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 本申请是为了响应被标识为NOT-CA的特别利益通知（NOSI）而提交的- 23-059.鼻腔鼻窦癌（Sinonasal carcinoma，SC）是一种重要的头颈部恶性肿瘤，但其预后仍不确定 扶贫SC在实验室和临床中研究不足。我们建议，SC在宠物狗代表一个 这种HNC的自发动物模型。我们的团队已经验证了研究免疫疗法的方法， 在犬SC临床试验中的立体定向体部放射治疗（SBRT）。我们目前的努力包括骨髓 细胞靶向免疫治疗（MTI），使用两种重新用途的药物（氯沙坦和普萘洛尔）来消耗或重新编程 骨髓细胞与SBRT结合时。我们在接受MTI + SBRT方案治疗的SC犬中的早期结果 提供了与单独SBRT相比增强的局部T细胞应答和改善的总体存活率的证据。 拟议的研究是对母项目（科罗拉多头颈癌）的合理补充 SPORE）旨在推进转化研究，以提高HNC患者的生存率和生活质量。 因此，我们的项目将与整体免疫治疗/放射治疗SPORE主题一致。在本研究中， 我们建议用更多的动物扩大犬MTI/SBRT试验，并增加新的免疫监测， 局部和全身肿瘤免疫，以及功能性肿瘤成像，以了解MTI/SBRT的影响 肿瘤灌注。我们将检验MTI与SBRT相结合将显著增加 SC肿瘤免疫，灌注，提高SBRT临床反应。这项MTI/SBRT研究的结果可以 对人类SC的管理产生直接和实质性的影响，因为 已经批准的用于MTI的安全药物可以容易地在临床上实施。 具体目标1：确定在SBRT中加入骨髓靶向免疫治疗（MTI）是否会增强 局部和全身肿瘤免疫在患有SC的犬中。Subaim 1.1将研究局部肿瘤免疫 SBRT和MTI/SBRT的反应，使用肿瘤活检和鼻灌洗样本，包括免疫分析， 细胞浸润（免疫组织化学，流式细胞术）和转录状态（scRNA-seq，bulk RNAseq）。在 在Subaim 1.2中，将使用淋巴结活检检查局部和全身肿瘤免疫应答（流式细胞术）。 流式细胞术，RNAseq）和PBMC样品（对SC肿瘤抗原的T细胞应答）。的临床影响 联合MTI/SBRT对肿瘤反应的影响将在Subaim 1.3中通过连续CT评估进行评估（治疗前， 3个月、6个月），并确定无进展间期（PFI）和总生存时间（OST）。 治疗组之间的比较。 具体目标2：阐明MTI/SBRT联合治疗对SC犬肿瘤灌注的影响。 在Subaim 2.1中将使用动态对比增强CT，以确定在SBRT中添加MTI如何影响肿瘤 治疗后3个月和6个月的灌注参数。在Subaim 2.2中，将MTI添加到SBRT对 使用连续的肿瘤活组织检查和IHC分析来确定肿瘤血管生成和血管结构。

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