Off-The-Shelf Dual Targeted NK Cells For NHL

用于 NHL 的现成双靶向 NK 细胞

• 批准号: 10613411
• 负责人: DANIEL J WEISDORF
• 金额: $ 38.18万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10613411
• 关键词: ATAC-seq; Adoptive Transfer; Affinity; Allogenic; Antigen Targeting; Antigens; Autologous; Autologous Transplantation; B-Cell Lymphomas; Binding; CD19 gene; CD34 gene; Cell Death Induction; Cell Line; Cell physiology; Cell surface; Cells; Cellular Metabolic Process; ChIP-seq; Clinical; Clinical Trials; Clip; Clone Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Data; Development; Dose; Dose Limiting; Engineering; Engraftment; Enzymes; Exhibits; FCGR3B gene; FDA approved; Failure; Funding; Future; Gene Deletion; Gene Modified; Genes; Genetic Engineering; Goals; Half-Life; Heterogeneity; Immune; In complete remission; Individual; Infusion procedures; Ink; Interleukin-15; Investigation; Knock-out; Lymphoma; MS4A1 gene; Maintenance Therapy; Malignant - descriptor; Mediating; Membrane; Metabolic; Metabolism; Minnesota; Modification; NK cell therapy; Natural Increases; Natural Killer Cells; Non-Hodgkin' s Lymphoma; Oral; Oxidative Stress Induction; Patients; Phenotype; Prevention strategy; Process; Production; Relapse; Reporting; Resistance; Role; Site; Specificity; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Translations; Transplantation; Universities; Variant; Work; antibody-dependent cell cytotoxicity; cancer therapy; cellular transduction; chimeric antigen receptor; chimeric antigen receptor T cells; cytokine; cytokine release syndrome; disorder risk; engineered NK cell; experience; gastrointestinal; high risk; improved; in vivo; induced pluripotent stem cell; inhibitor; manufacturing process; manufacturing run; metabolic abnormality assessment; metabolic fitness; metabolic profile; overexpression; patient derived xenograft model; phase 1 study; post-transplant; pre-clinical; preclinical trial; prevent; progenitor; programs; receptor; relapse prevention; response; rituximab; safety study; scale up; small molecule; stem cell differentiation; synergism; targeted treatment; transcriptome sequencing; transgene expression

Limiting relapse is the biggest challenge following autologous transplantation for non-Hodgkin’s lymphoma. Antigen-directed CAR T cell products and other targeted therapies may be changing the field, yet for high-risk lymphomas, new and safer approaches are needed. We will study the safety and efficacy of antigen-directed, off-the-shelf, induced pluripotent stem cell (iPSC)-derived NK cells engineered for dual-antigen targeting. We have optimized the differentiation of iPSC-derived CD34+ cells to highly potent NK cells, scaled production at the University of Minnesota, and can now produce hundreds of doses in a manufacturing run with a clonal iPSC transduced with a high-affinity, non-cleavable CD16 (called hnCD16). In late 2019, we initiated clinical trials testing this engineered iPSC product (designated FT516). The overarching hypothesis for this project is that dual targeting of NK cells with a CAR and through hnCD16 will protect against relapse after auto-transplant for lymphoma and that future gene edits to alter metabolism will enhance adoptive transfer. This hypothesis fits with the themes of this Program, and Project 2 will inform the Program on the development of off-the-shelf NK cells, NK CAR, and the role of membrane IL-15, as well as pre-clinically on whether manipulating metabolism will enhance NK cell therapy. These investigations are supported by the following Specific Aims. Aim 1 will test dual targeting of NK cells to CD19 and CD20 using two mechanisms of action, ADCC and an NK CAR, to prevent relapse after autologous transplantation for lymphoma. We will test a triple gene-modified iPSC-derived NK cell product (FT596) transduced with hnCD16, an NK cell-optimized CD19 CAR, and membrane bound 15/IL-15Ra fusions. FT596 will be combined with rituximab as maintenance therapy to limit relapse after autologous HCT. This trial is FDA-approved and will first establish an MTD at day +30 after engraftment and then, if single dosing is safe, move to day +7 before engraftment with the goal of 3 doses in the first hundred days to prevent relapse. Aim 2 will test enhancement of NK cell metabolic fitness by ARID5B overexpression and CD38 knockout. Our preliminary data shows both adaptive NK cells and CD38 knockout iPSC-derived NK cells resist oxidative stress- induced cell death. ARID5B overexpression, naturally increased in adaptive NK cells, mediates similar effects. We will generate new iPSC lines to build on FT596 with transgenic expression of ARID5B or a CRISPR knockout of CD38. These clones will be evaluated to probe the mechanisms on how they drive NK cell metabolism and augment function. Aim 3 will test whether manipulating ARID5B and CD38 will drive metabolic fitness and enhance FT596 persistence and function in vivo. These pre-clinical trials will inform future clinical trial modifications—all to promote enhanced anti-lymphoma activity by extending transferred NK cell persistence and potency. These metabolic and potency findings will directly inform Project 1 to improve cell targeting and metabolism, Project 3 for cell persistence, and all 3 Projects to define the advantages of autonomous presentation of IL-15.

