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 这一二期应用将推进MT-401，一种新的多肿瘤相关抗原(MTAA)特异性T细胞 用于治疗急性髓系白血病(AML)和其他癌症的产品。 在美国，每年约有3500名AML患者接受造血干细胞治疗(HSCT)，但总体存活率 保持30%，估计中位生存期为1年。尽管AML对以免疫/T细胞为基础的 这些干预措施是有限的，原因是：1)缺乏一个具有足够肿瘤特异性的抗原，2)肿瘤免疫 逃逸，以及3)淋巴耗竭的需要，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，从而将肿瘤降至最低 逃走。MT-401靶向4种抗原，在AML中高表达，但在健康人群中不表达或低表达 组织。MT-401由来自HSCT供体的同种异体分离材料制成，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，导致杀伤表达 这些抗原中的任何一个，以及其他免疫细胞的激活。MTAA特异性T细胞产品攻击相同 靶点MT-401显示出对表达这些抗原的HLA匹配细胞的特异性杀伤作用，并减少了 动物模型中肿瘤的生长。MTAA特异性治疗也被证明在临床上是安全的，用于170名患有 各种癌症。在HSCT后有活动性疾病的严重预处理的AML人群中，这种疗法 部分患者显示完全(CR)或部分(PR)反应，而辅助性患者仍 缓解期比预期的要长。重要的是，观察到表位的扩散导致了更持久的 反应与其他细胞疗法的对比。为了增强MT-401的疗效，我们用AML细胞 去甲基化药物(HMA)，它上调MT-401靶向的一些肿瘤抗原，然后是 MT-401。我们的体外数据显示，当HMA和MT-401一起处理时，杀伤作用增强，支持这一点 HSCT后复发AML患者的化疗方案。 在这项研究中，我们建议进行MT-401的第二阶段临床试验，作为HMA后复发的桥接疗法 急性髓系白血病患者接受造血干细胞移植后，为未来的商业化做准备。具体目标1包括疗效评价 和MT-401的安全性。具体目标2包括对患者样本的免疫监测，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、表位扩散。成功 完成这项授权将导致未来的BLA申请和商业批准的MT-401作为革命性的T 急性髓系白血病患者的细胞治疗。

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.