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

项目4：嵌合抗原受体T细胞疗法治疗急性髓系白血病

基本信息

批准号：
10474300
负责人：
Renier Joseph Brentjens
金额：
$ 36.77万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-24 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10474300
关键词：
Acute Myelocytic Leukemia Acute leukemia Address Adult Aftercare Antigen Targeting Antigens Antitumor Response CAR T cell therapy CD19 gene Cell surface Characteristics Chemoresistance Clinical Clinical Treatment Correlative Study Development Disease Disease Marker Disease remission Goals Hematopoiesis Hematopoietic stem cells Human Immune Immune Targeting Immune response Immunophenotyping Incidence Interleukin-18 Investigational Therapies Large-Cell Lymphomas Maximum Tolerated Dose Mediating Memorial Sloan-Kettering Cancer Center Minority Myeloid Cells Myeloid Leukemia Natural regeneration Outcome Pathologic Patients Phase I Clinical Trials Recurrent disease Refractory Regimen Relapse Remission Induction Safety Secondary to Survival Rate T cell response T-Lymphocyte Testing Therapeutic Toxic effect Transplantation Treatment outcome Tumor-infiltrating immune cells Vaccination Variant Vertebral column acute myeloid leukemia cell anti-tumor immune response base cancer cell chemotherapy chimeric antigen receptor T cells cytokine immune clearance immunogenicity improved leukemia leukemia/lymphoma leukemic stem cell neoplastic cell novel patient derived xenograft model pre-clinical reconstitution response response biomarker therapy development tumor tumor microenvironment

项目摘要

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).

抽象的迫切需要开发白血病干细胞（LSC）导向的治疗药物治疗急性髓系白血病（AML）的方法。其中一种策略是针对以下抗原：是 LSC 特有的，但正常造血干细胞 (HSC) 中不存在。 CD371（CLEC12A、CLL-1）、存在于成熟骨髓细胞上，鉴于其存在于大量 AML 细胞和 LSC 上。尽管并非在所有 AML 细胞中普遍表达，但它在高达 95% 的 AML 患者中表达，在 LSC 和化疗耐药 AML 亚群中富集，并且最重要的是，HSC 中不存在。我们已成功开发并验证了全人源 CD371 靶向嵌合抗原受体 (CAR) T 细胞产物，也分泌 IL-18。鉴于我们的 CD371 靶向基序完全是人类的，因此预计降低免疫原性，从而最大限度地减少宿主介导的 CAR T 细胞定向免疫消除 IL18 组成型分泌的背景。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（TME）渗透，导致诱导内源性 T 细胞介导的抗肿瘤免疫反应，根除抗原阴性肿瘤细胞亚群。我们的中心假设是，靶向 CD371 的分泌 IL18 的 CAR T 细胞将导致根除抗原 - 阳性耐药和 LSC 亚群，以及内源性 AML 反应性 T 细胞的诱导这种反应将导致抗原阴性疾病的消除，且没有长期 HSC 毒性。这将是在 AML 患者衍生的异质抗原阳性疾病异种移植模型中进行了测试（目标 1）和使用 CD371 靶向、分泌 IL18 的 CAR T 细胞治疗复发/难治性 AML 患者的 I 期临床试验（目标 2）。因此，这项工作将评估这种新型 CAR-T 细胞方法在以下两个方面的安全性和有效性：临床前和临床环境，还将解决许多反应和功效的生物标志物相关研究（目标 3）。