Colorado Head and Neck Cancer SPORE

科罗拉多头颈癌孢子

• 批准号: 10868331
• 负责人: Antonio Jimeno
• 金额: $ 47.5万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10868331
• 关键词: Affect; Anatomy; Animal Model; Animals; Architecture; Award; Biopsy; Biopsy Specimen; Blood Vessels; Brain Neoplasms; Canis familiaris; Carcinogens; Carcinoma; Cell Communication; Clinic; Clinical; Clinical Trials; Collaborations; Colorado; Combination immunotherapy; Complex; Drug Combinations; Endothelial Cells; Evaluation; Exposure to; Flow Cytometry; Genetic Transcription; Head and Neck Cancer; Human; Immune response; Immunity; Immunohistochemistry; Immunologic Monitoring; Immunologics; Immunotherapy; Irrigation; Laboratories; Link; Losartan; Manuscripts; Mentors; Modeling; Mus; Myelogenous; Myeloid Cells; Nose; Occupational; Operative Surgical Procedures; Parents; Patients; Perfusion; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Prognosis; Propranolol; Protocols documentation; Publishing; Quality of life; Radiation therapy; Sampling; Slice; T cell infiltration; T cell response; Testing; Therapy trial; Time; Toxic effect; Translational Research; Tumor Angiogenesis; Tumor Antigens; Tumor Immunity; Tumor Promotion; Universities; X-Ray Computed Tomography; anti-PD-L1; antigen-specific T cells; cancer imaging; career; contrast enhanced computed tomography; drug repurposing; head and neck cancer patient; immune cell infiltrate; improved; interest; lymph node biopsy; member; novel; novel therapeutic intervention; programs; response; sarcoma; single-cell RNA sequencing; tool; transcriptome sequencing; treatment group; treatment response; tumor; tumor microenvironment

Abstract This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 23-059. Sinonasal carcinoma (SC) is an important head and neck cancer (HNC) globally, but prognosis remains poor. SC is understudied in the laboratory and in the clinic. We propose that SC in pet dogs represents a spontaneous animal model of this HNC. Our team has validated approaches to investigate immunotherapy and stereotactic body radiation therapy (SBRT) in canine SC clinical trials. Our current efforts incorporate myeloid cell targeted immunotherapy (MTI) with two repurposed drugs (losartan and propranolol) to deplete or reprogram myeloid cells when combined with SBRT. Our early results in dogs with SC treated with the MTI + SBRT protocol provide evidence of enhanced local T cell responses and improved overall survival compared to SBRT alone. The proposed study represents a logical addition to the parent program (Colorado Head and Neck Cancer SPORE) which seeks to advance translational research to improve survival and quality of life for HNC patients. Our project will therefore be consistent with the overall immunotherapy/radiotherapy SPORE theme. In this study, we propose to expand the canine MTI/SBRT trial with more animals and add new immune monitoring to assess local and systemic tumor immunity, as well as functional tumor imaging to understand the impact of MTI/SBRT on tumor perfusion. We will test the overall hypothesis that combining MTI with SBRT will significantly increase SC tumor immunity, perfusion, and improve SBRT clinical responses. Results from this MTI/SBRT study can exert an immediate and substantial impact on the management of human SC, as the 2-drug combination of already approved and safe drugs for MTI can be readily implemented clinically. Specific Aim 1: Determine whether addition of myeloid-targeted immunotherapy (MTI) to SBRT augments local and systemic tumor immunity in dogs with SC. Subaim 1.1 will investigate local tumor immune responses to SBRT and MTI/SBRT, using tumor biopsy and nasal lavage samples, to include analysis of immune cell infiltrates (immunohistochemistry, flow cytometry) and transcriptional status (scRNA-seq, bulk RNAseq). In Subaim 1.2, regional and systemic tumor immune responses will be examined, using lymph node biopsies (flow cytometry, RNAseq) and PBMC samples (T cell responses to SC tumor antigens). The clinical impact of combined MTI/SBRT on tumor responses will be assessed in Subaim 1.3 by serial CT evaluation (pre-treatment, 3 mos, 6 mos) and determination of progression-free interval (PFI) and overall survival time (OST) will be compared between treatment groups. Specific Aim 2: Elucidate the impact of combined MTI/SBRT on tumor perfusion in dogs with SC. Dynamic contrast enhanced-CT will be used in Subaim 2.1 to determine how adding MTI to SBRT affects tumor perfusion parameters at 3- and 6-mos following treatment. In Subaim 2.2, the impact of adding MTI to SBRT on tumor angiogenesis and vessel architecture will be determined, using serial tumor biopsies and IHC analyses.

摘要

项目成果

Selective targeting of IL2Rβγ combined with radiotherapy triggers CD8- and NK-mediated immunity, abrogating metastasis in HNSCC.

• DOI: 10.1016/j.xcrm.2023.101150
• 发表时间: 2023-08-15
• 期刊: CELL REPORTS MEDICINE
• 影响因子: 14.3
• 作者: Gadwa, Jacob;Amann, Maria;Bickett, Thomas E.;Knitz, Michael W.;Darragh, Laurel B.;Piper, Miles;Van Court, Benjamin;Bukkapatnam, Sanjana;Pham, Tiffany T.;Wang, Xiao-Jing;Saviola, Anthony J.;Deak, Laura Codarri;Umana, Pablo;Klein, Christian;D'Alessandro, Angelo;Karam, Sana D.
• 通讯作者: Karam, Sana D.

Amateur antigen-presenting cells in the tumor microenvironment.

肿瘤微环境中的业余抗原细胞。

• DOI: 10.1002/mc.23354
• 发表时间: 2022-03
• 期刊: MOLECULAR CARCINOGENESIS
• 影响因子: 4.6
• 作者: Darragh, Laurel B.;Karam, Sana D.
• 通讯作者: Karam, Sana D.

Why responses to immune checkpoint inhibitors are heterogeneous in head and neck cancers: Contributions from tumor-intrinsic and host-intrinsic factors.

• DOI: 10.3389/fonc.2022.995434
• 发表时间: 2022
• 期刊: Frontiers in oncology
• 影响因子: 4.7

Measurement of mouse head and neck tumors by automated analysis of CBCT images.

• DOI: 10.1038/s41598-023-39159-6
• 发表时间: 2023-07-25
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Van Court, Benjamin;Neupert, Brooke;Nguyen, Diemmy;Ross, Richard;Knitz, Michael W.;Karam, Sana D.
• 通讯作者: Karam, Sana D.

Vasculitis, CA19-9, and Perineural Invasion Differentially Predict Response and Surgical Outcome in Pancreatic Ductal Adenocarcinoma.

血管炎、CA19-9 和神经周围浸润对胰管腺癌的反应和手术结果有不同的预测作用。

• DOI: 10.1016/j.ijrobp.2022.12.039
• 发表时间: 2023
• 期刊: International journal of radiation oncology, biology, physics
• 作者: Piper,Miles;Ross,RichardBlake;Hu,Junxiao;Watanabe,Shuichi;Knitz,Michael;Mehrotra,Sanjana;Shulick,Richard;Chiaro,MarcoDel;Karam,SanaD
• 通讯作者: Karam,SanaD