Efficacy of a Multi-Tumor-Associated Antigen-Specific T Cell Therapy in AML Patients following Allogeneic Stem Cell Transplant with Minimal Residual Disease

多肿瘤相关抗原特异性 T 细胞治疗在同种异体干细胞移植后具有最小残留疾病的 AML 患者中的疗效

• 批准号: 10502295
• 负责人: Juan fernando Vera
• 金额: $ 51.98万
• 依托单位: MARKER THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10502295
• 关键词: Efficacy; Multi; Tumor; Associated; Antigen

ABSTRACT Acute myeloid leukemia (AML) is a malignant neoplasm of myeloid lineage cells arising in the bone marrow and outgrowing normal hematopoietic elements. In the US, ~3,500 AML patients receive hematopoietic stem cell transplant (HSCT) every year, however relapse after HSCT remains a major cause of mortality, leading to poor 1-year survival and low complete remission rates. Although AML has been shown to be sensitive to immune-based interventions (e.g., donor lymphocyte infusion or CAR-T cells), these are limited in AML because of: 1) lack of one antigen with sufficient tumor specificity, 2) tumor immune escape, 3) requirement for lymphodepletion, preventing engagement of the endogenous immune system (epitope spreading), and 4) risk of graft-versus-host disease (GVHD) and other adverse effects. Marker is proposing a novel T cell-based therapy that targets multiple tumor-associated antigens (mTAAs) simultaneously, thereby minimizing tumor escape. Specifically, the product to be tested here, MT-401, targets 4 antigens which are highly expressed in AML but are absent or expressed at low levels in healthy tissues. Manufactured from allogeneic apheresis material from an HSCT donor, MT-401 recognizes the target cells via the native T cell receptors (TCRs), by interacting with both class I and II MHCs, leading to killing of cells expressing any of these antigens, as well activation of other immune cells. Pre-clinically, MT-401 T cells exhibited specific killing of HLA-matched leukemia cells expressing these antigens. Such mTAA-specific T cells were shown to be clinically safe in >150 patients with various kinds of cancer. In a heavily pretreated AML population with active disease post-HSCT, this therapy demonstrated objective clinical evidence resulting in complete (CR) or partial (PR) responses in some patients, while adjuvant patients remained in remission longer than expected. Additionally, a patient with measurable residual disease (MRD) showed a relatively steady decline in MRD levels post-treatment. Importantly, epitope spreading was observed due to the lack lymphodepletion, leading to more durable responses compared to other cellular therapies. This grant proposes a Phase 2 clinical study of MT-401, an innovative allogeneic T cell product for the treatment of patients with AML who have received their first allogeneic HSCT. Within the portion of the study covered by the proposed grant, 40 AML patients who are MRD+ following HSCT will be enrolled in the study. Specific Aim 1 will include execution of the clinical trial: enrolling, treating and following subjects until study completion. Specific Aim 2 will include evaluation of the primary and secondary efficacy and safety endpoints. Specific Aim 3 will include evaluation of patient samples for biomarker analysis, including expansion, persistence, clonality, anti-tumor immune effects of MT-401, and epitope spreading, as determined by exploratory objectives.

抽象的 急性髓系白血病（AML）是一种起源于骨髓和骨髓的髓系细胞的恶性肿瘤。 生长超过正常造血元素。在美国，约 3,500 名 AML 患者接受了造血干细胞治疗 每年都会进行移植（HSCT），但是 HSCT 后的复发仍然是死亡的主要原因，导致病情不佳 1 年生存率和低完全缓解率。 尽管 AML 已被证明对基于免疫的干预措施（例如供体淋巴细胞输注）敏感， 或 CAR-T 细胞），这些在 AML 中受到限制，因为：1）缺乏一种具有足够肿瘤特异性的抗原，2） 肿瘤免疫逃逸，3) 需要清除淋巴细胞，防止内源性免疫参与 系统（表位扩散），4）移植物抗宿主病（GVHD）和其他不良反应的风险。 Marker 提出了一种基于 T 细胞的新型疗法，针对多种肿瘤相关抗原 (mTAA) 同时，从而最大限度地减少肿瘤逃逸。具体来说，这里要测试的产品MT-401，目标4 在 AML 中高表达但在健康组织中不存在或低水平表达的抗原。 MT-401 由 HSCT 供体的同种异体血浆分离材料制成，通过 天然 T 细胞受体 (TCR)，通过与 I 类和 II 类 MHC 相互作用，导致细胞死亡 表达任何这些抗原，以及激活其他免疫细胞。 临床前，MT-401 T 细胞表现出对表达这些抗原的 HLA 匹配白血病细胞的特异性杀伤作用。 这种 mTAA 特异性 T 细胞在超过 150 名患有各种癌症的患者中被证明是安全的。在一个 接受过大量预处理的 HSCT 后疾病活动的 AML 人群，该疗法表现出客观的临床效果 有证据表明某些患者获得完全（CR）或部分（PR）缓解，而辅助患者仍然存在 缓解期比预期长。此外，一名患有可测量残留病灶（MRD）的患者表现出 治疗后 MRD 水平相对稳定下降。重要的是，观察到表位扩散是由于 缺乏淋巴细胞清除，与其他细胞疗法相比，可产生更持久的反应。 该拨款提议对 MT-401 进行 2 期临床研究，MT-401 是一种创新的同种异体 T 细胞产品，用于治疗 接受第一次同种异体 HSCT 的 AML 患者。在所涵盖的研究部分内 根据拟议的拨款，40 名 HSCT 后 MRD+ 的 AML 患者将被纳入该研究。 具体目标 1 将包括临床试验的执行：招募、治疗和跟踪受试者直至研究 完成。具体目标 2 将包括对主要和次要疗效和安全性终点的评估。 具体目标 3 将包括评估患者样本以进行生物标志物分析，包括扩展、持久性、 由探索性目标确定的克隆性、MT-401 的抗肿瘤免疫作用和表位扩散。