Development of Novel Therapies for Acute Lymphoblastic Leukemia

急性淋巴细胞白血病新疗法的开发

• 批准号: 10702695
• 负责人: Nirali Shah
• 金额: $ 94.3万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10702695
• 关键词: Achievement; Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Acute leukemia; Address; Age-Years; Antigen Targeting; Antigens; Award; B-Cell Acute Lymphoblastic Leukemia; B-Lymphocytes; Back; Biological; Biology; Blood Component Removal; CAR T cell therapy; CD19 gene; CD22 gene; Cardiotoxicity; Child; Childhood Acute Lymphocytic Leukemia; Childhood Precursor B Lymphoblastic Leukemia; Clinical; Clinical Trials; Collaborations; Development; Disease; Disease remission; Down-Regulation; Elements; Flow Cytometry; Future; Goals; Grant; Hematologic Neoplasms; Immune; Immunotherapeutic agent; Immunotherapy; Infrastructure; International; Malignant Neoplasms; Modality; Outcome; Patients; Pattern; Pediatric Oncology; Phenotype; Population; RNA Splicing; Refractory; Relapse; Research; Resistance; Role; Salvage Therapy; T cell response; Testing; Time; Toxic effect; Translating; United States National Institutes of Health; base; bench to bedside; bench-to-bedside translation; cellular engineering; chimeric antigen receptor; chimeric antigen receptor T cells; clinical center; clinical development; clinically relevant; cohort; combinatorial; cytokine release syndrome; density; early phase clinical trial; experience; familial hemophagocytic lymphohistiocytosis; high risk; improved; interest; leukemia; multidisciplinary; neurotoxicity; novel; novel therapeutics; prevent; programs; resistance mechanism; response; targeted treatment; young adult

Project 1: Development of Novel CAR T-cells for B-cell Acute Lymphoblastic Leukemia Specific Aim 1: Test Novel CAR T-cell constructs targeting non-CD19 antigens in ALL From the very inception of the CD22 targeted CAR T-cell trial, there was clear demonstration that this construct was clinically active in patients with CD19 negative/dim/positive disease and that modulation of CD22 antigen expression was an important determinant of durable CAR T-cell responses and/or relapse. My prior efforts in establishing a baseline for CD22 expression in children with r/r ALL, in collaboration with the NCI flow cytometry team, whose group is able to quantify antigen expression, were critical to understanding mechanisms of resistance to CD22 CAR. Indeed, antigen expression density impacting effective CAR T-cell response first became clinically apparent in this trial. Based on the response rate, we received FDA granting of "Breakthrough Therapy Designation" for our CD22 CAR T-cell construct (August 2019). This designation, based on an application that I fully authored, arises from our study's 70% complete remission rate and my section's cumulative experience with the largest cohort of ALL patients treated by CD22 CAR T-cell targeting. The FDA breakthrough therapy designation is for the treatment of children and young adults, 3-30 years of age, with CD22+ B-cell ALL that is either refractory or in second or later relapse, and that is either CD19 negative or relapsed/refractory to CD19 targeting. This represents the first designation for an effective salvage therapy specifically for children and young adults who fail CD19 targeting and encompasses the goals of our section: to develop novel therapies for unmet needs. Based on a vested interest in exploring limitations of CD22 targeting and mechanisms of resistance, over the past year in the past year I have embarked on studying the role of splicing as a mechanism of CD22 loss following inotuzumab treatment-- with a 2022 "Bench to Bedside" award as a Cancer Moonshot supplement (collaboration with Dr. Andrei Thomas-Tikhonenko), and am leading an internal consortium to identify mechanisms of CD22 escape following CD22-targeted therapies--FLEX award with Drs. Naomi Taylor and Jack Shern (POB). Additional collaborative efforts to further explore the biology of resistance are underway and include explorations of the impact of various modalities of manufacturing or elements of the starting apheresis material on toxicity (co-led by Dr. Naomi Taylor). Future efforts in targeting alternate antigens are underway with a trial targeting TSLPR in B-ALL patients anticipated to be open later this year. Specific Aim 2: Evaluate the Ability of Combinatorial Targeted Strategies to Prevent Antigen Negative Relapse Despite the high degree of efficacy of CD22 CAR T-cells, antigen escape remained problematic and was the leading cause of relapse following single-antigen targeting. Based on the hypothesis that simultaneous targeting of two antigens will help prevent antigen escape as a mechanism of relapse by covering a broader range of the phenotypic variability in leukemia and avoid selection for a dim or negative population, our group has been systematically testing novel combinatorial CD19/22 bispecific CAR T-cell constructs in pediatric ALL by translating constructs developed in the POB. Our first experience with CD19/CD22 CAR T-cells, a trial on which I fully led the clinical development and opened in 2018, has allowed us to identify both key salient features and limitations of this novel construct and to compare this to our prior trials with single antigen targeting. While highly effective in inducing remission, this contrast suboptimally targeted CD22 and lacked persistence, leading to development of a subsequent construct which will go into testing later this year.

