Goals; Growth; Human; Immune; Immune Evasion; Immune response; Immunocompetent; Immunodeficient Mouse; Immunophenotyping; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Inflammasome; Interleukin-6; Intravenous; Leukemic Cell; Macrophage; Malignant Neoplasms; Marrow; Mediating; Mediator; Modeling; Molecular; Mus; Myeloid Cells; NF-kappa B; Normal tissue morphology; Oligonucleotides; Oncogenes; Organ; Patient-Focused Outcomes; Patients; Positioning Attribute; Pre-Clinical Model; Property; Radiation; Radiation Dose Unit; Radiation Protection; Radiation therapy; Radiation-Induced Cancer; Radioimmunotherapy; Recurrence; Recurrent disease; Refractory; Refractory Disease; Regimen; Regulator Genes; Regulatory T-Lymphocyte; Relapse; Reporting; Research; Resistance; Role; Secondary acute myeloid leukemia; Signal Transduction; Small Interfering RNA; Solid Neoplasm; Stat3 protein; Sting Injury; Structure; Survival Rate; System; T cell infiltration; T-Lymphocyte; TLR9 gene; Testing; Therapeutic; Time; Tissues; Toxic effect; Treatment Efficacy; Tumor Debulking; Tumor-associated macrophages; Vascularization; acute myeloid leukemia cell; cancer cell; cancer therapy; cell mediated immune response; clinical biomarkers; clinically relevant; combinatorial; comparative efficacy; conditioning; cytokine; cytotoxic; cytotoxicity; design; efficacy evaluation; efficacy study; epigenomics; experience; hematopoietic cell transplantation; image guided; image-guided radiation; immune checkpoint; immunogenic; immunogenic cell death; immunogenicity; immunotoxicity; improved; in vivo; in vivo Model; inhibitor; innovation; leukemia; leukemia relapse; leukemia treatment; leukemic stem cell; lymphoid irradiation; neovascularization; novel; nuclease; personalized approach; potential biomarker; preclinical study; radiation resistance; recruit; sensor; small molecule; synergism; timeline; trafficking; transcriptomics; translational goal; treatment comparison; tumor; tumor microenvironment; uptake

PROJECT SUMMARY There has been little or no long-term improvement in outcomes for patients with treatment-refractory acute myeloid leukemia (AML). The recently developed image-guided radiation strategy, total marrow and lymphoid irradiation (TMLI) delivers high radiation doses to major leukemia reservoirs while sparing normal tissues. Although TMLI prior to allogeneic hematopoietic cell transplantation (HCT) improved patients’ 2-year overall survival (OS) rate from <10% to 48%, relapses remained common. Such radiation resistance is a consequence of both intrinsic cancer cell properties and the extrinsic influence of the tumor microenvironment. It was previously demonstrated that radiation-induced cell death causes the release of danger signals recruiting Toll-like Receptor- 9 (TLR9)-positive myeloid cells, which jump-start tumor vascularization and regrowth. These cancer-promoting, rather than immunostimulatory, effects are mediated by TLR9-mediated secretion of cytokines such as IL-6, thereby leading to activation of Signal Transducer and Activator of Transcription 3 (STAT3). STAT3 is a multifaceted oncogene and a central immune checkpoint regulator operating in AML cells as well as in tumor- associated myeloid cells in patients. However, it remains an elusive target, with no FDA-approved direct small molecule STAT3 inhibitors. To overcome this challenge, we previously developed a strategy to deliver oligonucleotide STAT3 inhibitors, such as siRNA or decoy DNA, specifically into commonly TLR9-positive AML and normal myeloid cells. The nuclease-resistant, second-generation CpG-STAT3 decoy inhibitor (CSI-2) injected intravenously showed efficacy in targeting STAT3, suppressing leukemia cell survival and/or inducing immune responses against moderate burden of human and mouse AML in vivo. The hypothesis is that combining the immunostimulatory CSI-2 strategy with conditioning TMLI treatments will improve treatment efficacy against AML even at high burden (>50% leukemic blasts in the bone marrow) by providing time for the generation of adaptive T-cell driven immune responses. The preliminary results demonstrated that the TMLI regimen can improve uptake of CSI-2 by AML, thereby reducing leukemia-initiating potential, augmenting AML immunogenicity, and thereby inducing potent CD8+ T cell-mediated antileukemic immune responses. We propose to: 1. elucidate the molecular mechanisms of TMLI/CSI-2 effect on AML cell differentiation; 2. optimize TMLI to maximize the effect on leukemic bone marrow vascular structure, CSI-2 delivery, leukemogenic potential, and immunogenicity; 3. assess the efficacy and cellular mode-of-action of the TMLI/CSI-2 combination treatment compared to either treatment alone in human or mouse AML models in humanized or syngeneic mice, respectively. The overarching goal of this interdisciplinary proposal is to produce a clinically relevant, effective, and safe combinatorial radiation-immunotherapy for patients with relapsed/recurrent AML, representing the highest unmet need in cancer therapy.

项目摘要 难治性急性胰腺炎患者的结局很少或没有长期改善， 骨髓性白血病（AML）。最近开发的图像引导放射治疗策略，全骨髓和淋巴 放射治疗（TMLI）向主要的白血病储库提供高放射剂量，同时保留正常组织。 尽管异基因造血细胞移植（HCT）前的TMLI改善了患者的2年总体 生存（OS）率从<10%到48%，复发仍然很常见。这种抗辐射性是 癌细胞的内在特性和肿瘤微环境的外在影响。此前有 证明辐射诱导的细胞死亡导致危险信号的释放，招募Toll样受体- 9（TLR 9）-阳性骨髓细胞，可启动肿瘤血管化和再生长。这些致癌的， 作用不是免疫刺激性的，而是由TLR 9介导的细胞因子如IL-6的分泌介导的， 从而导致信号转导和转录激活因子3（STAT 3）的激活。STAT 3是一种 多方面的癌基因和一个在AML细胞以及肿瘤细胞中起作用的中央免疫检查点调节因子， 相关的骨髓细胞。然而，它仍然是一个难以捉摸的目标，没有FDA批准的直接小 分子STAT 3抑制剂。为了克服这一挑战，我们之前制定了一项战略， 寡核苷酸STAT 3抑制剂，如siRNA或诱饵DNA，特异性进入常见的TLR 9阳性AML 和正常的骨髓细胞抗核酸酶的第二代CpG-STAT 3诱饵抑制剂（CSI-2） 静脉内注射显示出靶向STAT 3、抑制白血病细胞存活和/或诱导白血病细胞凋亡的功效。 在体内针对人类和小鼠AML的中等负荷的免疫应答。假设是， 免疫刺激性CSI-2策略与条件性TMLI治疗将改善治疗效果， 即使在高负荷（骨髓中白血病原始细胞>50%）下，通过提供时间产生 适应性T细胞驱动的免疫反应。初步结果表明，TMLI方案可以 改善AML对CSI-2摄取，从而降低白血病引发潜力，增强AML 免疫原性，从而诱导有效的CD 8 + T细胞介导的抗白血病免疫应答。我们 建议：1.阐明TMLI/CSI-2影响AML细胞分化的分子机制; 2.优化 TMLI最大化对白血病骨髓血管结构的影响，CSI-2递送，致白血病 潜在性和免疫原性; 3.评估TMLI/CSI-2联合治疗的疗效和细胞作用模式 与人源化或同基因小鼠中的人或小鼠AML模型中的单独治疗相比， 分别这个跨学科的建议的总体目标是产生一个临床相关的，有效的， 和安全的组合放射免疫治疗复发/复发性AML患者，代表了 癌症治疗中最高的未满足需求。