A phase I/II combination immunotherapy clinical trial: mesothelin-targeted chimeric antigen receptor T cells and checkpoint blockade agent in pleural mesothelioma

I/II期联合免疫治疗临床试验:间皮素靶向嵌合抗原受体T细胞和检查点阻断剂治疗胸膜间皮瘤

基本信息

  • 批准号:
    10658882
  • 负责人:
  • 金额:
    $ 71.28万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-06-01 至 2025-05-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY/ABSTRACT Malignant pleural mesothelioma (MPM) is a rare cancer with poor prognosis. There have been no FDA- approved therapies for MPM patients since 2003. Patients with MPM who present with high levels of cytotoxic tumor infiltrating lymphocytes (TILs) have better survival. To promote TILs in MPM, we developed an adoptive T-cell therapy using chimeric antigen receptors (CARs). We have developed and translated mesothelin (MSLN)–targeted CAR T cells to phase I clinical trials (NCT02414269 and NCT02792114). MSLN is a cell- surface antigen highly expressed in MPM, with very low expression in normal tissues. In our two clinical trials, no on-target, off-tumor toxicities were noted among 28 patients treated so far. CAR T cells are administered intrapleurally in NCT02414269, on the basis of our published data (Sci Transl Med 2014) that established regionally administered CAR T cells potentiate antitumor efficacy by augmenting CD4 T-cell helper function. Beyond safety, promising antitumor efficacy has been observed in our phase I trial of intrapleural CAR T cells. Following administration of a low dose of CAR T cells, tumor cells upregulate PD-L1/L2 and inhibit T cells via binding to PD-1. We have shown that administration of anti-PD-1 agents can overcome tumor-mediated adaptive resistance and promote CAR T-cell functional persistence (J Clin Inv 2016). Supported by these data, we treated 11 of 18 MPM patients with pembrolizumab, an anti-PD-1 agent, and noted no adverse events, and enhanced persistence of CAR T cells and antitumor efficacy. Building on these strong data, we propose an investigator-initiated phase I/II clinical trial combining CAR T-cell therapy with pembrolizumab. We hypothesize that cancer antigen-targeted CAR T cells can promote TILs and that anti-PD-1 agent can combat adaptive resistance by reversing exhaustion of both CAR and endogenous T cells. We will determine the safety of adoptive transfer of genetically modified, autologous, MSLN-targeted