SBIR-STTR Award

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.

Thesaurus Terms:
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Bladder cancer is the fifth most common cancer in the United States. Over 70 - 80% of patients initially present with non-muscle invasive bladder cancer (NMIBC) confined to the mucosa of the bladder. These patients are treated by tumor resection followed by intravesical chemotherapy or Bacillus Calmette-Gu¿rin (BCG) therapy. Despite treatment, 60% of NMIBC patients will experience tumor recurrence and, of these, ~30% will progress and succumb to their disease while another 50% will undergo radical cystectomy in an attempt at disease control. Since the FDA has not approved a drug for NMIBC in the last 20 years, novel therapies are desperately needed for NMIBC to prevent disease progression and allow bladder preservation. NMIBC is also the costliest of all cancers to treat due to its high recurrence rate. Thus, any effective drug for NMIBC will have a large impact on healthcare costs. Although the mechanisms leading to BCG-mediated efficacy are unclear, T cells and natural killer (NK) cells have been implicated as critical mediators of the antitumor immune response. Interleukin-15 (IL-15), previously considered by the NCI as the most promising immunotherapeutic that could potentially cure cancer, is a crucial factor for effector NK cell and CD8+ memory T cell proliferation and activation with high potency against established tumors in various animal models. To construct an improved version of IL-15, we have isolated a novel proprietary IL-15 superagonist mutant and associated it with an IL-15 receptor ¿-Fc fusion protein to generate a complex (referred to as ALT- 803) with enhanced pharmacokinetic (PK) and immunostimulatory properties. These significant improvements have recently led NCI to promote ALT-803 over native IL-15 as its top immunotherapeutic clinical candidate against cancer. We postulate that intravesical treatment of ALT-803 in combination with BCG will induce durable cell-mediated immune responses providing antitumor efficacy in patients with NMIBC. During the SBIR Phase I project, we found that in rodent NMIBC tumor models, intravesical ALT-803 could stimulate immune responses in the bladder leading to antitumor activity. Moreover, ALT-803 + BCG immunotherapy provided significantly greater efficacy than BCG monotherapy against carcinogen-induced NMIBC. These studies suggest that ALT-803 + BCG is a more effective treatment than BCG alone and provide a strong rationale for testing intravesical ALT-803 + BCG therapy in patients with NMIBC. To support such trials, we have completed non-clinical studies and ALT-803 clinical product manufacture allowing FDA acceptance of an IND for ALT-803 testing in patients with solid tumors. Under this SBIR Phase II proposal, we plan to conduct a dose escalation phase of a multicenter Phase 1/2 study to investigate the safety, PK, and immunostimulatory and clinical activities of intravesical ALT-803 + BCG treatment in patients with NMIBC. Successful outcomes in this study will pave the way for further evaluation of intravesical ALT-803 therapy in patients with NMIBC with the ultimate goal of developing more durable or curative therapies for BCG-na¿ve and/or BCG-refractory patients.

Thesaurus Terms:
Amendment;Animal Cancer Model;Animal Model;Arm;Bacillus (Bacterium);Base;Biodistribution;Biological;Biological Preservation;Bladder;Bladder Mucosa;Bladder Neoplasm;Cancer Immunotherapy;Cancer Model;Cancer Patient;Carcinogens;Cd8b1 Gene;Cell Killing;Cell Mediated Immune Response;Cells;Cessation Of Life;Chemotherapy;Chimeric Proteins;Clinical;Clinical Protocols;Clinical Trials;Complex;Cyclic Gmp;Cytokine;Development;Diagnosis;Disease;Disease Progression;Disorder Control;Dose;Drug Kinetics;Effective Therapy;Evaluation;Excision;Exhibits;Experience;Goals;Health Care Costs;Immune;Immune Response;Immunocompetent;Immunogenicity;Immunotherapeutic Agent;Immunotherapy;Improved;In Vivo;Infiltration;Interferons;Interleukin-15;Interleukin-15 Receptor;Interleukin-2;Interleukins;Intravesical;Intravesical Administration;Laboratory Animals;Lead;Macaca Fascicularis;Malignant Neoplasm Of Urinary Bladder;Malignant Neoplasms;Maximum Tolerated Dose;Mediating;Mediator Of Activation Protein;Memory;Metastatic Melanoma;Modeling;Mus;Mutant;Natural Killer Cells;Neoplastic Cell;Non-Drug;Novel;Novel Strategies;Outcome;Patients;Pharmaceutical Preparations;Pharmacodynamics;Phase;Phase 2 Study;Phase Iii Clinical Trials;Preclinical Study;Prevent;Property;Protein Complex;Public Health Relevance;Radical Cystectomy;Randomized;Rattus;Receptor;Recurrence;Refractory;Research Clinical Testing;Response;Rodent;Safety;Small Business Innovation Research Grant;Solid Neoplasm;Success;T Cell Response;T Memory Cell;T-Cell Proliferation;T-Lymphocyte;Testing;Therapeutic;Time;Toxic Effect;Toxicology;Transurethral Resection;Tumor;United States;Urothelium;