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

摘要 这项II期申请将推进MT-401，一种新型的多肿瘤相关抗原（mTAA）特异性T细胞 用于治疗急性髓性白血病（AML）和其他癌症的产品。 在美国，每年约有3，500名AML患者接受造血干细胞治疗（HSCT），但总体生存率 仍然<30%，估计中位生存期<1年。尽管AML对基于免疫/T细胞的免疫抑制剂敏感， 然而，由于以下原因，这些干预是有限的：1）缺乏一种具有足够肿瘤特异性的抗原，2）肿瘤免疫 逃避，和3）淋巴细胞清除的要求，这有助于防止内源性免疫的参与， 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抗原，从而最大限度地减少肿瘤 逃跑MT-401靶向4种在AML中高度表达的抗原，但在健康人中不表达或表达水平低。 组织. MT-401由HSCT供体的同种异体单采材料制成，可识别靶细胞 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。mTAA特异性T细胞产物攻击相同的 作为MT-401的靶点表现出特异性杀伤表达这些抗原的HLA匹配细胞， 动物模型中的肿瘤生长。mTAA特异性治疗在> 170例患者中也显示出临床安全性， 各种癌症。在HSCT后患有活动性疾病的重度预治疗AML人群中， 在一些患者中显示出完全（CR）或部分（PR）反应，而辅助治疗患者仍然存在 比预期的要长重要的是，观察到表位扩散导致更持久的免疫应答。 与其他细胞疗法相比。为了增强MT-401的功效，我们用MTT法处理AML细胞。 低甲基化剂（HMA），其上调MT-401靶向的一些肿瘤抗原，然后 MT-401我们的体外数据显示，当用HMA接着MT-401处理时，杀伤增强，支持这一点。 HSCT后复发的AML患者的治疗方案。 在这项研究中，我们提出了一项II期临床试验的MT-401后，HMA作为桥接治疗复发， HSCT后的AML患者为未来的商业化做准备。具体目标1包括疗效评价 MT-401的安全性具体目标2包括患者样品的免疫监测，包括T细胞扩增， 持久性、克隆性、抗肿瘤免疫效应、肿瘤抗原表达和表位扩散。成功 完成这一授权将导致未来的BLA申请和商业批准的MT-401作为一个革命性的T AML患者的细胞治疗。

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.