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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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In vivo cytotoxic activity toward a CT-26 tumor antigen. In the CT-26 colon carcinoma mouse model, anti-mCTLA-4 mAb was administered at a dose of 20 mg/kg on Days 8, 12, and 16. Etoposide was administered at a dose of 50 mg/kg on Days 7, 14, and 21, whereas gemcitabine was administered at a dose of 120 mg/kg on Days 7, 11, and 15. In vivo cell kill was determined on Days 18 and 23 post-implant. One day prior to analysis, a 50:50 mixture of peptide-pulsed ([H] SPSYVYHQF [OH], Sigma Genosys) and peptide non-pulsed carboxyfluorescein diacetate succinimidyl ester (CSFE)-labeled splenocytes from naive BALB/c donors were adoptively transferred via IV tail injection into treated animals; 24 h later, spleens were removed and analyzed via flow cytometry to determine the percent cell kill of peptide-pulsed cells. In vivo cytotoxicity against a CT-26 tumor antigen showed a slight increase in the CTLA-4 blockade and etoposide combination group without reaching statistical significance versus anti-mCTLA-4 mAb alone. At these time points, there were no significant enhancements of the cytotoxic activity against a CT-26 tumor antigen with the combination of anti-mCTLA-4 mAb and gemcitabine when compared with either treatment alone
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Fig3: In vivo cytotoxic activity toward a CT-26 tumor antigen. In the CT-26 colon carcinoma mouse model, anti-mCTLA-4 mAb was administered at a dose of 20 mg/kg on Days 8, 12, and 16. Etoposide was administered at a dose of 50 mg/kg on Days 7, 14, and 21, whereas gemcitabine was administered at a dose of 120 mg/kg on Days 7, 11, and 15. In vivo cell kill was determined on Days 18 and 23 post-implant. One day prior to analysis, a 50:50 mixture of peptide-pulsed ([H] SPSYVYHQF [OH], Sigma Genosys) and peptide non-pulsed carboxyfluorescein diacetate succinimidyl ester (CSFE)-labeled splenocytes from naive BALB/c donors were adoptively transferred via IV tail injection into treated animals; 24 h later, spleens were removed and analyzed via flow cytometry to determine the percent cell kill of peptide-pulsed cells. In vivo cytotoxicity against a CT-26 tumor antigen showed a slight increase in the CTLA-4 blockade and etoposide combination group without reaching statistical significance versus anti-mCTLA-4 mAb alone. At these time points, there were no significant enhancements of the cytotoxic activity against a CT-26 tumor antigen with the combination of anti-mCTLA-4 mAb and gemcitabine when compared with either treatment alone

Mentions: In the CT-26 colon carcinoma model, neither etoposide nor anti-mCTLA-4 mAb alone were active at OD levels, but their combination exhibited synergistic effects (Table 1; Fig. 2c). Mice that reached complete regression or naïve mice were rechallenged with 1 × 106 CT-26 cells subcutaneously on Day 77 post-tumor cell implantation. Although all naïve mice developed tumors that grew progressively, each of the mice treated with etoposide in combination with anti-mCTLA-4 mAb (n = 4) rejected tumor rechallenge, leading the authors to interpret that combination of CTLA-4 blockade plus etoposide generated a memory immune response (Table 1). In vivo cytotoxicity against a CT-26 tumor antigen showed a slight increase in the combination group versus anti-mCTLA-4 mAb without reaching statistical significance (Fig. 3).Fig. 3


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)

In vivo cytotoxic activity toward a CT-26 tumor antigen. In the CT-26 colon carcinoma mouse model, anti-mCTLA-4 mAb was administered at a dose of 20 mg/kg on Days 8, 12, and 16. Etoposide was administered at a dose of 50 mg/kg on Days 7, 14, and 21, whereas gemcitabine was administered at a dose of 120 mg/kg on Days 7, 11, and 15. In vivo cell kill was determined on Days 18 and 23 post-implant. One day prior to analysis, a 50:50 mixture of peptide-pulsed ([H] SPSYVYHQF [OH], Sigma Genosys) and peptide non-pulsed carboxyfluorescein diacetate succinimidyl ester (CSFE)-labeled splenocytes from naive BALB/c donors were adoptively transferred via IV tail injection into treated animals; 24 h later, spleens were removed and analyzed via flow cytometry to determine the percent cell kill of peptide-pulsed cells. In vivo cytotoxicity against a CT-26 tumor antigen showed a slight increase in the CTLA-4 blockade and etoposide combination group without reaching statistical significance versus anti-mCTLA-4 mAb alone. At these time points, there were no significant enhancements of the cytotoxic activity against a CT-26 tumor antigen with the combination of anti-mCTLA-4 mAb and gemcitabine when compared with either treatment alone
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig3: In vivo cytotoxic activity toward a CT-26 tumor antigen. In the CT-26 colon carcinoma mouse model, anti-mCTLA-4 mAb was administered at a dose of 20 mg/kg on Days 8, 12, and 16. Etoposide was administered at a dose of 50 mg/kg on Days 7, 14, and 21, whereas gemcitabine was administered at a dose of 120 mg/kg on Days 7, 11, and 15. In vivo cell kill was determined on Days 18 and 23 post-implant. One day prior to analysis, a 50:50 mixture of peptide-pulsed ([H] SPSYVYHQF [OH], Sigma Genosys) and peptide non-pulsed carboxyfluorescein diacetate succinimidyl ester (CSFE)-labeled splenocytes from naive BALB/c donors were adoptively transferred via IV tail injection into treated animals; 24 h later, spleens were removed and analyzed via flow cytometry to determine the percent cell kill of peptide-pulsed cells. In vivo cytotoxicity against a CT-26 tumor antigen showed a slight increase in the CTLA-4 blockade and etoposide combination group without reaching statistical significance versus anti-mCTLA-4 mAb alone. At these time points, there were no significant enhancements of the cytotoxic activity against a CT-26 tumor antigen with the combination of anti-mCTLA-4 mAb and gemcitabine when compared with either treatment alone
Mentions: In the CT-26 colon carcinoma model, neither etoposide nor anti-mCTLA-4 mAb alone were active at OD levels, but their combination exhibited synergistic effects (Table 1; Fig. 2c). Mice that reached complete regression or naïve mice were rechallenged with 1 × 106 CT-26 cells subcutaneously on Day 77 post-tumor cell implantation. Although all naïve mice developed tumors that grew progressively, each of the mice treated with etoposide in combination with anti-mCTLA-4 mAb (n = 4) rejected tumor rechallenge, leading the authors to interpret that combination of CTLA-4 blockade plus etoposide generated a memory immune response (Table 1). In vivo cytotoxicity against a CT-26 tumor antigen showed a slight increase in the combination group versus anti-mCTLA-4 mAb without reaching statistical significance (Fig. 3).Fig. 3

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