Novel IL-15 Superagonist Therapy for Bladder Cancer

DESCRIPTION provided by applicant Bladder cancer is the fifth most common cancer in the United States Over 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 of NMIBC patients will experience tumor recurrence and of these will progress and succumb to their disease while another will undergo radical cystectomy in an attempt at disease control Since the FDA has not approved a drug for NMIBC in the last 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 IL previously considered by the NCI as the most promising immunotherapeutic that could potentially cure cancer is a crucial factor for effector NK cell and CD memory T cell proliferation and activation with high potency against established tumors in various animal models To construct an improved version of IL we have isolated a novel proprietary IL superagonist mutant and associated it with an IL receptor Fc fusion protein to generate a complex referred to as ALT with enhanced pharmacokinetic PK and immunostimulatory properties These significant improvements have recently led NCI to promote ALT over native IL as its top immunotherapeutic clinical candidate against cancer We postulate that intravesical treatment of ALT 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 could stimulate immune responses in the bladder leading to antitumor activity Moreover ALT BCG immunotherapy provided significantly greater efficacy than BCG monotherapy against carcinogen induced NMIBC These studies suggest that ALT BCG is a more effective treatment than BCG alone and provide a strong rationale for testing intravesical ALT BCG therapy in patients with NMIBC To support such trials we have completed non clinical studies and ALT clinical product manufacture allowing FDA acceptance of an IND for ALT testing in patients with solid tumors Under this SBIR Phase II proposal we plan to conduct a dose escalation phase of a multicenter Phase study to investigate the safety PK and immunostimulatory and clinical activities of intravesical ALT BCG treatment in patients with NMIBC Successful outcomes in this study will pave the way for further evaluation of intravesical ALT 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 PUBLIC HEALTH RELEVANCE The results of the SBIR Phase I project revealed that ALT a novel interleukin based immunostimulatory protein complex alone and in combination with standard Bacillus Calmette Gu rin BCG immunotherapy promotes immune responses and exhibits potent antitumor activity against non muscle invasive bladder cancer NMIBC when administered into the bladders of tumor bearing rodents As these studies strongly support clinical development of ALT against NMIBC we propose to conduct a multicenter Phase study to investigate the safety pharmacokinetic and pharmacodynamic and clinical activities of intravesical ALT BCG in patients with NMIBC Successful completion of this study will pave the way for further evaluation of intravesical ALT therapy in patients with NMIBC with the ultimate goal of developing more durable or curative therapeutic options for treatment na ve and or refractory NMIBC patients