Phase 2 clinical trial of a novel T cell therapy following bridging therapy with hypomethylating agents for relapsed AML patients post-stem cell transplant

干细胞移植后复发性 AML 患者使用低甲基化药物桥接治疗后新型 T 细胞疗法的 2 期临床试验

• 批准号: 10761513
• 负责人: LAURA S ANGELO
• 金额: $ 66.48万
• 依托单位: MARKER THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-10 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10761513
• 关键词: Acute Myelocytic Leukemia; Adjuvant; Adverse event; Allogenic; Animal Model; Antigen Targeting; Antigens; Authorization documentation; Azacitidine; Benefits and Risks; Biological Markers; Blood Component Removal; CAR T cell therapy; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Therapy; Cells; Characteristics; Clinical; Clinical Research; Clonality; Data; Decitabine; Disease; Disease remission; Dose; Environment; Epitope spreading; Evaluable Disease; Exhibits; Future; Grant; Hematopoietic Neoplasms; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Immune; Immune system; Immunologic Monitoring; In Vitro; Infusion procedures; Intervention; Killer Cells; Laboratories; Leukocytes; Malignant Neoplasms; Marketing; Multicenter Studies; Orphan; Partial Remission; Patient Monitoring; Patients; Phase; Phase II Clinical Trials; Phenotype; Population; Protocols documentation; Regimen; Relapse; Research Design; Residual Neoplasm; Safety; Sampling; Signal Transduction; Specificity; Stem cell transplant; Subgroup; Surface; Survival Rate; T cell therapy; T-Lymphocyte; TCR Activation; Testing; Tissues; Training; Tumor Antigens; Tumor Escape; acute myeloid leukemia cell; antigen-specific T cells; arm; authority; cancer cell; cell killing; chemotherapy; cohort; commercialization; cytokine; design; effective therapy; efficacy evaluation; experience; human leukocyte antigen testing; improved; in vivo; in vivo monitoring; innovation; manufacture; mortality; neoplastic cell; neurotoxicity; novel; novel therapeutics; partial response; participant enrollment; post-transplant disease; pre-clinical; prevent; recruit; response; safety assessment; side effect; standard of care; stem cell therapy; targeted treatment; tumor; tumor growth; tumor specificity

ABSTRACT This Phase II application will advance MT-401, a novel multi-tumor associated antigen (mTAA)-specific T cell product for the treatment of acute myeloid leukemia (AML) and other cancers. In the USA, ~3,500 AML patients receive hematopoietic stem cell therapy (HSCT) every year, but overall survival remains <30%, with an estimated median survival of <1 year. Although AML is sensitive to immune-/T cell-based interventions, these are limited due to: 1) lack of one antigen with sufficient tumor specificity, 2) tumor immune escape, and 3) requirement for lymphodepletion which helps prevent engagement of the endogenous immune system (epitope spreading) and leads to adverse events. mTAA-specific T cells target multiple tumor associated antigens simultaneously, thereby minimizing tumor escape. MT-401 targets 4 antigens highly expressed in AML, but with absent or low expression levels in healthy tissue. Manufactured from allogeneic apheresis material from the HSCT donor, MT-401 recognizes target cells via native T cell receptors (TCRs), by interacting with both class I and II MHC, leading to killing of cells expressing any of these antigens, as well activation of other immune cells. mTAA-specific T cell products attacking the same targets as MT-401 exhibited specific killing of HLA-matched cells expressing these antigens and reduction of tumor growth in animal models. mTAA-specific therapy was also shown to be clinically safe in >170 patients with various kinds of cancer. In a heavily pretreated AML population with active disease post-HSCT, this therapy demonstrated complete (CR) or partial (PR) responses in some of the patients, while adjuvant patients remained in remission longer than expected. Importantly, epitope spreading was observed leading to more durable responses versus other cellular therapies. In order to enhance the efficacy of MT-401, we treated AML cells with hypomethylating agents (HMA), which upregulate some of the tumor antigens targeted by MT-401, followed by MT-401. Our in vitro data shows enhanced killing when treating with HMA followed by MT-401, supporting this regimen in relapsed AML patients post-HSCT. In this study, we are proposing a Phase II clinical trial of MT-401 following HMA as bridging therapy in relapsed AML patients post-HSCT to prepare for future commercialization. Specific Aim 1 includes evaluation of efficacy and safety of MT-401. Specific Aim 2 includes immune monitoring of patient samples including T cell expansion, persistence, clonality, anti-tumor immune effects, tumor antigen expression, and epitope spreading. Successful completion of this grant will lead to future BLA filing and commercial approval of MT-401 as a revolutionary T cell therapy for AML patients.

抽象的 此II期应用将推进MT-401，这是一种新型的多肿瘤相关抗原（MTAA）特异性T细胞 治疗急性髓样白血病（AML）和其他癌症的产物。 在美国，每年约有3,500名AML患者接受造血干细胞疗法（HSCT），但总体生存率 仍然<30％，估计中位存活率<1年。尽管AML对基于免疫/T细胞的敏感 干预措施，由于：1）缺乏足够肿瘤特异性的一种抗原，2）肿瘤免疫 逃脱和3）需要淋巴结伸的要求，这有助于防止内源性免疫接合 系统（表位扩散）并导致不良事件。 MTAA特异性T细胞同时靶向多种肿瘤相关的抗原，从而最大程度地减少肿瘤 逃脱。 MT-401靶向4位在AML中高表达的抗原，但在健康中没有表达水平或低表达水平 组织。 MT-401由HSCT供体的同种异体形成材料制造，识别靶细胞 通过天然T细胞受体（TCR），通过与I类和II类MHC相互作用，导致表达细胞的杀伤 这些抗原中的任何一种，以及其他免疫细胞的激活。 MTAA特异性T细胞产品攻击相同 作为MT-401的靶标表现出表达这些抗原的HLA匹配细胞的特异性杀伤和还原 动物模型中的肿瘤生长。 MTAA特异性疗法在> 170例患者中也证明是临床安全的 各种癌症。在HSCT后有活性疾病的大量预处理的AML人群中，这种疗法 在某些患者中显示出完整的（CR）或部分（PR）反应，而辅助患者仍保持 缓解比预期的时间长。重要的是，观察到表位传播导致更耐用 反应与其他细胞疗法。为了提高MT-401的功效，我们用 低甲基化剂（HMA）上调了MT-401靶向的一些肿瘤抗原，其次是 MT-401。我们的体外数据显示，用HMA接和MT-401治疗时，杀戮增强了，支持了这一点 HSCT后复发AML患者的方案。 在这项研究中，我们提出了HMA之后作为MT-401的II期临床试验作为复发的桥接治疗 HSCT后AML患者为将来的商业化做准备。特定目标1包括评估功效 和MT-401的安全性。特定的目标2包括对包括T细胞扩张在内的患者样本的免疫监测， 持久性，克隆性，抗肿瘤免疫作用，肿瘤抗原表达和表位扩散。成功的 这笔赠款的完成将导致MT-401的未来BLA提交和商业认可作为革命性的T AML患者的细胞疗法。