Intracerebroventricular (ICV) Administration of CD19-Targeting Chimeric Antigen Receptor (CAR) T cells for Treatment of Primary Central Nervous System Lymphoma

脑室内 (ICV) 施用靶向 CD19 的嵌合抗原受体 (CAR) T 细胞治疗原发性中枢神经系统淋巴瘤

基本信息

项目摘要

PROJECT SUMMARY Primary central nervous system lymphoma (PCNSL) is a rare hematologic maligancy in which non-Hodgkin lymphoma (NHL) initially presents in the central nervous system (CNS). Therapeutic options for PCNSL are limited; standard of care high-dose methotrexate-containing regimens have been unchanged for over 40 years, and are not curative in most patients. Chimeric antigen receptor (CAR) T cell therapy targeting CD19 (CD19- CAR T cells) is a powerful form of immunotherapy that has an established safety profile when delivered intravenously (IV) to treat patients with NHL. Our clinical platform for manufacturing CD19-CAR T cells at City of Hope (COH) has been evaluated in a series of phase 1 clinical trials for B cell acute lymphoblastic leukemia (ALL) and for NHL. To date, all previous and ongoing CD19-CAR T cell trials have infused the CAR T cell product IV. We have preliminary evidence that IV-administered CD19-CAR T cells can be detected in the CNS and have anti-tumor activity in treating patients with PCNSL. However, the efficacy of IV CAR T cell therapies for patients with PCNSL is limited, possibly due to poor trafficking of CAR T cells from blood to CNS that may result in reduced activity against PCNSL compared to systemic NHL. In phase 1 trials at COH, locoregional delivery of CAR T cells to treat CNS malignancies such as glioblastoma has led to improved outcomes. Studies in our animal models show improved disease response, durability and resistence to tumor rechallenge using intracerebroventricular (ICV)- vs IV- delivered CD19-CAR T cells in xenograft mouse models of CNS lymphoma. Thus, to optimize the efficacy of CD19-CAR T cells and improve the outcomes of patients with PCNSL, we propose to administer CD19-CAR T cells via ICV delivery. We hypothesize that ICV-delivered CD19-CAR T cells will be safe and demonstrate high anti-PCNSL activity. In Specific Aim 1, we will conduct a phase 1 clinical trial to assess the safety and activity, and determine the recommended phase 2 dose (RP2D) of ICV delivered CD19-CAR T cells in participants with PCNSL. In Specific Aim 2, we will conduct a series of correlative studies to assess mechanisms of toxicity, CAR T cell persistance, trafficking to the peripheral blood, immune cell phenotype, and effect on tumor. We plan to examine the effects of ICV-delivered CAR T cells on normal CD19+ B cells in the peripheral blood to determine whether CAR T cells traffic from the CNS to the blood, as we expect based on our preclinical animal models of PCNSL. Activity against normal B cells in the blood would indicate that ICV delivery could be a viable treatment option for patients with secondary CNS lymphoma, who have both CNS and systemic disease. Successful completion of the proposed clinical trial and correlative studies will expand therapeutic options for patients with PCNSL and could inform the design of a potential subsequent clinical trial to evaluate the safety and efficacy of treating patients with secondary CNS lymphoma.
项目摘要 原发性中枢神经系统淋巴瘤(PCNSL)是一种罕见的血液系统恶性肿瘤,其中非霍奇金淋巴瘤(NHL)是一种恶性肿瘤。 淋巴瘤(NHL)最初出现在中枢神经系统(CNS)中。PCNSL的治疗选择包括 有限的;标准的护理高剂量的含甲氨蝶呤的方案已经超过40年没有改变, 并且对大多数患者没有疗效。靶向CD 19的嵌合抗原受体(CAR)T细胞疗法(CD 19- CAR T细胞)是一种强大的免疫疗法,在递送时具有既定的安全性 静脉内(IV)给药以治疗NHL患者。我们在纽约市生产CD 19-CAR T细胞的临床平台 Hope(COH)已在一系列治疗B细胞急性淋巴细胞白血病的I期临床试验中进行了评价 (ALL)对于NHL。到目前为止,所有先前和正在进行的CD 19-CAR T细胞试验都已输注了CAR T细胞产品。 四.我们有初步证据表明,静脉注射的CD 19-CAR T细胞可以在CNS中检测到, 治疗PCNSL患者的抗肿瘤活性。然而,IV CAR T细胞疗法对患者的疗效 与PCNSL的结合是有限的,可能是由于CAR T细胞从血液到CNS的运输较差,这可能导致 与系统性NHL相比,对PCNSL的活性降低。在COH的I期试验中, CAR T细胞治疗中枢神经系统恶性肿瘤如胶质母细胞瘤已导致改善的结果。在我们的研究 动物模型显示出改善的疾病反应、耐久性和对肿瘤再攻击的抗性, 在CNS淋巴瘤的异种移植小鼠模型中,脑室内(ICV)递送的CD 19-CAR T细胞与IV递送的CD 19-CAR T细胞的比较。 因此,为了优化CD 19-CAR T细胞的功效并改善PCNSL患者的结局,我们 建议通过ICV递送施用CD 19-CAR T细胞。我们假设ICV递送的CD 19-CAR T 细胞将是安全的,并表现出高抗PCNSL活性。在具体目标1中,我们将进行1期临床试验, 评估安全性和活性并确定ICV给药的推荐II期剂量(RP 2D)的试验 PCNSL参与者中的CD 19-CAR T细胞。在具体目标2中,我们将进行一系列相关研究 评估毒性机制、CAR T细胞持久性、向外周血的运输、免疫细胞 表型和对肿瘤的影响。我们计划检查ICV递送的CAR T细胞对正常CD 19 + T细胞的影响。 外周血中的B细胞,以确定CAR T细胞是否如我们所预期的那样从CNS运输到血液 基于我们的PCNSL临床前动物模型。对血液中正常B细胞的活性表明 ICV输送可能是继发性CNS淋巴瘤患者的可行治疗选择, CNS和全身性疾病。成功完成拟定的临床试验和相关研究将 扩大PCNSL患者的治疗选择,并可为潜在的后续临床研究设计提供信息。 评估治疗继发性CNS淋巴瘤患者的安全性和有效性的试验。