T cells into the pleural cavity of MPM patients (with previous administration of cyclophosphamide), followed by treatment with pembrolizumab until tumor eradication or toxicity (Aim 1). The primary endpoint is to determine the safety and maximum tolerated dose (MTD) of MSLN-directed CAR T cells in combination with pembrolizumab (phase I) and to estimate the response rate of the combination therapy (phase II). We will analyze serially collected pleural fluid, tumor biopsy specimens, and peripheral blood to assess the ability of PD-1 blockade to reverse CAR T-cell exhaustion (Aim 2) and activate antitumor endogenous immunity (Aim 3), compared with treatment with pembrolizumab alone. Investigating regional versus systemic endogenous and CAR T-cell immunity following activation with anti-PD-1 agent, compared with anti-PD1 agent alone, is mechanistic, innovative, and translational. The ensuing results are directly applicable to 150,000 patients with pleural metastatic tumors (from MSLN+ve lung and breast cancers) and extendable to more than 2 million patients with MSLN-expressing solid tumors per year in the U.S. alone.
项目概要/摘要 恶性胸膜间皮瘤(MPM)是一种罕见的癌症,预后不良。目前还没有FDA—— 自 2003 年起批准用于 MPM 患者的治疗方法。具有高水平细胞毒性的 MPM 患者 肿瘤浸润淋巴细胞(TIL)具有更好的存活率。为了在 MPM 中推广 TIL,我们开发了一种采用 使用嵌合抗原受体 (CAR) 的 T 细胞疗法。我们开发并翻译了间皮素 (MSLN)——靶向 CAR T 细胞进入 I 期临床试验(NCT02414269 和 NCT02792114)。 MSLN 是一种细胞 表面抗原在MPM中高表达,在正常组织中表达极低。在我们的两项临床试验中, 迄今为止,在接受治疗的 28 名患者中未发现任何靶向、非肿瘤毒性。 CAR T 细胞是 根据我们发表的数据 (Sci Transl Med 2014),在 NCT02414269 中进行胸腔内给药 建立的区域施用 CAR T 细胞通过增强 CD4 T 辅助细胞来增强抗肿瘤功效 功能。除了安全性之外,在我们的胸膜腔内注射的 I 期试验中还观察到了有希望的抗肿瘤功效。 CAR T 细胞。给予低剂量的 CAR T 细胞后,肿瘤细胞上调 PD-L1/L2, 通过与 PD-1 结合抑制 T 细胞。我们已经证明,使用抗 PD-1 药物可以克服 肿瘤介导的适应性抵抗并促进 CAR T 细胞功能持久性 (J Clin Inv 2016)。 在这些数据的支持下,我们使用抗 PD-1 药物派姆单抗 (pembrolizumab) 治疗了 18 名 MPM 患者中的 11 名, 没有发现任何不良事件,并且增强了 CAR T 细胞的持久性和抗肿瘤功效。 基于这些强有力的数据,我们建议开展一项由研究者发起的 I/II 期临床试验,结合 使用派姆单抗进行 CAR T 细胞治疗。我们假设癌症抗原靶向的 CAR T 细胞可以 促进 TIL,并且抗 PD-1 药物可以通过逆转两种 CAR 的耗竭来对抗适应性耐药 和内源性 T 细胞。我们将确定转基因、自体、 MSLN 靶向 T 细胞进入 MPM 患者的胸膜腔(之前接受过 环磷酰胺),然后用派姆单抗治疗,直至肿瘤根除或毒性(目标 1)。这 主要终点是确定 MSLN 定向 CAR T 细胞的安全性和最大耐受剂量 (MTD) 与 pembrolizumab 联合(I 期)并估计联合治疗的反应率 (第二阶段)。我们将分析连续收集的胸水、肿瘤活检标本和外周血,以 评估 PD-1 阻断逆转 CAR T 细胞耗竭(目标 2)和激活抗肿瘤的能力 与单独使用派姆单抗治疗相比,内源性免疫(目标 3)。调查区域 与抗 PD-1 药物激活后的全身内源性和 CAR T 细胞免疫相比 单独使用抗PD1药物,具有机械性、创新性和转化性。接下来的结果就是直接 适用于 150,000 名胸膜转移瘤患者(MSLN+ve 肺癌和乳腺癌)和 仅在美国,每年就有超过 200 万表达 MSLN 的实体瘤患者。

