Intravesical Immunotherapy of Spontaneous Canine Invasive Urothelial Carcinoma

犬自发性浸润性尿路上皮癌的膀胱内免疫治疗

基本信息

批准号：
10669242
负责人：
PAUL R HESS
金额：
$ 52.23万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
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/10669242
关键词：
Abscopal effect Adverse effects Adverse event Antibodies Antitumor Response Appointment Behavior Biological Assay Biomedical Engineering Biopolymers Bladder Bladder Neoplasm Cancer Patient Canis familiaris Cells Chitosan Client Clinical Trials Collaborations Complement Correlative Study Data Diagnosis Disease Distant Dose Drug Kinetics Enrollment Environment Evaluation Evolution Excision Exposure to Flow Cytometry Gene Expression Genes Heterogeneity Histologic Human Immune Immune checkpoint inhibitor Immunity Immunobiology Immunogenomics Immunologics Immunooncology Immunophenotyping Immunotherapy Implant In Vitro Interleukin-12 Interleukin-12 therapy Intravesical Administration Intravesical Instillation Laboratories Life Malignant Neoplasms Malignant neoplasm of urinary bladder Measures Medical Medical Oncologist Medical Oncology Modeling Monitor Mus Mutation Neoplasm Metastasis Oncology PD-1/PD-L1 Pathology Patients Peripheral Persons Pharmacodynamics Phase Phenotype Positioning Attribute Public Health Recombinants Recommendation Refractory Research Personnel Rodent Model Route Safety Serum Site T cell clonality T cell receptor repertoire sequencing T cell response T-Lymphocyte Testing Transitional Cell Carcinoma Translations Tumor Immunity Tumor Volume UNC Lineberger Comprehensive Cancer Center Urology Veterinary Medicine Work anti-tumor immune response antigen-specific T cells bladder transitional cell carcinoma cancer genetics cancer immunotherapy cancer infiltrating T cells cancer subtypes checkpoint therapy clinical examination clinical translation cohort college comparative cytokine design effective therapy effectiveness evaluation exome sequencing immune-related adverse events immunotoxicity intravesical molecular subtypes multidisciplinary muscle invasive bladder cancer nano-string neoantigens novel pre-clinical research preclinical study prevent programs recruit response safety assessment transcriptome transcriptome sequencing trial design tumor tumor-immune system interactions tumorigenesis uptake

项目摘要

PROJECT SUMMARY Invasive bladder cancer is a lethal disease that often requires life-altering surgical removal of the bladder to prevent or limit metastasis. Recent approvals of five checkpoint inhibitors for advanced or refractory bladder cancers demonstrate its responsiveness to immunotherapy. However, less than half of advanced bladder cancer patients benefit from checkpoint immunotherapy and antitumor responses are often transient. Our previous preclinical studies in mice demonstrated that intravesical immunotherapy with interleukin- 12 (IL-12) formulated with the mucoadhesive biopolymer chitosan (CS), i.e., CS/IL-12, can eliminate nearly all established orthotopic bladder tumors in a T cell-dependent manner. These studies also demonstrated that intravesical CS/IL-12 can induce robust abscopal responses with the elimination of distant, untreated bladder tumors in most mice. Although these data are promising, several limitations of implanted murine bladder tumor models have hindered clinical translation. Thus, this application proposes to evaluate the safety and activity of intravesical CS/canine IL-12 (caIL-12) immunotherapy in pet dogs with spontaneous invasive urothelial carcinoma (UC) of the bladder. There are numerous similarities between canine and human bladder cancers including mechanisms of tumorigenesis, rates and sites of metastasis, and distinguishable molecular subtypes. Given these similarities, treatments found to be successful in dogs are more likely to be successful in people. The objectives of this project are: 1) to demonstrate that intravesical CS/caIL-12 immunotherapy can safely induce antitumor immunity against canine invasive UC; and 2) to determine if canine bladder cancer is a useful model for the evaluation of this and other novel immunotherapies. The first objective will help prepare intravesical CS/IL-12 for translation into human clinical trials, while the second objective will help bladder cancer researchers overcome the limitations of rodent models and provide a more faithful representation of human bladder cancer. To accomplish these objectives, 2 specific aims have been designed. Aim 1 is focused on safety, as CS/caIL-12 has never been evaluated in dogs. After synthesizing and validating recombinant caIL-12 in vitro, we will perform a dose-escalation study of intravesical CS/caIL-12 in pet dogs with spontaneous invasive UC of the bladder. Aim 1 will establish a recommended dose (RD) based on safety readouts that utilize a combination of clinical examinations and laboratory tests. Proposed pharmacokinetic and immunophenotyping studies will investigate the possible systemic uptake and dissemination of intravesical immunotherapy and the resulting immune impacts. Aim 2 will assess antitumor and immunological responses to the RD of intravesical CS/caIL-12 in an expanded cohort of dogs with bladder cancer. Correlative studies will determine if intravesical CS/caIL-12 influences T cell infiltration, the tumor- immune microenvironment, neoantigen reactivity and/or T cell clonality. The influence of molecular subtype and tumor mutational burden on antitumor and/or immune responsiveness will be assessed.

