Defining Pre-treatment Correlates of Patient GD2 CAR T Cell Exhaustion and Memory Using Multi-Dimensional Immune Profiling

使用多维免疫分析定义患者 GD2 CAR T 细胞耗竭和记忆的预处理相关性

基本信息

  • 批准号:
    10606473
  • 负责人:
  • 金额:
    $ 21.21万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-05-01 至 2027-08-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY While chimeric antigen receptor T cells (CAR-Ts) have provided impressive responses in hematologic malignancies, children and young adults with metastatic or relapsed solid tumors have not yet benefited from CAR-Ts and continue to suffer dismal outcomes. A major barrier to CAR-T efficacy in solid tumors is inadequate CAR-T expansion, driven in part by CAR-T exhaustion and poor memory potential. Preclinically, CAR-T exhaustion results from excessive CAR signaling, and can be rescued by eliminating the CD28 T cell costimulatory domain from CAR design. Clinically, in samples from general pediatric oncology patients, poor memory potential in T cells is associated with chemotherapy exposure. Preclinical models further suggest that CAR-T exhaustion can be reduced by overexpressing a transcription factor, cJun, and that memory potential can be enhanced by exposing T cells to a drug, Ibrutinib. Based on these observations, Dr. Ramakrishna will apply novel single-cell and multi-dimensional technologies to CAR-T patient samples to assess the impact of CAR costimulatory domain or pre-apheresis chemotherapy exposure on CAR-T exhaustion and memory potential and ultimately on patient CAR-T fitness, defined as CAR-T molecular signature paired with functionality. To accomplish her aims, Dr. Ramakrishna will innovatively compare CAR-T samples across three GD2 CAR-T clinical trials. In Aim 1, with training in multi-dimensional data analysis, Dr. Ramakrishna will integrate phenotypic (CyTOF), epigenetic (ATACseq), and transcriptomic (RNAseq) molecular signature with CAR-T functional assessments to determine whether GD2.Ox40.CD28.z CAR-Ts (NCT02107963) confer exhaustion, thereby affecting CAR-T fitness, as compared to GD2.41BB.z CAR-Ts (NCT04539366) in osteosarcoma patients. In Aim 2, with training on cancer immune biology, Dr. Ramakrishna will use CyTOF, ATACseq, and in vitro cytokine production, to test the hypothesis that apheresis and CAR-T products from chemotherapy-naïve patients (diffuse midline glioma; NCT04196413) have improved CAR-T fitness as compared to those from chemotherapy-treated patients (osteosarcoma; NCT04539366), followed by single-cell RNAseq to track persistent CAR-T transcriptional profiles in patients. In Aim 3, with training in immune regulation, Dr. Ramakrishna will evaluate whether CAR-T fitness in chemotherapy-treated patient aphereses can be enhanced through modulating molecular pathways by cJun or Ibrutinib. To build upon her substantial prior CAR-T research and clinical experience, Dr. Ramakrishna has developed a strong training plan and mentorship team, including her primary mentor, Dr. Crystal Mackall, a pioneer in translational immunotherapy research; co-mentor, Dr. Sean Bendall, an innovator in multi-dimensional immune assays; advisory committee, Dr. David Miklos, Dr. Holden Maecker, and Dr. Michelle Monje; and collaborators, Dr. Rosie Kaplan and Dr. Steven Feldman. In completing her proposed plan with this team, Dr. Ramakrishna will be prepared to compete for R01 funding and to launch a translational research program identifying and overcoming CAR-T limitations for pediatric solid tumors patients.
项目概要 虽然嵌合抗原受体 T 细胞 (CAR-T) 在血液学方面提供了令人印象深刻的反应 恶性肿瘤、患有转移性或复发性实体瘤的儿童和年轻人尚未受益 CAR-T 并继续遭受惨淡的结果。实体瘤中 CAR-T 疗效的主要障碍是不足 CAR-T 扩张,部分原因是 CAR-T 耗尽和记忆潜力不佳。临床前,CAR-T 过度的 CAR 信号传导导致疲劳,可以通过消除 CD28 T 细胞来挽救 来自 CAR 设计的共刺激域。临床上,在普通儿科肿瘤患者的样本中, T 细胞的记忆潜力与化疗暴露有关。临床前模型进一步表明 CAR-T 耗竭可以通过过度表达转录因子 cJun 来减少,并且记忆潜力可以 通过将 T 细胞暴露于药物依鲁替尼 (Ibrutinib) 中可以增强这种能力。根据这些观察,罗摩克里希纳博士将申请 利用新颖的单细胞和多维技术对 CAR-T 患者样本进行评估,以评估 CAR 的影响 共刺激域或血浆分离术前化疗暴露对 CAR-T 衰竭和记忆潜力的影响 最终取决于患者的 CAR-T 适应性,定义为 CAR-T 分子特征与功能配对。到 为了实现她的目标,Ramakrishna 博士将创新性地比较三个 GD2 CAR-T 的 CAR-T 样本 临床试验。在目标 1 中,通过多维数据分析培训,Ramakrishna 博士将整合表型 具有 CAR-T 功能的 (CyTOF)、表观遗传学 (ATACseq) 和转录组 (RNAseq) 分子特征 评估以确定 GD2.Ox40.CD28.z CAR-T (NCT02107963) 是否会导致衰竭,从而 与骨肉瘤患者中的 GD2.41BB.z CAR-T (NCT04539366) 相比,影响 CAR-T 适应性。瞄准 2、经过癌症免疫生物学培训,Ramakrishna博士将使用CyTOF、ATACseq和体外细胞因子 生产,以检验来自未接受过化疗的患者的单采术和 CAR-T 产品(弥漫性 中线神经胶质瘤; NCT04196413)与接受化疗的患者相比,CAR-T 适应性有所改善 患者(骨肉瘤;NCT04539366),然后通过单细胞 RNAseq 追踪持久性 CAR-T 患者的转录谱。在目标 3 中,通过免疫调节方面的培训,Ramakrishna 博士将评估 是否可以通过调节来增强化疗患者血浆分离术中的 CAR-T 适应性 cJun 或 Ibrutinib 的分子途径。以她之前大量的 CAR-T 研究和临床为基础 经验丰富,罗摩克里希纳博士制定了强大的培训计划和指导团队,包括她的主要 导师Crystal Mackall博士,转化免疫疗法研究的先驱;共同导师 Sean Bendall 博士, 多维免疫测定的创新者;顾问委员会,David Miklos 博士,Holden Maecker 博士, 和 Michelle Monje 博士;以及合作者 Rosie Kaplan 博士和 Steven Feldman 博士。在完成她的过程中 Ramakrishna 博士将与该团队一起提出计划,准备竞争 R01 资金并启动 转化研究项目确定并克服儿童实体瘤患者的 CAR-T 局限性。

项目成果

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Sneha Ramakrishna其他文献

Sneha Ramakrishna的其他文献

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{{ truncateString('Sneha Ramakrishna', 18)}}的其他基金

Defining Pre-treatment Correlates of Patient GD2 CAR T Cell Exhaustion and Memory Using Multi-Dimensional Immune Profiling
使用多维免疫分析定义患者 GD2 CAR T 细胞耗竭和记忆的预处理相关性
  • 批准号:
    10351423
  • 财政年份:
    2022
  • 资助金额:
    $ 21.21万
  • 项目类别:

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