限制继电器是非霍奇金淋巴瘤自体移植后最大的挑战。 抗原指导的汽车T细胞产物和其他靶向疗法可能正在改变现场，但对于高风险 需要淋巴瘤，新的和安全的方法。我们将研究抗原导向的安全性和效率， 现成的，诱导的多能干细胞（IPSC）衍生的NK细胞，用于双抗原靶向。我们 已经优化了IPSC衍生的CD34+细胞与高潜力NK细胞的分化，在 明尼苏达大学，现在可以用克隆IPSC在制造业中生产数百种剂量 用高亲和力，不可裂解的CD16（称为HNCD16）转导。在2019年底，我们开始了临床试验 测试该工程的IPSC产品（指定的FT516）。该项目的总体假设是 用汽车和通过HNCD16双重靶向NK细胞的双重靶向将防止自动移植后退休 淋巴瘤和未来基因编辑以改变代谢将增强适应性转移。这个假设与 该计划的主题和项目2将告知该计划的开发现成的NK单元， NK汽车以及膜IL-15的作用，以及在操纵新陈代谢的前临时行动 增强NK细胞疗法。这些调查得到以下特定目标的支持。 AIM 1将测试双重 使用两种动作机理ADCC和NK CAR将NK细胞靶向CD19和CD20，以防止 自体移植后淋巴瘤复发。我们将测试一个三重基因修饰的IPSC衍生的NK细胞 产品（FT596）用HNCD16，NK细胞优化的CD19车和膜结合15/IL-15RA翻译的产品（FT596） 融合。 FT596将与利妥昔单抗作为维持疗法结合使用，以限制自体HCT后继电器。 该试验经过FDA批准，在植入后首先在+30的第二天建立MTD，然后，如果是单一的给药 是安全的，在植入之前，请移至第二天+7，在前一百天内进行3剂的目标，以防止退休。 AIM 2将通过ARID5B过表达和CD38敲除测试NK细胞代谢适应性的增强。我们的 初步数据显示自适应NK细胞和CD38敲除IPSC衍生的NK细胞抗氧化应激 - 诱导细胞死亡。自适应NK细胞中自然增加的Arid5b过表达介导相似的作用。 我们将生成新的IPSC线，以FT596的形式建立，并以ARID5B或CRISPR敲除的转基因表达 CD38。这些克隆将进行评估以探测它们如何驱动NK细胞代谢和 增强功能。 AIM 3将测试操纵ARID5B和CD38是否会推动代谢健身和 增强FT596体内的持久性和功能。这些临床前试验将为未来的临床试验提供信息 修改 - 通过扩展转移的NK细胞持久性和 效力。这些代谢和效力发现将直接通知项目1，以改善细胞靶向和 代谢，细胞持久性项目3，以及所有3个项目来定义自主的优势 IL-15的介绍。