Novel IL-15 Superagonist Therapy for Bladder Cancer

Project SummaryBladder cancer is the fifth most common cancer in the U SUp toof patients initially present with non muscle invasive bladder cancerNMIBCconfined to the mucosa of the bladderThese patients are treated by tumor resection followed by intravesical chemotherapy or Bacillus Calmette Gu rinBCGtherapyDespite treatmentup toof patients will experience tumor recurrence andof theseaboutwill undergo radical cystectomy in an attempt to control disease progression andof these patients will progress and succumb to their diseaseDue to its high recurrence rateNMIBC is the costliest of all cancers to treatSince the FDA has not approved a drug for NMIBC in the lastyearsnovel therapies are desperately needed to prevent NMIBC disease progression and allow bladder preservationT cells and natural killerNKcells have been implicated as critical mediators of the antitumor immune response using BCG therapyInterleukinILconsidered by the NCI as the most promising immunotherapeutic that could potentially cure canceris a crucial factor for effector NK cell and CDmemory T cell stimulation and exhibits potent efficacy against tumors in various animal modelsTo advance ILbased therapies into clinical developmentwe have isolated a novel proprietary ILsuperagonist mutant and associated it with an ILreceptorFc fusion protein to generate a complex referred to as ALTIn numerous preclinical modelsALTwas shown to have improved pharmacokineticbiodistribution and immunostimulatory properties and greater antitumor activity than ILaloneWe postulate that intravesical treatment of ALTin combination with BCG will induce durable cell mediated immune responses providing antitumor efficacy in patients with NMIBCIn clinically relevant rodent NMIBC tumor modelswe found that intravesical ALTBCG therapy provided significantly better immune responses and antitumor activity than BCG monotherapyBased on these resultsa multicenter Phaseclinical trial of intravesical ALTBCG in NMIBC patients was initiated under the SBIR Phase II project and the dose escalation portion has now been successfully completedThe recommended Phasedose of ALTwas established based on a safety profile comparable to BCG monotherapyHigh response rate with impressive durabilityi eno disease recurrence at up tomonthsand bladder localized immune cell activation were observed in all treated patientsThese findings strongly support advancing to the randomizedarm dose expansion portion of the Phaseclinical trial as proposed in this Phase IIb applicationIn the PhasestudyNMIBC patients will receive intravesicular instillation of either ALTBCG or BCG alone and the disease free response rateduration of recurrenceand localized and systemic immune activation will be assessedImproved clinical outcomes using ALTBCG would support a Phaseevaluation of intravesical ALTtherapy in patients with NMIBC with the ultimate goal of developing more durable or curative therapies in this indication Project Narrative The results of a SBIR Phase I pre clinical study revealed that ALTa novel interleukinbased immunostimulatory protein complexalone and in combination with standard Bacillus Calmette Gu rinBCGimmunotherapy promotes immune responses and exhibits potent antitumor activity against non muscle invasive bladder cancerNMIBCwhen administered into the bladders of tumor bearing rodentsBased on these resultsa multicenter Phaseclinical trial of intravesical ALTBCG was initiated under the SBIR Phase II project and the dose escalation was successfully completed with a determination of a recommended dose level of ALTthat exhibits favorable safetyimmunostimulatory propertiesand clinical benefit to patientsThese findings allowed advancement into a randomized Phasetrial as proposed in this application to further evaluate the safety and efficacy of intravesical ALTBCG therapy in patients with NMIBC with the ultimate goal of developing more durable or curative therapeutic options in this indication