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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 ixabepilone and paclitaxel in tumor models. In the SA1N fibrosarcoma model (a), combination of anti-mCTLA-4 mAb with either ixabepilone or paclitaxel resulted in therapeutic synergy, with the majority of mice displaying substantially delayed tumor growth over time. In the EMT-6 mammary carcinoma model (b), combination of anti-mCTLA-4 mAb with ixabepilone yielded synergistic effects over time, resulting in complete regression of tumors on Day 18; anti-mCTLA-4 mAb paired with paclitaxel improved antitumor activity without achieving a synergistic effect. Anti-mCTLA-4 mAb in combination with ixabepilone expanded T lymphocytes with cytolytic function by Day 19 (CD8+CD107+), supporting synergistic efficacy in the EMT-6 mammary carcinoma model (c, d). In the M109 lung carcinoma model (e), tumor-free mice previously treated with ixabepilone monotherapy or in combination with anti-mCTLA-4 mAb were rechallenged on Day 95 with live tumor cells. The majority of mice (75 %) treated with the combination of anti-mCTLA-4 mAb and ixabepilone rejected the tumor rechallenge, suggestive of a memory immune response. In the CT-26 colon carcinoma model (f), treatment of mice with anti-mCTLA-4 mAb and either ixabepilone or paclitaxel resulted in synergy between CTLA-4 blockade and these chemotherapeutic agents. Expansion of activated T cells (CD8+/CD69+ and CD4+/CD69+) was observed with anti-mCTLA-4 mAb alone and in combination with either ixabepilone or paclitaxel (g, h)
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Fig1: Therapeutic synergy observed with CTLA-4 blockade in combination with ixabepilone and paclitaxel in tumor models. In the SA1N fibrosarcoma model (a), combination of anti-mCTLA-4 mAb with either ixabepilone or paclitaxel resulted in therapeutic synergy, with the majority of mice displaying substantially delayed tumor growth over time. In the EMT-6 mammary carcinoma model (b), combination of anti-mCTLA-4 mAb with ixabepilone yielded synergistic effects over time, resulting in complete regression of tumors on Day 18; anti-mCTLA-4 mAb paired with paclitaxel improved antitumor activity without achieving a synergistic effect. Anti-mCTLA-4 mAb in combination with ixabepilone expanded T lymphocytes with cytolytic function by Day 19 (CD8+CD107+), supporting synergistic efficacy in the EMT-6 mammary carcinoma model (c, d). In the M109 lung carcinoma model (e), tumor-free mice previously treated with ixabepilone monotherapy or in combination with anti-mCTLA-4 mAb were rechallenged on Day 95 with live tumor cells. The majority of mice (75 %) treated with the combination of anti-mCTLA-4 mAb and ixabepilone rejected the tumor rechallenge, suggestive of a memory immune response. In the CT-26 colon carcinoma model (f), treatment of mice with anti-mCTLA-4 mAb and either ixabepilone or paclitaxel resulted in synergy between CTLA-4 blockade and these chemotherapeutic agents. Expansion of activated T cells (CD8+/CD69+ and CD4+/CD69+) was observed with anti-mCTLA-4 mAb alone and in combination with either ixabepilone or paclitaxel (g, h)

Mentions: In the SA1N fibrosarcoma model, use of ixabepilone in combination with anti-mCTLA-4 mAb demonstrated therapeutic synergy, yielding 112 % TGI, with 71.4 % (n = 5/7) of the animals displaying complete tumor regression (Table 1; Fig. 1a). Although paclitaxel monotherapy had no therapeutic effect, addition of anti-mCTLA-4 mAb to paclitaxel treatment yielded complete responses in 87.5 % (n = 7/8) of the animals in the SA1N fibrosarcoma model (Table 1; Fig. 1a) [32]. Both combination regimens enhanced the antitumor effect of each monotherapy and significantly delayed tumor growth to target size, resulting in therapeutic synergy.Fig. 1


