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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：
10535023
负责人：
Yi Lin
金额：
$ 63.24万
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/10535023
关键词：
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 Recurrence 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 Tumor-infiltrating immune cells 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 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/文摘