项目摘要侵入性膀胱癌是一种致命的疾病，通常需要改变生活的外科手术膀胱以防止或限制转移。最近批准了五个检查点抑制剂的高级或耐火塔抑制剂膀胱癌证明了其对免疫疗法的反应。但是，不到一半的高级膀胱癌患者受益于检查点免疫疗法，抗肿瘤反应通常是短暂的。我们以前在小鼠的临床前研究表明，插入室内免疫疗法与白介素 - 12（IL-12）用粘膜粘附生物聚合物壳聚糖（CS），即CS/IL-12，几乎可以消除所有以T细胞依赖性方式建立的原位膀胱肿瘤。这些研究还表明静脉内CS/IL-12可以通过消除远处，未处理的膀胱诱导强大的潜线反应大多数小鼠的肿瘤。尽管这些数据是有希望的，但植入的鼠膀胱肿瘤的几个局限性模型阻碍了临床翻译。因此，该应用建议评估静脉内CS/犬IL-12（CAIL-12）自发侵入性尿路上皮的宠物犬免疫疗法膀胱的癌（UC）。犬和人膀胱癌之间有许多相似之处包括肿瘤发生的机制，转移的速率和位点以及可区分的分子亚型。鉴于这些相似之处，发现在狗中成功的治疗方法更有可能在人中取得成功。该项目的目标是：1）证明静脉内CS/CAIL-12免疫疗法可以安全诱发抗肿瘤免疫力针对犬类侵入性UC； 2）确定犬膀胱癌是否是一个评估该免疫疗法的有用模型。第一个目标将有助于准备用于转化为人类临床试验的静脉内CS/IL-12，而第二个目标将有助于膀胱癌症研究人员克服了啮齿动物模型的局限性，并提供了更忠实的代表人膀胱癌。为了实现这些目标，已经设计了2个具体目标。 AIM 1专注于安全性，因为CS/CAIL-12从未在狗中进行评估。合成后在体外验证重组CAIL-12，我们将对静脉内CS/CAIL-12进行剂量升级研究宠物犬具有膀胱的自发侵入性UC。 AIM 1将建立建议的剂量（RD）关于使用临床检查和实验室测试的安全读数。建议的药代动力学和免疫表型研究将研究可能的全身摄取和传播静脉免疫疗法和由此产生的免疫影响。 AIM 2将评估抗肿瘤对膀胱膨胀的狗队列中静脉内CS/CAIL-12的免疫学反应癌症。相关研究将确定静脉内CS/CAIL-12是否影响T细胞浸润，肿瘤 - 免疫微环境，新抗原反应性和/或T细胞克隆性。分子亚型的影响将评估抗肿瘤和/或免疫反应性的肿瘤突变负担。