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 急性髓系白血病(AML)是一种起源于骨髓的髓系细胞的恶性肿瘤。 生长超过正常的造血元素。在美国，约3500名AML患者接受造血干细胞治疗 每年移植(HSCT)，但HSCT后复发仍然是死亡的主要原因，导致贫穷 1年存活率低，完全缓解率低。 尽管AML已被证明对基于免疫的干预(例如，供者淋巴细胞输注)敏感 或CAR-T细胞)，这些在AML中是有限的，因为：1)缺乏一种具有足够的肿瘤特异性的抗原，2) 肿瘤免疫逃逸，3)淋巴耗竭的需要，阻止内源性免疫的参与 (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细胞的治疗方法，针对多种肿瘤相关抗原(MTAAs) 同时，从而最大限度地减少肿瘤逃逸。具体地说，这里测试的产品MT-401的目标是4 在急性髓系白血病中高表达，但在健康组织中不表达或低水平表达的抗原。 MT-401由来自HSCT供体的同种异体分离材料制造，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 表达这些抗原中的任何一种，以及激活其他免疫细胞。 在临床前，MT-401T细胞对表达这些抗原的人类白细胞抗原相合的白血病细胞具有特异性杀伤作用。 这种MTAA特异性T细胞在患有各种癌症的150名患者中被证明是临床安全的。在一个 HSCT后有活动性疾病的急性髓系白血病患者经过严格的前处理，这项治疗显示了客观的临床意义。 在一些患者中导致完全(CR)或部分(PR)反应的证据，而辅助性患者仍然存在 缓解期比预期的要长。此外，一名患有可测量残留病(MRD)的患者显示出 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 缺乏淋巴消耗，与其他细胞疗法相比，导致更持久的反应。 这笔赠款建议对MT-401进行二期临床研究，MT-401是一种用于治疗的创新同种异体T细胞产品 接受了首次异基因造血干细胞移植的AML患者的比例。在以下内容所涵盖的研究部分内 根据建议的拨款，40名HSCT后MRD+的AML患者将被纳入这项研究。 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到研究 完成了。具体目标2将包括对初级和次级疗效和安全终点的评价。 具体目标3将包括对患者样本进行生物标记物分析的评估，包括扩展、持久性、 克隆性，MT-401的抗肿瘤免疫效果，以及表位扩展，由探索目标决定。

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.