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

摘要 急性髓性白血病（AML）是骨髓中产生的髓系细胞的恶性肿瘤， 超过正常造血细胞的生长在美国，约3，500名AML患者接受造血干细胞治疗。 每年都有大量的人接受造血干细胞移植（HSCT），然而HSCT后复发仍然是死亡的主要原因， 1-年生存率和低完全缓解率。 虽然AML已被证明对基于免疫的干预措施敏感（例如，供者淋巴细胞输注 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）需要淋巴细胞清除，防止内源性免疫参与 系统（表位扩散），和4）移植物抗宿主病（GVHD）和其他不良反应的风险。 Marker提出了一种新的基于T细胞的疗法，靶向多种肿瘤相关抗原（mTAAs） 同时，使肿瘤逃逸最小化。具体而言，这里要测试的产品MT-401靶向4 在AML中高度表达但在健康组织中不存在或以低水平表达的抗原。 MT-401由HSCT供体的同种异体单采材料制成，通过以下方式识别靶细胞： 天然T细胞受体（TCR）通过与I类和II类MHC相互作用，导致细胞杀伤 表达任何这些抗原，以及激活其他免疫细胞。 临床前，MT-401 T细胞表现出特异性杀伤表达这些抗原的HLA匹配的白血病细胞。 这种mTAA特异性T细胞在>150名患有各种癌症的患者中显示出临床安全性。中 对于HSCT后患有活动性疾病的重度预治疗AML人群，该疗法表现出客观的临床疗效。 一些患者出现完全（CR）或部分（PR）缓解的证据，而辅助治疗患者仍然存在 比预期的要长此外，1例可测量残留病变（MRD）患者显示 治疗后MRD水平相对稳定下降。重要的是，观察到表位扩散，这是由于表位扩散导致的。 缺乏淋巴细胞清除，导致比其他细胞疗法更持久的反应。 该基金提出了MT-401的2期临床研究，MT-401是一种创新的同种异体T细胞产品， 首次接受同种异体HSCT的AML患者。在本研究所涵盖的部分内， 根据拟议的拨款，40名HSCT后MRD+的AML患者将入组研究。 具体目标1将包括临床试验的执行：入组、治疗和随访受试者直至研究 建成具体目标2将包括主要和次要疗效和安全性终点的评价。 具体目标3将包括评价用于生物标志物分析的患者样本，包括扩增、持久性， 克隆性、MT-401的抗肿瘤免疫作用和表位扩散，如通过探索性目的所确定的。

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.