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
- 来源:
- 关键词:Adoptive TransferAdverse eventAntigen TargetingAntigensAutologousBindingBiopsy SpecimenCAR T cell therapyCD19 geneCD4 Positive T LymphocytesCell physiologyClinical TrialsCombination immunotherapyCombined Modality TherapyCyclophosphamideDataDiseaseDistant MetastasisDoseFDA approvedFaceGuidelinesHumanImmune responseImmunityImmunotherapyInsuranceInvadedLiquid substanceMalignant NeoplasmsMalignant Pleural MesotheliomaMalignant neoplasm of lungMaximum Tolerated DoseMediatingNational Comprehensive Cancer NetworkNatureNeoplasm MetastasisNivolumabNormal tissue morphologyPathway interactionsPatient-Focused OutcomesPatientsPhasePhase I Clinical TrialsPhase I/II Clinical TrialPleuralPleural MesotheliomaPleural cavityPrognosisPublishingReportingResearch PersonnelResistanceSafetySamplingSeriesSolid NeoplasmStressSurface AntigensT cell therapyT-Cell ActivationT-LymphocyteTherapeuticToxic effectTranslatingTreatment CostTumor AntigensTumor PromotionTumor-Infiltrating Lymphocytesanti-PD-1chimeric antigen receptorchimeric antigen receptor T cellscombatcytotoxicexhaustiongenetically modified cellsimmune checkpoint blockadeimmune resistanceimmunotherapy clinical trialsimproved outcomeinnovationleukemia/lymphomamalignant breast neoplasmmesothelinneoplastic cellpembrolizumabperipheral bloodphase I trialprimary endpointprogrammed cell death ligand 1programmed cell death protein 1rare cancerresponsesafety assessmentstandard of caretargeted deliverytargeted treatmenttumortumor eradication
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.
项目总结/摘要
恶性胸膜间皮瘤是一种罕见的癌症,预后差。没有FDA-
自2003年以来,已批准用于MPM患者的治疗。存在高水平细胞毒性的MPM患者
肿瘤浸润淋巴细胞(TIL)具有更好的存活。为了在MPM中促进TILs,我们开发了一种采用
使用嵌合抗原受体(汽车)的T细胞疗法。我们开发并翻译了间皮素
在第一阶段临床试验(NCT 02414269和NCT 02792114)中,使用靶向MSLN的CAR T细胞。MSLN是一个细胞-
表面抗原在MPM中高表达,在正常组织中极低表达。在我们的两个临床试验中,
迄今为止,在28名接受治疗的患者中未观察到靶向、肿瘤外毒性。CAR T细胞
在NCT 02414269中,根据我们发表的数据(Sci Transl Med 2014),
建立的区域施用的CAR T细胞通过增强CD 4 T细胞辅助物来增强抗肿瘤功效
功能除了安全性外,在我们的I期胸膜内给药试验中观察到了有希望的抗肿瘤疗效。
CAR T细胞。在施用低剂量的CAR T细胞后,肿瘤细胞上调PD-L1/L2和PD-L3。
通过结合PD-1抑制T细胞。我们已经证明,施用抗PD-1药物可以克服
肿瘤介导的适应性抗性并促进CAR T细胞功能持久性(J Clin Inv 2016)。
在这些数据的支持下,我们用抗PD-1药物pembrolizumab治疗了18例MPM患者中的11例,
没有发现不良事件,CAR T细胞的持久性和抗肿瘤功效增强。
基于这些强有力的数据,我们提出了一项由药物启动的I/II期临床试验,
使用pembrolizumab的CAR T细胞疗法。我们假设靶向癌症抗原的CAR T细胞可以
而抗PD-1剂可通过逆转两种CAR耗竭来对抗适应性抗性
和内源性T细胞。我们将确定过继转移转基因,自体,
将靶向MSLN的T细胞注入MPM患者的胸膜腔中(先前施用MSLN)。
环磷酰胺),然后用派姆单抗治疗直至肿瘤根除或毒性(目的1)。的
主要终点是确定MSLN导向的CAR T细胞的安全性和最大耐受剂量(MTD
与帕博利珠单抗联合治疗(I期),并估计联合治疗的缓解率
(第二阶段)。我们将分析连续收集的胸腔积液、肿瘤活检标本和外周血,
评估PD-1阻断逆转CAR T细胞耗竭(Aim 2)并激活抗肿瘤活性的能力
内源性免疫(目的3),与单独使用派姆单抗治疗相比。调查区域
与用抗PD-1剂活化后的全身内源性和CAR T细胞免疫相比,
与单独的抗PD 1剂,是机械的,创新的,和翻译。结果直接导致
适用于150,000例胸膜转移性肿瘤患者(来自MSLN+ve肺癌和乳腺癌),
仅在美国,每年就可扩展至超过200万名表达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
Comparative analysis of assays to measure CAR T-cell-mediated cytotoxicity.
- DOI:10.1038/s41596-020-00467-0
- 发表时间:2021-03
- 期刊:
- 影响因子:14.8
- 作者:Kiesgen S;Messinger JC;Chintala NK;Tano Z;Adusumilli PS
- 通讯作者:Adusumilli PS
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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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