Radiation and dendritic cells to hepatomas to improve immunotherapy response

放疗和树突状细胞治疗肝癌以改善免疫治疗反应

基本信息

批准号：
10680559
负责人：
Yi Lin
金额：
$ 61.21万
依托单位：
MAYO CLINIC ROCHESTER
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：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10680559
关键词：
Antigen Presentation Autologous Dendritic Cells Blood CD14 gene CD8-Positive T-Lymphocytes Cancer Etiology Cell Death Cells Cellular Immunity Cholangiocarcinoma Clinical Clonal Expansion Combination immunotherapy Combined Modality Therapy Correlative Study Cytotoxic T-Lymphocytes Dendritic Cells Disease Distant Dose Dose Limiting Excision Galactose Binding Lectin Image Cytometry Immune Immune checkpoint inhibitor Immunotherapy Inflammatory Injections Interferon Type II Intervention Investigation Liver Liver neoplasms Mediating Methods Morbidity - disease rate Multicenter Studies Operative Surgical Procedures PD-1 inhibitors PDL1 inhibitors Patient-Focused Outcomes Patients Phase Phase II Clinical Trials Pilot Projects Primary Malignant Neoplasm of Liver Primary carcinoma of the liver cells Progression-Free Survivals Radiation Radiation therapy Recurrent disease Reporting Role Running Safety Serious Adverse Event Signal Transduction Stable Disease Survival Rate T cell receptor repertoire sequencing T cell response T-Lymphocyte Technology Testing Therapeutic Toxic effect Tumor Antigens Tumor Expansion Tumor-Derived Unresectable Up-Regulation Vegf Inhibitor bevacizumab checkpoint receptors clinical efficacy cooperative study curative treatments cytotoxic exhaustion improved improved outcome in vivo inhibitor innovation insight liver transplantation manufacture monocyte mortality neoantigens neoplastic cell novel novel therapeutics partial response phase 2 study primary endpoint programmed cell death ligand 1 programmed cell death protein 1 resistance mechanism response spatial relationship standard of care therapeutic development transcriptome treatment center tumor uptake

项目摘要

Summary/Abstract Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer with dismal survival for patients with unresectable disease. Recent approval for PD-L1 inhibitor atezolizumab (atezo) and VEGF inhibitor bevacizumab (bev) in frontline treatment is a landmark advance; however further improvement is needed with a median progression free survival of less than 7 months. We have found through a multi-center cooperative study that tumor transcriptome signature high in interferon-gamma and MHC-II signaling (INFAP signature) is correlated with increased response and survival to PD-1 inhibitor. We propose to add high dose external beam radiotherapy (EBRT) followed by intra-tumor injection of autologous dendritic cells (DC) to atezo/bev to further enhance the immune stimulatory effect. Radiation can induce inflammatory tumor cell death that can be favorable for tumor neoantigen presentation. Injection of autologous DC after EBRT would be a novel method of boosting in vivo tumor antigen uptake and presentation to expand tumor-reactive cytotoxic T cells. We have treated subjects with unresectable liver tumors (HCC and cholangiocarcinoma) in a pilot study with this EBRT and DC approach with promising response and acceptable toxicity (no grade ≥3 toxicity). Three of the five subjects had partial response, including a patient with ongoing response beyond 1 year. Both emergence of new TCR clones and expansion of existing TCR clones, including clones with tumor reactive and cytotoxic profile, have been observed, suggesting this combination could enhance tumor reactive cytotoxic T cell response. However, many of the TCR clones also have early exhaustion signal with upregulation of multiple checkpoint receptors. Thus, combining DC injection with atezo/bev may help further enhance the cytotoxic functions of these TCR clones. We hypothesize that combining EBRT followed by intratumor DC injections with atezolizumab and bevacizumab can improve the PFS for patients with unresectable HCC and that the effect is mediated by systemic expansion of a tumor reactive T cell repertoire. We will test the hypothesis through 2 aims. 1) Assess the clinical efficacy of this combination therapy in a phase II study with a safety run-in phase. Increased PFS rate at 1 year will be the primary endpoint. 2) identify the effect of this novel combination immunotherapy on tumor reactive T cell repertoire. We will use scRNAseq and TCRseq to identify TCR clonal expansion and transcriptome profile of the TCR clones in the blood and tumor, with a focus on tumor reactive TCR clones. We will also use scRNAseq and flow to profile the changes of other immune cells in the tumor and blood, with a focus on the changes in expression of the INFAP signature. Finally, we will use imaging cytometry to examine the tumor and immune spatial relationship in the tumor. Our study will not only identify the clinical activities of this novel combination therapy but also use state-of-the-art technology to improve our understanding on the mechanism of action to this immunotherapy.

摘要/摘要肝细胞癌（HCC）是最常见的原发性肝癌类型患有无法切除的疾病的患者。最近批准了PD-L1抑制剂Atezolizumab（Atezo）和VEGF 一线治疗中的抑制剂贝伐单抗（BEV）是一个具有里程碑意义的进步。但是进一步的进步是需要少于7个月的中位无进展生存期。我们已经通过一个多中心发现合作研究表明，干扰素伽马和MHC-II信号传导中的肿瘤转录组签名高（INSTAP）签名）与对PD-1抑制剂的反应和存活率增加相关。我们建议增加高剂量外束放射疗法（EBRT），然后注入自体树突内注射（DC） atezo/bev进一步增强免疫刺激作用。辐射可以诱导炎症性肿瘤细胞可以有利于肿瘤新抗原呈递的死亡。 EBRT后注入自体DC 成为增强体内肿瘤抗原摄取和表现以扩大肿瘤反应性的新方法细胞毒性T细胞。我们已经用不可切除的肝肿瘤（HCC和胆管癌）治疗了受试者。通过这种EBRT和DC方法进行的试点研究，具有承诺反应和可接受的毒性（无≥3级毒性）。五个受试者中有三个有部分反应，包括一个持续反应以上的患者年。新的TCR克隆的出现和现有TCR克隆的扩展，包括具有肿瘤的克隆已经观察到了反应性和细胞毒性特征，表明这种组合可以增强肿瘤反应性细胞毒性T细胞反应。但是，许多TCR克隆也有早期的耗尽信号多个检查点受体的上调。那就是将直流注入与atezo/bev结合起来可能有助于进一步增强这些TCR克隆的细胞毒性功能。我们假设结合EBRT，然后是肿瘤内直流注射atezolizumab和bevacizumab可以改善患有PFS的PFS 无法切除的HCC，并且该作用是由肿瘤反应性T细胞库的全身扩张介导的。我们将通过2个目标检验假设。 1）评估该联合疗法的临床效率 II阶段研究具有安全磨合阶段。 1年时的PFS率提高将是主要终点。 2）确定这种新型组合免疫疗法对肿瘤反应性T细胞库的影响。我们将使用Scrnaseq和TCRSEQ识别TCR克隆扩展和TCR克隆的转录组轮廓血液和肿瘤，重点是肿瘤反应性TCR克隆。我们还将使用scrnaseq和Flow进行配置文件肿瘤和血液中其他免疫细胞的变化，重点是 Instrap签名。最后，我们将使用成像细胞仪检查肿瘤和免疫空间关系在肿瘤中。我们的研究不仅会识别这种新型组合疗法的临床活动，还可以使用最先进的技术，以提高我们对这种免疫疗法的作用机理的理解。