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Synergy between chemotherapeutic agents and CTLA-4 blockade in preclinical tumor models.

Jure-Kunkel M, Masters G, Girit E, Dito G, Lee F, Hunt JT, Humphrey R - Cancer Immunol. Immunother. (2013)

Bottom Line: Results of CTLA-4 blockade in combination with one of various chemotherapeutic agents demonstrate that synergy occurs in settings where either agent alone was not effective in inducing tumor regression.Furthermore, when combined with CTLA-4 blockade, ixabepilone, etoposide, and gemcitabine elicited prolonged antitumor effects in some murine models with induction of a memory immune response.Future investigations are warranted to determine which specific chemo-immunotherapy combinations, if any, will produce synergistic antitumor effects in the clinical setting.

View Article: PubMed Central - PubMed

Affiliation: Bristol-Myers Squibb Company, PO Box 4000, Princeton, NJ 08543, USA. maria.jurekunkel@bms.com

ABSTRACT
Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) binding agent, has proven to be an effective monotherapy for metastatic melanoma and has shown antitumor activity in trials when administered with other therapeutic agents. We hypothesized that the combination of ipilimumab with chemotherapeutic agents, such as ixabepilone, paclitaxel, etoposide, and gemcitabine, may produce therapeutic synergy based on distinct but complementary mechanisms of action for each drug and unique cellular targets. This concept was investigated using a mouse homolog of ipilimumab in preclinical murine tumor models, including SA1N fibrosarcoma, EMT-6 mammary carcinoma, M109 lung carcinoma, and CT-26 colon carcinoma. Results of CTLA-4 blockade in combination with one of various chemotherapeutic agents demonstrate that synergy occurs in settings where either agent alone was not effective in inducing tumor regression. Furthermore, when combined with CTLA-4 blockade, ixabepilone, etoposide, and gemcitabine elicited prolonged antitumor effects in some murine models with induction of a memory immune response. Future investigations are warranted to determine which specific chemo-immunotherapy combinations, if any, will produce synergistic antitumor effects in the clinical setting.

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Therapeutic synergy observed with CTLA-4 blockade in combination with gemcitabine in tumor models. In the SA1N fibrosarcoma model (a), the combination of anti-mCTLA-4 mAb with gemcitabine did not produce therapeutic synergy. In the M109 lung carcinoma model (b) and CT-26 colon carcinoma model (c), therapeutic synergy was observed with administration of anti-mCTLA-4 mAb in combination with gemcitabine relative to the treatment of mice with either monotherapy
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Fig4: Therapeutic synergy observed with CTLA-4 blockade in combination with gemcitabine in tumor models. In the SA1N fibrosarcoma model (a), the combination of anti-mCTLA-4 mAb with gemcitabine did not produce therapeutic synergy. In the M109 lung carcinoma model (b) and CT-26 colon carcinoma model (c), therapeutic synergy was observed with administration of anti-mCTLA-4 mAb in combination with gemcitabine relative to the treatment of mice with either monotherapy

Mentions: Co-administration of gemcitabine and anti-mCTLA-4 mAb demonstrated synergy in the CT-26 colon carcinoma and M109 lung carcinoma models, but not in the SA1N fibrosarcoma model (Table 1; Fig. 4). In the SA1N fibrosarcoma model, anti-mCTLA-4 mAb alone and gemcitabine alone showed modest activity but the combination of both agents in this model did not result in therapeutic synergy (Table 1; Fig. 4a). In the M109 lung metastasis tumor model, OD levels of gemcitabine and anti-mCTLA-4 mAb in combination resulted in therapeutic synergy with animals demonstrating increased survival, relative to animals treated with either agent alone (Table 1; Fig. 4b). In the CT-26 colon carcinoma model, this combination resulted in synergistic effects, with 62.5 % (n = 5/8) of animals displaying complete regressions (Table 1; Fig. 4c); however, a lack of synergistic effects was observed in the CT-26 colon carcinoma model when a sequential dosing regimen was explored, where 3 doses of gemcitabine were administered first (120 mg/kg) followed by administration of 3 doses of anti-mCTLA-4 mAb (20 mg/kg) (data not shown).Fig. 4


Synergy between chemotherapeutic agents and CTLA-4 blockade in preclinical tumor models.

