Effectiveness of two different dose administration regimens of an IL-15 superagonist complex (ALT-803) in an orthotopic bladder cancer mouse model

摘要

BackgroundIn the US alone, the number of new bladder cancer (BCa) cases will be approximately 81,190 (with a preponderance of these patients being men over the age of 50?years) and BCa will result in approximately 17,240 deaths in 2018 [1]. Seventy percent of patients with newly diagnosed BCa present with non-muscle invasive bladder cancer (NMIBC), which is disease confined to the mucosa and submucosal tissues. In patients with NMIBC, the administration of adjuvant intravesical chemotherapy or Bacillus Calmette-Guérin (BCG) often can prolong the progression-free interval after initial tumor resection [2]. Unfortunately, despite these therapies, patients with NMIBC remain at high risk of tumor recurrence (~?70%), making BCa one of the most prevalent cancers in the US, second only to colorectal cancer [2, 3]. In addition to this high rate of tumor recurrence, 30% of patients with NMIBC will progress to muscle invasive bladder cancer (MIBC), which is associated with a reduced overall survival (5-year survival??90%), whilst another 50% of these NMIBC patients will undergo removal of their bladders in an attempt to control their disease [4]. In the management of NMIBC, no new drug has been FDA approved in over 15?years [5].Recently, we published our results of intravesical administration of ALT-803 (novel IL-15N72D/IL-15Rα-Fc superagonist complex) along with intravesical BCG in a well-established carcinogen induced rat model. In this study we noted: (a) intravesical ALT-803 was safe and well tolerated alone and in combination with BCG, (b) as a single treatment agent, ALT-803 reduced tumor burden by 35% compared to a tumor reduction of 15% with BCG alone, (c) combination of ALT-803 plus BCG reduced tumor burden by 46% compared to control and was associated with natural killer (NK) cell activation [6]. Motivated by these compelling preclinical data related to IL-15, we tested the therapeutic efficacy of intravesical ALT-803 with intravesical BCG in a phase Ib clinical trial in subjects with BCG-na?ve NMIBC. The induction treatment regimen was administered according to a previously published Southwest Oncology Group intravesical BCG protocol [7]. Patients had a routine cystoscopy and voided urinary cytology (VUC) every 3?months for 2?years to determine response. We noted that the combination therapy was well-tolerated and all patients were disease-free (i.e., complete response) at 24?months follow-up with no patients experiencing disease recurrence or progression [8].Promising early phase clinical results with intravenous and subcutaneous ALT-803 administration have been also reported in allogeneic hematopoietic cell transplantation, non-small cell lung cancer, melanoma, renal cell carcinoma and head and neck cancers, suggesting that systemic ALT-803 may have a therapeutic effect on NMIBC [9,10,11]. To date, no systemic therapy has been proven to be effective in the NMIBC setting, thus there is a need to evaluate systemic ALT-803 therapy given subcutaneously prior to embarking on human clinical trial. In this report, we set out to determine if subcutaneous (SQ) ALT-803 given in the setting of NMIBC was non-inferior to intravesical BCG.