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: 10658882
• 负责人: Prasad S. Adusumilli
• 金额: $ 71.28万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10658882
• 关键词: Adoptive Transfer; Adverse event; Antigen Targeting; Antigens; Autologous; Binding; Biopsy Specimen; CAR T cell therapy; CD19 gene; CD4 Positive T Lymphocytes; Cell physiology; Clinical Trials; Combination immunotherapy; Combined Modality Therapy; Cyclophosphamide; Data; Disease; Distant Metastasis; Dose; FDA approved; Face; Guidelines; Human; Immune response; Immunity; Immunotherapy; Insurance; Invaded; Liquid substance; Malignant Neoplasms; Malignant Pleural Mesothelioma; Malignant neoplasm of lung; Maximum Tolerated Dose; Mediating; National Comprehensive Cancer Network; Nature; Neoplasm Metastasis; Nivolumab; Normal tissue morphology; Pathway interactions; Patient-Focused Outcomes; Patients; Phase; Phase I Clinical Trials; Phase I/II Clinical Trial; Pleural; Pleural Mesothelioma; Pleural cavity; Prognosis; Publishing; Reporting; Research Personnel; Resistance; Safety; Sampling; Series; Solid Neoplasm; Stress; Surface Antigens; T cell therapy; T-Cell Activation; T-Lymphocyte; Therapeutic; Toxic effect; Translating; Treatment Cost; Tumor Antigens; Tumor Promotion; Tumor-Infiltrating Lymphocytes; anti-PD-1; chimeric antigen receptor; chimeric antigen receptor T cells; combat; cytotoxic; exhaustion; genetically modified cells; immune checkpoint blockade; immune resistance; immunotherapy clinical trials; improved outcome; innovation; leukemia/lymphoma; malignant breast neoplasm; mesothelin; neoplastic cell; pembrolizumab; peripheral blood; phase I trial; primary endpoint; programmed cell death ligand 1; programmed cell death protein 1; rare cancer; response; safety assessment; standard of care; targeted delivery; targeted treatment; tumor; tumor eradication

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/文摘

项目成果

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: Molecular therapy oncolytics
• 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: EXPERT OPINION ON INVESTIGATIONAL DRUGS
• 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: LUNG CANCER
• 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: The Lancet. Digital health
• 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: Nature protocols
• 影响因子: 14.8
• 作者: Kiesgen S;Messinger JC;Chintala NK;Tano Z;Adusumilli PS
• 通讯作者: Adusumilli PS