项目成果

期刊论文数量(16)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Expanding the role of interventional oncology for advancing precision immunotherapy of solid tumors.
  • DOI:
    10.1016/j.omto.2021.12.018
  • 发表时间:
    2022-03-17
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Kimura Y;Ghosn M;Cheema W;Adusumilli PS;Solomon SB;Srimathveeralli G
  • 通讯作者:
    Srimathveeralli G
Next-generation immunotherapy for solid tumors: combination immunotherapy with crosstalk blockade of TGFβ and PD-1/PD-L1.
  • DOI:
    10.1080/13543784.2022.2152323
  • 发表时间:
    2022-11
  • 期刊:
  • 影响因子:
    6.1
  • 作者:
    Quach, Hue Tu;Hou, Zhaohua;Bellis, Rebecca Y. Y.;Saini, Jasmeen K. K.;Amador-Molina, Alfredo;Adusumilli, Prasad S. S.;Xiong, Yuquan
  • 通讯作者:
    Xiong, Yuquan
Image-guided interventional radiological delivery of chimeric antigen receptor (CAR) T cells for pleural malignancies in a phase I/II clinical trial.
在I/II期临床试验中,图像引导的嵌合抗原受体(CAR)T细胞的介入放射学递送用于胸膜恶性肿瘤。
  • DOI:
    10.1016/j.lungcan.2022.01.003
  • 发表时间:
    2022-03
  • 期刊:
  • 影响因子:
    5.3
  • 作者:
    Ghosn, Mario;Cheema, Waseem;Zhu, Amy;Livschitz, Jennifer;Maybody, Majid;Boas, Franz E.;Santos, Ernesto;Kim, DaeHee;Beattie, Jason A.;Offin, Michael;Rusch, Valerie W.;Zauderer, Marjorie G.;Adusumilli, Prasad S.;Solomon, Stephen B.
  • 通讯作者:
    Solomon, Stephen B.
The use of a next-generation sequencing-derived machine-learning risk-prediction model (OncoCast-MPM) for malignant pleural mesothelioma: a retrospective study.
  • DOI:
    10.1016/s2589-7500(21)00104-7
  • 发表时间:
    2021-09
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Zauderer MG;Martin A;Egger J;Rizvi H;Offin M;Rimner A;Adusumilli PS;Rusch VW;Kris MG;Sauter JL;Ladanyi M;Shen R
  • 通讯作者:
    Shen R
Regional CAR T cell therapy: An ignition key for systemic immunity in solid tumors.
  • DOI:
    10.1016/j.ccell.2022.04.006
  • 发表时间:
    2022-06-13
  • 期刊:
  • 影响因子:
    50.3
  • 作者:
    Cherkassky, Leonid;Hou, Zhaohua;Amador-Molina, Alfredo;Adusumilli, Prasad S.
  • 通讯作者:
    Adusumilli, Prasad S.
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Prasad S. Adusumilli其他文献

臨床病期I期の肺腺癌における組織亜型による経時的再発ハザードの層別化の有用性
根据临床 I 期肺腺癌的组织学亚型随时间推移对复发风险进行分层的实用性
  • DOI:
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    0
  • 作者:
    高橋 祐介;Prasad S. Adusumilli
  • 通讯作者:
    Prasad S. Adusumilli
原核生物由来ナトリウムチャネルに創出された二価カチオ ンによる電流阻害の分子機構
原核钠通道中产生的二价阳离子抑制电流的分子机制
  • DOI:
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    0
  • 作者:
    高橋 祐介;Prasad S. Adusumilli;入江 克雅
  • 通讯作者:
    入江 克雅
Therapeutic effect of oncolytic herpes simplex virus (NV1066) on radioresistant head and neck squamous cell carcinoma
  • DOI:
    10.1016/j.jamcollsurg.2005.06.146
  • 发表时间:
    2005-09-01
  • 期刊:
  • 影响因子:
  • 作者:
    Se-Heon Kim;Richard J. Wong;David Eisenberg;Yun Shin Chun;Zhenkun Yu;Prasad S. Adusumilli;Jatin P. Shah;Yuman Fong
  • 通讯作者:
    Yuman Fong
Commission on Cancer Standards for Lymph Node Sampling and Oncologic Outcomes After Lung Resection
癌症委员会关于肺切除术后淋巴结采样及肿瘤学预后的标准
  • DOI:
    10.1016/j.athoracsur.2024.09.009
  • 发表时间:
    2025-02-01
  • 期刊:
  • 影响因子:
    3.900
  • 作者:
    Benjamin J. Resio;Kay See Tan;Matthew Skovgard;Joe Dycoco;Prasad S. Adusumilli;Manjit S. Bains;Matthew J. Bott;Robert J. Downey;Katherine D. Gray;James Huang;Daniela Molena;Bernard J. Park;Valerie W. Rusch;Smita Sihag;Gaetano Rocco;David R. Jones;James M. Isbell
  • 通讯作者:
    James M. Isbell
The Emerging Role of Immunotherapy in Resectable Non-Small Cell Lung Cancer
  • DOI:
    10.1016/j.athoracsur.2024.01.024
  • 发表时间:
    2024-07-01
  • 期刊:
  • 影响因子:
  • 作者:
    Elizabeth G. Dunne;Cameron N. Fick;James M. Isbell;Jamie E. Chaft;Nasser Altorki;Bernard J. Park;Jonathan Spicer;Patrick M. Forde;Daniel Gomez;Puneeth Iyengar;David H. Harpole;Thomas E. Stinchcombe;Moishe Liberman;Matthew J. Bott;Prasad S. Adusumilli;James Huang;Gaetano Rocco;David R. Jones
  • 通讯作者:
    David R. Jones