Jure-Kunkel M, Masters G, Girit E, Dito G, Lee F, Hunt JT, Humphrey R - Cancer Immunol. Immunother. (2013)

Therapeutic synergy observed with CTLA-4 blockade in combination with gemcitabine in tumor models. In the SA1N fibrosarcoma model (a), the combination of anti-mCTLA-4 mAb with gemcitabine did not produce therapeutic synergy. In the M109 lung carcinoma model (b) and CT-26 colon carcinoma model (c), therapeutic synergy was observed with administration of anti-mCTLA-4 mAb in combination with gemcitabine relative to the treatment of mice with either monotherapy
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3755230&req=5

Fig4: Therapeutic synergy observed with CTLA-4 blockade in combination with gemcitabine in tumor models. In the SA1N fibrosarcoma model (a), the combination of anti-mCTLA-4 mAb with gemcitabine did not produce therapeutic synergy. In the M109 lung carcinoma model (b) and CT-26 colon carcinoma model (c), therapeutic synergy was observed with administration of anti-mCTLA-4 mAb in combination with gemcitabine relative to the treatment of mice with either monotherapy
Mentions: Co-administration of gemcitabine and anti-mCTLA-4 mAb demonstrated synergy in the CT-26 colon carcinoma and M109 lung carcinoma models, but not in the SA1N fibrosarcoma model (Table 1; Fig. 4). In the SA1N fibrosarcoma model, anti-mCTLA-4 mAb alone and gemcitabine alone showed modest activity but the combination of both agents in this model did not result in therapeutic synergy (Table 1; Fig. 4a). In the M109 lung metastasis tumor model, OD levels of gemcitabine and anti-mCTLA-4 mAb in combination resulted in therapeutic synergy with animals demonstrating increased survival, relative to animals treated with either agent alone (Table 1; Fig. 4b). In the CT-26 colon carcinoma model, this combination resulted in synergistic effects, with 62.5 % (n = 5/8) of animals displaying complete regressions (Table 1; Fig. 4c); however, a lack of synergistic effects was observed in the CT-26 colon carcinoma model when a sequential dosing regimen was explored, where 3 doses of gemcitabine were administered first (120 mg/kg) followed by administration of 3 doses of anti-mCTLA-4 mAb (20 mg/kg) (data not shown).Fig. 4

Bottom Line: Results of CTLA-4 blockade in combination with one of various chemotherapeutic agents demonstrate that synergy occurs in settings where either agent alone was not effective in inducing tumor regression.Furthermore, when combined with CTLA-4 blockade, ixabepilone, etoposide, and gemcitabine elicited prolonged antitumor effects in some murine models with induction of a memory immune response.Future investigations are warranted to determine which specific chemo-immunotherapy combinations, if any, will produce synergistic antitumor effects in the clinical setting.

View Article: PubMed Central - PubMed

Affiliation: Bristol-Myers Squibb Company, PO Box 4000, Princeton, NJ 08543, USA. maria.jurekunkel@bms.com

ABSTRACT
Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) binding agent, has proven to be an effective monotherapy for metastatic melanoma and has shown antitumor activity in trials when administered with other therapeutic agents. We hypothesized that the combination of ipilimumab with chemotherapeutic agents, such as ixabepilone, paclitaxel, etoposide, and gemcitabine, may produce therapeutic synergy based on distinct but complementary mechanisms of action for each drug and unique cellular targets. This concept was investigated using a mouse homolog of ipilimumab in preclinical murine tumor models, including SA1N fibrosarcoma, EMT-6 mammary carcinoma, M109 lung carcinoma, and CT-26 colon carcinoma. Results of CTLA-4 blockade in combination with one of various chemotherapeutic agents demonstrate that synergy occurs in settings where either agent alone was not effective in inducing tumor regression. Furthermore, when combined with CTLA-4 blockade, ixabepilone, etoposide, and gemcitabine elicited prolonged antitumor effects in some murine models with induction of a memory immune response. Future investigations are warranted to determine which specific chemo-immunotherapy combinations, if any, will produce synergistic antitumor effects in the clinical setting.

Show MeSH
Related in: MedlinePlus