U01CA272258

Intravesical immunotherapy of spontaneous canine invasive urothelial carcinoma - 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.

North Carolina State University

TO DEVELOP THE MEANS TO CURE AS MANY CANCER PATIENTS AS POSSIBLE AND TO CONTROL THE DISEASE IN THOSE PATIENTS WHO ARE NOT CURED. CANCER TREATMENT RESEARCH INCLUDES THE DEVELOPMENT AND EVALUATION OF IMPROVED METHODS OF CANCER TREATMENT THROUGH THE SUPPORT AND PERFORMANCE OF BOTH FUNDAMENTAL AND APPLIED LABORATORY AND CLINICAL RESEARCH. RESEARCH IS SUPPORTED IN THE DISCOVERY, DEVELOPMENT, AND CLINICAL TESTING OF ALL MODES OF THERAPY INCLUDING: SURGERY, RADIOTHERAPY, CHEMOTHERAPY, AND BIOLOGICAL THERAPY INCLUDING MOLECULARLY TARGETED THERAPIES, BOTH INDIVIDUALLY AND IN COMBINATION. IN ADDITION, RESEARCH IS CARRIED OUT IN AREAS OF NUTRITIONAL SUPPORT, STEM CELL AND BONE MARROW TRANSPLANTATION, IMAGE GUIDED THERAPIES AND STUDIES TO REDUCE TOXICITY OF CYTOTOXIC THERAPIES, AND OTHER METHODS OF SUPPORTIVE CARE THAT MAY SUPPLEMENT AND ENHANCE PRIMARY TREATMENT. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.395 - Cancer Treatment Research

National Cancer Institute (NCI) [HHS - NIH]

Raleigh, North Carolina 276950001 United States

Single Zip Code

Canine Cancer Immunotherapy Network (K9CIN; U01 Clinical Trial Not Allowed) (RFA-CA-21-050)

Amendment Since initial award the total obligations have increased 392% from $538,904 to $2,649,907.