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

• 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
• 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

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).

摘要 因此，迫切需要开发白血病干细胞（LSC）靶向治疗药物。 治疗急性髓细胞白血病（AML）的方法。一种这样的策略是靶向抗原， 对LSC是特异性的，但不存在于正常造血干细胞（HSC）中。CD371（CLEC12A，CLL-1）， 存在于成熟的骨髓细胞上，已经被描述为一种这样的可靶向的疾病标志物， 存在于大量AML细胞和LSC上。虽然不是在所有AML细胞上普遍表达，但它是 在高达95%的AML患者中表达，在LSC和化疗耐药AML亚群上富集， 最重要的是，它在HSC上不存在。 我们已经成功开发并验证了一种完全人CD 371靶向的嵌合抗原受体（CAR）， 也分泌IL-18的T细胞产物。考虑到我们的CD 371靶向基序完全是人类的， 具有降低的免疫原性，从而使宿主介导的CAR T细胞介导的免疫消除最小化， 组成型IL 18分泌的背景。此外，预计IL 18分泌可增强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） 浸润，导致诱导内源性T细胞介导的抗肿瘤免疫应答， 根除抗原阴性肿瘤细胞亚群。 我们的中心假设是，CD 371靶向的分泌IL 18的CAR T细胞将导致抗原的根除。 阳性化疗耐药和LSC亚群，以及诱导内源性AML反应性T细胞 这将导致抗原阴性疾病的消除，而没有长期的HSC毒性。这将是 在异源性抗原阳性疾病的AML患者来源的异种移植物模型（Aim 1）和 在复发性/难治性AML患者中使用CD 371靶向IL 18分泌CAR T细胞的I期临床试验 (Aim 2）。因此，这项工作将评估这种新型CAR-T细胞方法在两种疾病中的安全性和有效性。 临床前和临床环境，并将解决生物标志物的反应和疗效，在许多 相关研究（目标3）。