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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 E, Miyake M, Goodison S, Sriharan A, Zhang G, You L, Egan JO, Rhode PR, Parker AS, Chai KX, Wong HC, Rosser CJ - PLoS ONE (2014)

Bottom Line: 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.Intravesical ALT-803 was safe and well tolerated alone and in combination with BCG.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.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research Institute, MD Anderson Cancer Center Orlando, Orlando, Florida, United States of America.

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.

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Changes in serum and urinary cytokine profiles following intravesical treatment.A) Serum cytokines - Serum samples from female rats with carcinogen induced NMIBC was compared among the four treatment groups. Serum levels of a panel of cytokines were measured by Rat Inflammatory Cytokines Multi-Analyte ELISArray Kit (SABiosciences, Valencia CA). Mean ± SEM of each cytokine is reported for each treatment group. B) Urinary cytokines - Voided urine samples from female rats with carcinogen induced NMIBC was compared among the four treatment groups. Rat Inflammatory Cytokines Multi-Analyte ELISArray Kit measured urine levels of a panel of cytokines. Mean ± SEM of each cytokine is reported for each treatment group. *, p<0.05, **, p<0.01, ***, p<0.001.
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pone-0096705-g005: Changes in serum and urinary cytokine profiles following intravesical treatment.A) Serum cytokines - Serum samples from female rats with carcinogen induced NMIBC was compared among the four treatment groups. Serum levels of a panel of cytokines were measured by Rat Inflammatory Cytokines Multi-Analyte ELISArray Kit (SABiosciences, Valencia CA). Mean ± SEM of each cytokine is reported for each treatment group. B) Urinary cytokines - Voided urine samples from female rats with carcinogen induced NMIBC was compared among the four treatment groups. Rat Inflammatory Cytokines Multi-Analyte ELISArray Kit measured urine levels of a panel of cytokines. Mean ± SEM of each cytokine is reported for each treatment group. *, p<0.05, **, p<0.01, ***, p<0.001.

Mentions: Sera from rats treated on this protocol were collected and immediately stored at −80°C. For the cytokine analysis, sera samples were thawed and then subjected to analysis with the rat inflammatory cytokines multi-analyte ELISArray assay. Along with proliferation and activation of NK cells noted above, the intravesical administration of ALT-803 in combination with BCG was associated with increased serum levels of the inflammatory and immune response cytokines, IL-1α and IL-1β by 52% and 52%, respectively, compared to that of the PBS control group. Furthermore, the increase in IL-1α and IL-1β was maintained when ALT-803 plus BCG was compared to BCG alone and ALT-803 alone (Fig. 5a). Next, urine from rats treated on this protocol were collected and stored at −80°C immediately after the animals were sacrificed. When ready for analysis, urine samples were thawed and subjected to the rat inflammatory cytokines multi-analyte ELISArray assay. Once again, the cytokines, IL-1α, IL-1β and RANTES were increased by 437%, 437% and 196%, respectively, in the urine of the ALT-803 plus BCG treated rats compared to the PBS control group. Nevertheless, BCG alone and ALT-803 alone were associated with increases in IL-1α, IL-1β. Only RANTES was significantly elevated in ALT-803 plus BCG when compared to BCG alone and ALT-803 alone (Fig. 5b). Within the serum, IL-1α and IL-1β are key cytokines, while locally RANTES is the key cytokine.


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 E, Miyake M, Goodison S, Sriharan A, Zhang G, You L, Egan JO, Rhode PR, Parker AS, Chai KX, Wong HC, Rosser CJ - PLoS ONE (2014)

Changes in serum and urinary cytokine profiles following intravesical treatment.A) Serum cytokines - Serum samples from female rats with carcinogen induced NMIBC was compared among the four treatment groups. Serum levels of a panel of cytokines were measured by Rat Inflammatory Cytokines Multi-Analyte ELISArray Kit (SABiosciences, Valencia CA). Mean ± SEM of each cytokine is reported for each treatment group. B) Urinary cytokines - Voided urine samples from female rats with carcinogen induced NMIBC was compared among the four treatment groups. Rat Inflammatory Cytokines Multi-Analyte ELISArray Kit measured urine levels of a panel of cytokines. Mean ± SEM of each cytokine is reported for each treatment group. *, p<0.05, **, p<0.01, ***, p<0.001.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4045574&req=5

pone-0096705-g005: Changes in serum and urinary cytokine profiles following intravesical treatment.A) Serum cytokines - Serum samples from female rats with carcinogen induced NMIBC was compared among the four treatment groups. Serum levels of a panel of cytokines were measured by Rat Inflammatory Cytokines Multi-Analyte ELISArray Kit (SABiosciences, Valencia CA). Mean ± SEM of each cytokine is reported for each treatment group. B) Urinary cytokines - Voided urine samples from female rats with carcinogen induced NMIBC was compared among the four treatment groups. Rat Inflammatory Cytokines Multi-Analyte ELISArray Kit measured urine levels of a panel of cytokines. Mean ± SEM of each cytokine is reported for each treatment group. *, p<0.05, **, p<0.01, ***, p<0.001.
Mentions: Sera from rats treated on this protocol were collected and immediately stored at −80°C. For the cytokine analysis, sera samples were thawed and then subjected to analysis with the rat inflammatory cytokines multi-analyte ELISArray assay. Along with proliferation and activation of NK cells noted above, the intravesical administration of ALT-803 in combination with BCG was associated with increased serum levels of the inflammatory and immune response cytokines, IL-1α and IL-1β by 52% and 52%, respectively, compared to that of the PBS control group. Furthermore, the increase in IL-1α and IL-1β was maintained when ALT-803 plus BCG was compared to BCG alone and ALT-803 alone (Fig. 5a). Next, urine from rats treated on this protocol were collected and stored at −80°C immediately after the animals were sacrificed. When ready for analysis, urine samples were thawed and subjected to the rat inflammatory cytokines multi-analyte ELISArray assay. Once again, the cytokines, IL-1α, IL-1β and RANTES were increased by 437%, 437% and 196%, respectively, in the urine of the ALT-803 plus BCG treated rats compared to the PBS control group. Nevertheless, BCG alone and ALT-803 alone were associated with increases in IL-1α, IL-1β. Only RANTES was significantly elevated in ALT-803 plus BCG when compared to BCG alone and ALT-803 alone (Fig. 5b). Within the serum, IL-1α and IL-1β are key cytokines, while locally RANTES is the key cytokine.

Bottom Line: 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.Intravesical ALT-803 was safe and well tolerated alone and in combination with BCG.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.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research Institute, MD Anderson Cancer Center Orlando, Orlando, Florida, United States of America.

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.

Show MeSH
Related in: MedlinePlus