项目 1：开发用于 B 细胞急性淋巴细胞白血病的新型 CAR T 细胞 具体目标 1：在 ALL 中测试针对非 CD19 抗原的新型 CAR T 细胞构建体 从 CD22 靶向 CAR T 细胞试验一开始，就有清楚地证明该构建体在 CD19 阴性/暗淡/阳性疾病患者中具有临床活性，并且 CD22 抗原表达的调节是持久 CAR 的重要决定因素T 细胞反应和/或复发。我之前与 NCI 流式细胞术团队合作，建立了 r/r ALL 儿童 CD22 表达的基线，该团队能够量化抗原表达，这对于理解 CD22 CAR 耐药机制至关重要。事实上，影响有效 CAR T 细胞反应的抗原表达密度在本次试验中首次在临床上变得明显。根据反应率，我们的 CD22 CAR T 细胞构建体获得 FDA 授予的“突破性治疗指定”（2019 年 8 月）。这一称号基于我完全撰写的一份申请，源于我们研究的 70% 完全缓解率，以及我的部门在接受 CD22 CAR T 细胞靶向治疗的最大 ALL 患者群体中积累的经验。 FDA 突破性疗法指定用于治疗 3-30 岁的儿童和年轻人，患有难治性或第二次或以后复发的 CD22+ B 细胞 ALL，并且 CD19 阴性或复发/难治性CD19 靶向。这代表了第一个专门针对 CD19 靶向失败的儿童和年轻人的有效挽救疗法的指定，并包含了我们部分的目标：针对未满足的需求开发新疗法。基于探索 CD22 靶向的局限性和耐药机制的既得利益，在过去的一年里，我开始研究剪接作为 inotuzumab 治疗后 CD22 丢失机制的作用——并制定了 2022 年“Bench to Bedside”奖作为 Cancer Moonshot 补充（与 Andrei Thomas-Tikhonenko 博士合作），并领导一个内部联盟来确定 CD22 逃逸机制CD22 靶向疗法——与 Drs. 一起获得 FLEX 奖娜奥米·泰勒和杰克·申恩（POB）。进一步探索耐药性生物学的其他合作工作正在进行中，包括探索各种制造方式或起始单采材料元素对毒性的影响（由 Naomi Taylor 博士共同领导）。未来针对替代抗原的努力正在进行中，针对 B-ALL 患者的 TSLPR 试验预计将于今年晚些时候开放。具体目标 2：评估组合靶向策略预防抗原阴性复发的能力尽管 CD22 CAR T 细胞具有很高的功效，但抗原逃逸仍然存在问题，并且是单抗原靶向后复发的主要原因。基于这样的假设，即同时靶向两种抗原将有助于通过覆盖白血病更广泛的表型变异性来防止抗原逃逸作为复发机制，并避免选择暗淡或阴性群体，我们的小组一直在系统地测试新型组合 CD19 /22 通过翻译 POB 中开发的构建体，在儿科 ALL 中构建双特异性 CAR T 细胞构建体。我们对 CD19/CD22 CAR T 细胞的首次体验是我完全领导临床开发并于 2018 年启动的一项试验，使我们能够确定这种新型构建体的关键显着特征和局限性，并将其与我们之前的试验进行比较具有单一抗原靶向。 虽然在诱导缓解方面非常有效，但这种对比对 CD22 的靶向效果不佳且缺乏持久性，导致后续构建体的开发，该构建体将于今年晚些时候投入测试。