项目成果

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Stephen J Forman其他文献

Development and optimization of PSCA-specific CAR T cells for the treatment of bone metastatic prostate cancer
  • DOI:
    10.1186/2051-1426-3-s2-p115
  • 发表时间:
    2015-11-04
  • 期刊:
  • 影响因子:
    10.600
  • 作者:
    Ethan Gerdts;Saul Priceman;Dileshni Tilakawardane;Anthony Park;Wen-Chung Chang;Sarah Wright;Christine E Brown;Stephen J Forman
  • 通讯作者:
    Stephen J Forman
Nivolumab Plus ICE As First Salvage Therapy in High-Risk Relapsed/Refractory Hodgkin Lymphoma
  • DOI:
    10.1182/blood-2022-167626
  • 发表时间:
    2022-11-15
  • 期刊:
  • 影响因子:
  • 作者:
    Matthew Mei;Joycelynne Palmer;Ni-Chun Tsai;Hun Ju Lee;Iris Isufi;Leslie L. Popplewell;Lynne Smith;Lacolle Peters;Lara Rodriguez;James Godfrey;John H. Baird;Joo Y. Song;Steven T. Rosen;Larry W. Kwak;Stephen J Forman;Alex F. Herrera
  • 通讯作者:
    Alex F. Herrera
Multicenter Pilot Clinical Trial of Enasidenib As Maintenance Therapy after Allogeneic Hematopoietic Cell Transplantation in Patients with Acute Myeloid Leukemia (AML) Carrying IDH2 Mutations
  • DOI:
    10.1182/blood-2022-169964
  • 发表时间:
    2022-11-15
  • 期刊:
  • 影响因子:
  • 作者:
    Amandeep Salhotra;Nelli Bejanyan;Dongyun Yang;Sally Mokhtari;Monzr M. Al Malki;Karamjeet S. Sandhu;Rawan Faramand;Ibrahim Aldoss;Andrew S. Artz;Ahmed Aribi;Hany Elmariah;Firoozeh Sahebi;Joshua Mansour;Brian J Ball;Vaibhav Agrawal;Ling Li;Vinod A. Pullarkat;Stephen J Forman;Guido Marcucci;Ryotaro Nakamura
  • 通讯作者:
    Ryotaro Nakamura
Positive Coombs Test in Hodgkin's Disease: Significance and Implications
  • DOI:
    10.1182/blood.v55.4.607.607
  • 发表时间:
    1980-04-01
  • 期刊:
  • 影响因子:
  • 作者:
    Alexandra M Levine;Phyllis Thornton;Stephen J Forman;Philip Van Hale;Diane Holdorf;Charles L Rouault;Darlene Powars;Donald I Feinstein;Robert J Lukes
  • 通讯作者:
    Robert J Lukes
Development of chimeric antigen receptor (CAR) T-cell immunotherapy for glioblastoma targeting epidermal growth factor receptor variant III (EGFRvIII)
  • DOI:
    10.1186/2051-1426-3-s2-p119
  • 发表时间:
    2015-11-04
  • 期刊:
  • 影响因子:
    10.600
  • 作者:
    Anthony K Park;Saul Priceman;Ethan Gerdts;Wen-Chung Chang;Sarah Wright;Stephen J Forman;Christine E Brown
  • 通讯作者:
    Christine E Brown