Prasad S. Adusumilli的其他文献

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{{ truncateString('Prasad S. Adusumilli', 18)}}的其他基金

A phase I/II combination immunotherapy clinical trial: mesothelin-targeted chimeric antigen receptor T cells and checkpoint blockade agent in pleural mesothelioma
I/II期联合免疫治疗临床试验:间皮素靶向嵌合抗原受体T细胞和检查点阻断剂治疗胸膜间皮瘤
  • 批准号:
    10208821
  • 财政年份:
    2019
  • 资助金额:
    $ 71.28万
  • 项目类别:
A phase I/II combination immunotherapy clinical trial: mesothelin-targeted chimeric antigen receptor T cells and checkpoint blockade agent in pleural mesothelioma
I/II期联合免疫治疗临床试验:间皮素靶向嵌合抗原受体T细胞和检查点阻断剂治疗胸膜间皮瘤
  • 批准号:
    10445296
  • 财政年份:
    2019
  • 资助金额:
    $ 71.28万
  • 项目类别:
Image-guided irreversible electroporation directed CAR T-cell delivery to solid tumors
图像引导不可逆电穿孔引导 CAR T 细胞递送至实体瘤
  • 批准号:
    10221646
  • 财政年份:
    2018
  • 资助金额:
    $ 71.28万
  • 项目类别:
Image-guided irreversible electroporation directed CAR T-cell delivery to solid tumors
图像引导不可逆电穿孔引导 CAR T 细胞递送至实体瘤
  • 批准号:
    10478835
  • 财政年份:
    2018
  • 资助金额:
    $ 71.28万
  • 项目类别:
Image-guided irreversible electroporation directed CAR T-cell delivery to solid tumors
图像引导不可逆电穿孔引导 CAR T 细胞递送至实体瘤
  • 批准号:
    9764302
  • 财政年份:
    2018
  • 资助金额:
    $ 71.28万
  • 项目类别:
Imaging the efficacy of TRAIL-enhanced cancer immunotherapy
TRAIL 增强癌症免疫疗法的功效成像
  • 批准号:
    9387986
  • 财政年份:
    2017
  • 资助金额:
    $ 71.28万
  • 项目类别:
Mesothelin as a biomarker for clinical management of esophageal adenocarcinoma
间皮素作为食管腺癌临床治疗的生物标志物
  • 批准号:
    8508213
  • 财政年份:
    2012
  • 资助金额:
    $ 71.28万
  • 项目类别:
Mesothelin as a biomarker for clinical management of esophageal adenocarcinoma
间皮素作为食管腺癌临床治疗的生物标志物
  • 批准号:
    8386226
  • 财政年份:
    2012
  • 资助金额:
    $ 71.28万
  • 项目类别:
Validation of a risk model for stage I lung adenocarcinoma
I 期肺腺癌风险模型的验证
  • 批准号:
    8386244
  • 财政年份:
    2012
  • 资助金额:
    $ 71.28万
  • 项目类别:
Validation of a risk model for stage I lung adenocarcinoma
I 期肺腺癌风险模型的验证
  • 批准号:
    8508212
  • 财政年份:
    2012
  • 资助金额:
    $ 71.28万
  • 项目类别:

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