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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.

项目总结