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 急性髓样白血病（AML）是骨髓中出现的髓样谱系细胞的恶性肿瘤 正常造血元素的长期超越。在美国，约有3500名AML患者接受造血干细胞 每年移植（HSCT），但是HSCT后的复发仍然是死亡率的主要原因，导致较差 1年生存率和较低的完整缓解率。 尽管已显示AML对基于免疫的干预措施敏感（例如，供体淋巴细胞输注 或CAR-T细胞），由于：1）缺乏具有足够肿瘤特异性的抗原，2） 肿瘤免疫逃生，3）要求淋巴结蛋白的要求，以防止内源性免疫接合 系统（表位扩散）和4）患者抗宿主病（GVHD）和其他不良反应的风险。 Marker提出了一种基于T细胞的新型治疗，该治疗靶向多种肿瘤相关抗原（MTAA） 同时，最大程度地减少了肿瘤逃生。具体而言，在这里要测试的产品MT-401，目标4 在AML中高表达但在健康组织中低水平表达的抗原。 MT-401由HSCT供体的同种异体形成材料制造，MT-401通过 通过与I类和II类MHC相互作用的天然T细胞受体（TCR），导致细胞杀死 表达这些抗原中的任何一种，以及其他免疫细胞的激活。 在链式链接情况下，MT-401 T细胞表现出表达这些抗原的HLA匹配的白血病细胞的特异性杀伤。 在> 150种各种癌症患者中，这种MTAA特异性T细胞在临床上是安全的。在 该疗法在HSCT后用活跃疾病进行了大量预处理的AML人群，证明了客观的临床 导致某些患者的完全（CR）或部分（PR）反应的证据，而辅助患者仍保持 缓解比预期的时间长。此外，患有可测量残留疾病（MRD）的患者显示 治疗后MRD水平相对稳定下降。重要的是，由于 与其他细胞疗法相比，缺乏淋巴结序，导致更耐用的反应。 该赠款提出了MT-401的2期临床研究，MT-401是一种用于治疗的创新同种异体T细胞产物 AML患者接受了第一个同种异体HSCT。在研究的部分中 拟议的赠款将纳入HSCT后MRD+的40名AML患者。 具体目标1将包括执行临床试验：注册，治疗和以下受试者直到研究 完成。具体目标2将包括评估初级和次要功效和安全终点。 特定的目标3将包括评估患者样本的生物标志物分析，包括扩展，持久性， 克隆性，MT-401的抗肿瘤免疫作用和表位扩散，由探索性目标确定。