Stephen J Forman的其他文献

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{{ truncateString('Stephen J Forman', 18)}}的其他基金

Intracerebroventricular (ICV) Administration of CD19-Targeting Chimeric Antigen Receptor (CAR) T cells for Treatment of Primary Central Nervous System Lymphoma
脑室内 (ICV) 施用靶向 CD19 的嵌合抗原受体 (CAR) T 细胞治疗原发性中枢神经系统淋巴瘤
  • 批准号:
    10522948
  • 财政年份:
    2022
  • 资助金额:
    $ 70.52万
  • 项目类别:
Transfer of COVID-19 Immunity Between
COVID-19 免疫力的转移
  • 批准号:
    10268483
  • 财政年份:
    2020
  • 资助金额:
    $ 70.52万
  • 项目类别:
Image-guided irradiation safely intensifies HSCT regimen for refractory leukemia
图像引导照射安全强化难治性白血病的 HSCT 治疗方案
  • 批准号:
    9011868
  • 财政年份:
    2015
  • 资助金额:
    $ 70.52万
  • 项目类别:
15th ISCT Annual Meeting
第15届ISCT年会
  • 批准号:
    7743362
  • 财政年份:
    2009
  • 资助金额:
    $ 70.52万
  • 项目类别:
Radioimmunotherapy Based Transplant Regimens for Treatment of B-Cell Lymphoma and
基于放射免疫疗法的 B 细胞淋巴瘤和移植治疗方案
  • 批准号:
    7016807
  • 财政年份:
    2006
  • 资助金额:
    $ 70.52万
  • 项目类别:
Administration/Regulatory Affairs
行政/监管事务
  • 批准号:
    7016811
  • 财政年份:
    2006
  • 资助金额:
    $ 70.52万
  • 项目类别:
CMV/CD19 bi-Specific CAR T cells combined with CMV vaccine as post-transplantation immunotherapy for non-Hodgkin lymphoma
CMV/CD19双特异性CAR T细胞联合CMV疫苗作为非霍奇金淋巴瘤移植后免疫治疗
  • 批准号:
    10242159
  • 财政年份:
    2004
  • 资助金额:
    $ 70.52万
  • 项目类别:
City of Hope Lymphoma SPORE
希望之城淋巴瘤孢子
  • 批准号:
    7932588
  • 财政年份:
    2004
  • 资助金额:
    $ 70.52万
  • 项目类别:
CMV/CD19 bi-Specific CAR T cells combined with CMV vaccine as post-transplantation immunotherapy for non-Hodgkin lymphoma
CMV/CD19双特异性CAR T细胞联合CMV疫苗作为非霍奇金淋巴瘤移植后免疫治疗
  • 批准号:
    10456960
  • 财政年份:
    2004
  • 资助金额:
    $ 70.52万
  • 项目类别:
City of Hope Lymphoma SPORE
希望之城淋巴瘤孢子
  • 批准号:
    7124751
  • 财政年份:
    2004
  • 资助金额:
    $ 70.52万
  • 项目类别:

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