title: Intravesical ALT-803 and BCG treatment reduces tumor burden in a carcinogen induced bladder cancer rat model; a role for cytokine production and NK cell expansion.
abstract: Intravesical Bacillus Calmette-Guérin (BCG) has been shown to induce a specific immunologic response (i.e., activation of IL-2 and effector T-cells), while preclinical studies using ALT-803 (mutated IL-15 analogue combined with IL-15Rα-Fc fusion) have shown promising results by prolonging the agent's half-life and stimulating CD8+ T-cells. Based on these results, we hypothesized that the intravesical administration of ALT-803 along with BCG will generate an immunologic response leading to significant bladder tumor burden reduction. Using a well-established carcinogen induced rat non-muscle invasive bladder cancer (NMIBC) model, we studied the effects of intravesical ALT-803 with and without BCG. Rat tissues were evaluated to document treatment response. Intravesical ALT-803 was safe and well tolerated alone and in combination with BCG. As a single treatment agent, ALT-803 reduced tumor burden by 35% compared to control whereas BCG alone only reduced tumor burden by 15%. However, the combination of ALT-803 plus BCG reduced tumor burden by 46% compared to control. Immune monitoring suggested that the antitumor response was linked to the production and secretion of IL-1α, IL-1β and RANTES, which in turn, induced the proliferation and activation of NK cells. Lastly, tumoral responses of the combinational treatment were associated with 76% reduction in angiogenesis, which is significantly higher than when assessed with either agent alone. The enhanced therapeutic index seen with this duplet provides justification for the development of this regimen for future clinical trials.
authors.affiliation: Cancer Research Institute, MD Anderson Cancer Center Orlando, Orlando, Florida, United States of America.
authors.forename: Evan
authors.initials: E
authors.lastname: Gomes-Giacoia
authors.affiliation: Cancer Research Institute, MD Anderson Cancer Center Orlando, Orlando, Florida, United States of America.
authors.forename: Makito
authors.initials: M
authors.lastname: Miyake
authors.affiliation: Cancer Research Institute, MD Anderson Cancer Center Orlando, Orlando, Florida, United States of America; Department of Health Sciences Research, Mayo Clinic, Jacksonville, Florida, United States of America.
authors.forename: Steve
authors.initials: S
authors.lastname: Goodison
authors.affiliation: Department of Pathology, MD Anderson Cancer Center Orlando, Orlando, Florida, United States of America.
authors.forename: Aravindhan
authors.initials: A
authors.lastname: Sriharan
authors.affiliation: Cancer Research Institute, MD Anderson Cancer Center Orlando, Orlando, Florida, United States of America.
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Altor Bioscience Corporation, Miramar, Florida, United States of America.
authors.forename: Lijing
authors.initials: L
authors.lastname: You
authors.affiliation: Altor Bioscience Corporation, Miramar, Florida, United States of America.
authors.forename: Jack O
authors.initials: JO
authors.lastname: Egan
authors.affiliation: Altor Bioscience Corporation, Miramar, Florida, United States of America.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Rhode
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Jacksonville, Florida, United States of America.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Parker
authors.affiliation: Burnett College of Biomedical Sciences, University of Central Florida, Orlando, Florida, United States of America.
authors.forename: Karl X
authors.initials: KX
authors.lastname: Chai
authors.affiliation: Altor Bioscience Corporation, Miramar, Florida, United States of America.
authors.forename: Hing C
authors.initials: HC
authors.lastname: Wong
authors.affiliation: Cancer Research Institute, MD Anderson Cancer Center Orlando, Orlando, Florida, United States of America; Clinical and Translational Research, University of Hawaii Cancer Center, Honolulu, Hawaii, United States of America.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Rosser
mesh_terms: D000283:Administration, Intravesical; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016207:Cytokines / Q000096:biosynthesis*; D004195:Disease Models, Animal; D005260:Female; D007694:Killer Cells, Natural / Q000276:immunology*; D009163:Mycobacterium bovis / Q000276:immunology*; D011506:Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins; D047368:Tumor Burden / Q000187:drug effects*; D001743:Urinary Bladder / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology
chemical_list: C582303:ALT-803; D000970:Antineoplastic Agents; D016207:Cytokines; D011506:Proteins; D011993:Recombinant Fusion Proteins