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 ixabepilone and paclitaxel in tumor models. In the SA1N fibrosarcoma model (a), combination of anti-mCTLA-4 mAb with either ixabepilone or paclitaxel resulted in therapeutic synergy, with the majority of mice displaying substantially delayed tumor growth over time. In the EMT-6 mammary carcinoma model (b), combination of anti-mCTLA-4 mAb with ixabepilone yielded synergistic effects over time, resulting in complete regression of tumors on Day 18; anti-mCTLA-4 mAb paired with paclitaxel improved antitumor activity without achieving a synergistic effect. Anti-mCTLA-4 mAb in combination with ixabepilone expanded T lymphocytes with cytolytic function by Day 19 (CD8+CD107+), supporting synergistic efficacy in the EMT-6 mammary carcinoma model (c, d). In the M109 lung carcinoma model (e), tumor-free mice previously treated with ixabepilone monotherapy or in combination with anti-mCTLA-4 mAb were rechallenged on Day 95 with live tumor cells. The majority of mice (75 %) treated with the combination of anti-mCTLA-4 mAb and ixabepilone rejected the tumor rechallenge, suggestive of a memory immune response. In the CT-26 colon carcinoma model (f), treatment of mice with anti-mCTLA-4 mAb and either ixabepilone or paclitaxel resulted in synergy between CTLA-4 blockade and these chemotherapeutic agents. Expansion of activated T cells (CD8+/CD69+ and CD4+/CD69+) was observed with anti-mCTLA-4 mAb alone and in combination with either ixabepilone or paclitaxel (g, h)
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Related In: Results  -  Collection

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Fig1: Therapeutic synergy observed with CTLA-4 blockade in combination with ixabepilone and paclitaxel in tumor models. In the SA1N fibrosarcoma model (a), combination of anti-mCTLA-4 mAb with either ixabepilone or paclitaxel resulted in therapeutic synergy, with the majority of mice displaying substantially delayed tumor growth over time. In the EMT-6 mammary carcinoma model (b), combination of anti-mCTLA-4 mAb with ixabepilone yielded synergistic effects over time, resulting in complete regression of tumors on Day 18; anti-mCTLA-4 mAb paired with paclitaxel improved antitumor activity without achieving a synergistic effect. Anti-mCTLA-4 mAb in combination with ixabepilone expanded T lymphocytes with cytolytic function by Day 19 (CD8+CD107+), supporting synergistic efficacy in the EMT-6 mammary carcinoma model (c, d). In the M109 lung carcinoma model (e), tumor-free mice previously treated with ixabepilone monotherapy or in combination with anti-mCTLA-4 mAb were rechallenged on Day 95 with live tumor cells. The majority of mice (75 %) treated with the combination of anti-mCTLA-4 mAb and ixabepilone rejected the tumor rechallenge, suggestive of a memory immune response. In the CT-26 colon carcinoma model (f), treatment of mice with anti-mCTLA-4 mAb and either ixabepilone or paclitaxel resulted in synergy between CTLA-4 blockade and these chemotherapeutic agents. Expansion of activated T cells (CD8+/CD69+ and CD4+/CD69+) was observed with anti-mCTLA-4 mAb alone and in combination with either ixabepilone or paclitaxel (g, h)
Mentions: In the SA1N fibrosarcoma model, use of ixabepilone in combination with anti-mCTLA-4 mAb demonstrated therapeutic synergy, yielding 112 % TGI, with 71.4 % (n = 5/7) of the animals displaying complete tumor regression (Table 1; Fig. 1a). Although paclitaxel monotherapy had no therapeutic effect, addition of anti-mCTLA-4 mAb to paclitaxel treatment yielded complete responses in 87.5 % (n = 7/8) of the animals in the SA1N fibrosarcoma model (Table 1; Fig. 1a) [32]. Both combination regimens enhanced the antitumor effect of each monotherapy and significantly delayed tumor growth to target size, resulting in therapeutic synergy.Fig. 1

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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Related in: MedlinePlus