Project 4: Chimeric Antigen Receptor T Cell Therapy for the Treatment of Acute Myeloid Leukemia

摘要 迫切需要发展白血病干细胞(LSC)导向的治疗方法 急性髓系白血病(AML)的治疗方法一种这样的策略是将目标抗原 是LSCs特异性的，但在正常的造血干细胞(HSCs)中缺失。CD371(Clec12a，CLL-1)， 它存在于成熟的髓系细胞上，已经被描述为这样的靶向疾病标记物，因为它 大量AML细胞和LSCs上均有表达。尽管它并不是在所有的AML细胞上普遍表达，但它是 在高达95%的AML患者中表达，在LSCs和耐药AML亚群上得到丰富，并且 最重要的是，在HSC上没有。 我们成功地开发并验证了一种完全以人CD371为靶标的嵌合抗原受体(CAR) 也分泌IL-18的T细胞产物。鉴于我们的CD371靶向基元完全是人类的，预计 降低免疫原性，从而最大限度地减少宿主介导的CAR T细胞导向的免疫消除 结构性IL-18分泌的背景。此外，IL18的分泌预计会增强CAR T细胞 通过增加和激活免疫细胞来维持和调节肿瘤微环境 侵袭，导致内源性T细胞介导的抗肿瘤免疫反应能够 根除抗原阴性的肿瘤细胞亚群。 我们的中心假设是，以CD371为靶点的分泌IL18的CAR T细胞将导致抗原- 化疗耐药和LSC阳性亚群及内源性AML反应性T细胞的诱导 这将导致消除抗原阴性疾病的反应，而不会产生长期的HSC毒性。这将是 在异种抗原阳性疾病的AML患者来源的异种移植模型中进行测试(AIM 1)和 CD371靶向分泌IL18的CAR T细胞治疗复发/难治性AML的I期临床试验 (目标2)。因此，这项工作将评估这种新的CAR-T细胞方法在两种情况下的安全性和有效性 临床前和临床环境，还将解决许多反应和疗效的生物标记物 相关研究(目标3)。

ABSTRACT There is an urgent and critical need for the development of leukemia stem cell (LSC)-directed therapeutic approaches for the treatment of acute myeloid leukemia (AML). One such strategy is targeting antigens that are specific to LSCs but absent from normal hematopoietic stem cells (HSCs). CD371 (CLEC12A, CLL-1), which is present on mature myeloid cells, has been described as one such targetable disease marker given its presence on both bulk AML cells and LSCs. Although not ubiquitously expressed on all AML cells, it is expressed in up to 95% of AML patients, is enriched on LSCs and chemoresistant AML subpopulations, and most importantly, is absent on HSCs. We have successfully developed and validated a fully-human CD371-targeted chimeric antigen receptor (CAR) T cell product which also secretes IL-18. Given that our CD371-targeting motif is entirely human, it is expected to have reduced immunogenicity and thus minimizes host-mediated CAR T cell-directed immune elimination in the context of constitutive IL18 secretion. In addition, IL18 secretion is predicted to enhance CAR T cell persistence and modulation the tumor microenvironment (TME) by increasing and activating immune cell infiltrates, leading to the induction of an endogenous T cell mediated anti-tumor immune-response capable of eradicating antigen-negative tumor cell subpopulations. Our central hypothesis is that CD371-targeted IL18-secreting CAR T cells will lead to eradication of antigen- positive chemoresistant and LSC subpopulations, and the induction of an endogenous AML-reactive T cell response that will lead to elimination of antigen-negative disease, without long-term HSC toxicity. This will be tested in AML patient-derived xenograft models of heterogeneously antigen-positive disease (Aim 1) and a phase I clinical trial with CD371-targeted IL18-secreting CAR T cells in patients with relapsed/refractory AML (Aim 2). This effort will therefore assess the safety and efficacy of this novel CAR-T cell approach in both preclinical and clinical settings, and will also address biomarkers of response and efficacy in numerous correlative studies (Aim 3).