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Project

Novel IL-15 Superagonist Therapy for Bladder Cancer

Funder: National Cancer Institute

Funding period
USD 225 K
Funding amount
Abstract
DESCRIPTION (provided by applicant): Non-Muscle Invasive Bladder cancer (NMIBC), the fifth most common cancer in the United States and the costliest to treat per patient of all cancers, tends to recur, requiring repeated intervention and long-term follow-up. NMIBC are usually treated by surgical resection and intravesical chemotherapy and immunotherapy. Immunotherapy usually consists of intravesical administration of Bacillus Calmette-Guerin (BCG), a live, attenuated bacterium. A recent meta-analysis of nine randomized studies confirmed the superiority of intravesical immunotherapy with BCG for high-grade NMIBC both in terms of efficacy and decreasing disease recurrence. However, BCG immunotherapy is associated with significant toxicity, and approximately 20 percent of patients fail to complete the course of therapy. In addition, as many as 30 percent of patients either fail to respond to therapy or suffer disease recurrence within 5 years. Of these, 30 percent will eventually die of bladder cancer and 50 percent will undergo radical cystectomy. Thus, a novel therapy, either as first-line or salvage therapy, is desperately needed for NMIBC to prevent disease progression and allow for bladder preservation to improve quality of life of patients. Although the mechanism of action for BCG therapy leading to clinical efficacy is unclear, T lymphocytes and natural killer (NK) cells are implicated as the critical mediators of the anti-tumor immune response. IL-15 is a necessary factor for the development, proliferation and activation of effector NK and CD8+ memory T cells. This cytokine exhibits potent anti-tumor activities against well-established tumors in laboratory animal models and is listed by a recent NCI review as the most promising product candidate among twelve immunotherapy drugs that could potentially cure cancer. We have reported the isolation of a novel IL-15 mutant with a 4-fold increase in biological activity. The pharmacokinetics and biological activity of this superagonistic IL-15 (hIL-15G72D) have been further improved by creating a complex with an IL-15 receptor 1 - IgG1 fusion protein (IL-15R1-Fc). We postulate that transurethral administration of this IL-15G72D/IL-15R1-Fc superagonistic complex will provide a durable, potent and broad cell-mediated immune responses which would result in a safer and more efficacious immunotherapy than that of BCG for the treatment of patients with NMIBC. In this proposal, we propose to evaluate the efficacy of the IL-15G72D/IL-15R1-Fc superagonist in an implanted NMIBC tumor model in immunocompetent mice. Success of this proposed feasibility study will prompt us to create a high-production cell line for generating IL-15N72D/IL-15R1-Fc superagonist complex and to further refine the purification procedure. These efforts will pave the way for pre-clinical studies, which will include additional efficacy studies to determine optimal dosing and pharmacokinetics and toxicology evaluation of the complex, as part of the SBIR Phase II project, to support clinical development. Our ultimate goal is to enter the IND phase and to conduct clinical trials using the IL-15N72D/IL-15R1-Fc superagonist complex against NMIBC. PUBLIC HEALTH RELEVANCE: In this proposal, we propose to evaluate the efficacy of the IL-15N72D/IL-15R1-Fc superagonist complex against non-muscle invasive bladder cancer (NMIBC) in an immunocompetent mouse model. Positive outcomes from this proposed study would provide justification for developing IL-15N72D/IL-15R1-Fc superagonistic complex as a safe, durable, potent and cell-mediated immunotherapy to replace Bacillus Calmette-Guerin for the treatment of patients with NMIBC.
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System

Categories
  • FOR (ANZSRC)

    1107 Immunology

  • FOR (ANZSRC)

    1112 Oncology and Carcinogenesis

  • RCDC

    Cancer

  • RCDC

    Immunization

  • RCDC

    Urologic Diseases

  • HRCS HC

    Cancer

  • HRCS RAC

    5.1 Pharmaceuticals

  • HRCS RAC

    5.2 Cellular and gene therapies

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Basic Science