Colorado Head and Neck Cancer SPORE

科罗拉多头颈癌孢子

基本信息

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
项目类别：
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

项目摘要

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.

抽象的本申请是为了响应被识别为 NOT-CA- 的特殊利益通知 (NOSI) 而提交的 23-059。鼻窦癌 (SC) 是全球重要的头颈癌 (HNC)，但预后仍然不佳贫穷的。 SC 在实验室和临床中都得到了充分研究。我们认为宠物狗中的 SC 代表该 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和犬 SC 临床试验中的立体定向身体放射治疗 (SBRT)。我们目前的努力包括骨髓使用两种重新用途药物（氯沙坦和普萘洛尔）进行细胞靶向免疫治疗 (MTI)，以消除或重新编程与 SBRT 联合使用时的骨髓细胞。我们对使用 MTI + SBRT 方案治疗 SC 的狗的早期结果提供了与单独 SBRT 相比增强的局部 T 细胞反应和改善的总体生存率的证据。拟议的研究是对母项目（科罗拉多头颈癌）的合理补充 SPORE）致力于推进转化研究，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 主题保持一致。在这项研究中，我们建议扩大犬类 MTI/SBRT 试验，使用更多动物，并添加新的免疫监测来评估局部和全身肿瘤免疫，以及功能性肿瘤成像，以了解 MTI/SBRT 的影响关于肿瘤灌注。我们将检验总体假设，即 MTI 与 SBRT 结合将显着提高 SC 肿瘤免疫、灌注和改善 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 2 种药物的组合已经批准且安全的 MTI 药物可以很容易地应用于临床。具体目标 1：确定在 SBRT 基础上添加骨髓靶向免疫疗法 (MTI) 是否会增强疗效 SC 犬的局部和全身肿瘤免疫。 Subaim 1.1将研究局部肿瘤免疫使用肿瘤活检和鼻腔灌洗样本对 SBRT 和 MTI/SBRT 的反应进行分析，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 Subaim 1.2，将使用淋巴结活检（流程细胞计数、RNAseq）和 PBMC 样本（T 细胞对 SC 肿瘤抗原的反应）。的临床影响 Subaim 1.3 中将通过系列 CT 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）治疗组之间进行比较。具体目标 2：阐明联合 MTI/SBRT 对 SC 犬肿瘤灌注的影响。 Subaim 2.1 将使用动态对比增强 CT 来确定在 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 对将使用连续肿瘤活检和 IHC 分析来确定肿瘤血管生成和血管结构。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

通过 CBCT 图像的自动分析测量小鼠头颈部肿瘤。

DOI：
发表时间：
2023-07-25
期刊：
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

Author Correction: A phase I/Ib trial and biological correlate analysis of neoadjuvant SBRT with single-dose durvalumab in HPV-unrelated locally advanced HNSCC.

作者更正：针对 HPV 无关局部晚期 HNSCC 的新辅助 SBRT 与单剂量 durvalumab 的 I/Ib 期试验和生物学相关分析。

DOI：
发表时间：
2023-01
期刊：
影响因子：
22.7
作者：
Darragh, Laurel B;Knitz, Michael M;Hu, Junxiao;Clambey, Eric T;Backus, Jennifer;Dumit, Andrew;Samedi, Von;Bubak, Andrew;Greene, Casey;Waxweiler, Timothy;Mehrotra, Sanjana;Bhatia, Shilpa;Gadwa, Jacob;Bickett, Thomas;Piper, Miles;Fakhoury, Ka
通讯作者：
Fakhoury, Ka

The dichotomy of regulatory B cells in cancer versus allergic disease.

癌症与过敏性疾病中调节性 B 细胞的二分法。

DOI：
发表时间：
2024-01
期刊：
影响因子：
4.6
作者：
Dang, Melissa;Yu, Justin;Galant;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呈递细胞。

DOI：
发表时间：
2022-02
期刊：
影响因子：
4.6
作者：
Darragh, Laurel B;Karam, Sana D
通讯作者：
Karam, Sana D

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

选择性靶向IL2Rβγ 结合放疗触发CD8 和NK 介导的免疫，消除HNSCC 的转移。

DOI：
发表时间：
2023-08-15
期刊：
影响因子：
0
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;Saviola, Anthony J;Deak, Laura Codarri;Umaña, Pablo;Klein, Christian;D'Aless
通讯作者：
D'Aless