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

Evan Gomes-Giacoia, Makito Miyake, Steven Goodison, Aravindhan Sriharan, Ge Zhang, Lijing You, Jack O. Egan, Peter R. Rhode, Alexander Parker, Karl X. Chai, Hing C. Wong, Charles J. Rosser

Research output: Contribution to journalArticle

45 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere96705
JournalPLoS One
Volume9
Issue number6
DOIs
StatePublished - Jun 4 2014

Fingerprint

natural killer cells
carcinogens
Bacilli
Tumor Burden
Urinary Bladder Neoplasms
Natural Killer Cells
Carcinogens
Bacillus
Rats
Tumors
cytokines
animal models
interleukin-1
Cytokines
neoplasms
T-lymphocytes
T-cells
rats
angiogenesis
interleukin-2

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

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. / Gomes-Giacoia, Evan; Miyake, Makito; Goodison, Steven; Sriharan, Aravindhan; Zhang, Ge; You, Lijing; Egan, Jack O.; Rhode, Peter R.; Parker, Alexander; Chai, Karl X.; Wong, Hing C.; Rosser, Charles J.

In: PLoS One, Vol. 9, No. 6, e96705, 04.06.2014.

Research output: Contribution to journalArticle

Gomes-Giacoia, Evan ; Miyake, Makito ; Goodison, Steven ; Sriharan, Aravindhan ; Zhang, Ge ; You, Lijing ; Egan, Jack O. ; Rhode, Peter R. ; Parker, Alexander ; Chai, Karl X. ; Wong, Hing C. ; Rosser, Charles J. / 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. In: PLoS One. 2014 ; Vol. 9, No. 6.
@article{5d3c9ea10cec4573af7d9aa70fdaedac,
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-Gu{\'e}rin (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.",
author = "Evan Gomes-Giacoia and Makito Miyake and Steven Goodison and Aravindhan Sriharan and Ge Zhang and Lijing You and Egan, {Jack O.} and Rhode, {Peter R.} and Alexander Parker and Chai, {Karl X.} and Wong, {Hing C.} and Rosser, {Charles J.}",
year = "2014",
month = "6",
day = "4",
doi = "10.1371/journal.pone.0096705",
language = "English (US)",
volume = "9",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "6",

}

TY - JOUR

T1 - 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

AU - Gomes-Giacoia, Evan

AU - Miyake, Makito

AU - Goodison, Steven

AU - Sriharan, Aravindhan

AU - Zhang, Ge

AU - You, Lijing

AU - Egan, Jack O.

AU - Rhode, Peter R.

AU - Parker, Alexander

AU - Chai, Karl X.

AU - Wong, Hing C.

AU - Rosser, Charles J.

PY - 2014/6/4

Y1 - 2014/6/4

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84902438193&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84902438193&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0096705

DO - 10.1371/journal.pone.0096705

M3 - Article

C2 - 24896845

AN - SCOPUS:84902438193

VL - 9

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 6

M1 - e96705

ER -