Repurposing ospemifene for potentiating an antigen-specific immune response

Chiao Jung Kao, Gregory T. Wurz, Yi Chen Lin, Daniel P. Vang, Brian Phong, Michael W. DeGregorio

Research output: Contribution to journalArticle

Abstract

OBJECTIVE:: Ospemifene, an estrogen receptor agonist/antagonist approved for the treatment of dyspareunia and vaginal dryness in postmenopausal women, has potential new indications as an immune modulator. The overall objective of the present series of preclinical studies was to evaluate the immunomodulatory activity of ospemifene in combination with a peptide cancer vaccine. METHODS:: Immune regulating effects, mechanism of action and structure activity relationships of ospemifene and related compounds were evaluated by examining expression of T-cell activating cytokines in vitro, and antigen-specific immune response and cytotoxic T-lymphocyte activity in vivo. The effects of ospemifene (OSP) on the immune response to a peptide cancer vaccine (PV) were evaluated after chronic [control (n?=?22); OSP 50?mg/kg (n?=?16); PV (n?=?6); OSP+PV (n?=?11)], intermittent [control (n?=?10); OSP 10 and 50?mg/kg (n?=?11); PV (n?=?11); combination treatment (n?=?11 each dose)] and pretreatment [control; OSP 100?mg/kg; PV 100?μg; combination treatment (n?=?8 all groups)] ospemifene oral dosing schedules in a total of 317 mixed-sex tumor-bearing and nontumor-bearing mice. RESULTS:: The results showed that ospemifene induced expression of the key TH1 cytokines interferon gamma and interleukin-2 in vitro, which may be mediated by stimulating T-cells through phosphoinositide 3-kinase and calmodulin signaling pathways. In combination with an antigen-specific peptide cancer vaccine, ospemifene increased antigen-specific immune response and increased cytotoxic T-lymphocyte activity in tumor-bearing and nontumor-bearing mice. The pretreatment, intermittent, and chronic dosing schedules of ospemifene activate naive T-cells, modulate antigen-induced tolerance and reduce tumor-associated, pro-inflammatory cytokines, respectively. CONCLUSIONS:: Taken together, ospemifeneʼs dose response and schedule-dependent immune modulating activity offers a method of tailoring and augmenting the efficacy of previously failed antigen-specific cancer vaccines for a wide range of malignancies.

Original languageEnglish (US)
JournalMenopause
DOIs
StateAccepted/In press - Dec 5 2016

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Histocompatibility Antigens Class II
Cancer Vaccines
Subunit Vaccines
Appointments and Schedules
Cytotoxic T-Lymphocytes
Cytokines
T-Lymphocytes
Antigens
Ospemifene
Neoplasms
Dyspareunia
1-Phosphatidylinositol 4-Kinase
Calmodulin
Structure-Activity Relationship
Interferon-gamma
Interleukin-2
Estrogens
Therapeutics

ASJC Scopus subject areas

  • Obstetrics and Gynecology

Cite this

Kao, C. J., Wurz, G. T., Lin, Y. C., Vang, D. P., Phong, B., & DeGregorio, M. W. (Accepted/In press). Repurposing ospemifene for potentiating an antigen-specific immune response. Menopause. https://doi.org/10.1097/GME.0000000000000776

Repurposing ospemifene for potentiating an antigen-specific immune response. / Kao, Chiao Jung; Wurz, Gregory T.; Lin, Yi Chen; Vang, Daniel P.; Phong, Brian; DeGregorio, Michael W.

In: Menopause, 05.12.2016.

Research output: Contribution to journalArticle

Kao, Chiao Jung ; Wurz, Gregory T. ; Lin, Yi Chen ; Vang, Daniel P. ; Phong, Brian ; DeGregorio, Michael W. / Repurposing ospemifene for potentiating an antigen-specific immune response. In: Menopause. 2016.
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AU - Kao, Chiao Jung

AU - Wurz, Gregory T.

AU - Lin, Yi Chen

AU - Vang, Daniel P.

AU - Phong, Brian

AU - DeGregorio, Michael W.

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N2 - OBJECTIVE:: Ospemifene, an estrogen receptor agonist/antagonist approved for the treatment of dyspareunia and vaginal dryness in postmenopausal women, has potential new indications as an immune modulator. The overall objective of the present series of preclinical studies was to evaluate the immunomodulatory activity of ospemifene in combination with a peptide cancer vaccine. METHODS:: Immune regulating effects, mechanism of action and structure activity relationships of ospemifene and related compounds were evaluated by examining expression of T-cell activating cytokines in vitro, and antigen-specific immune response and cytotoxic T-lymphocyte activity in vivo. The effects of ospemifene (OSP) on the immune response to a peptide cancer vaccine (PV) were evaluated after chronic [control (n?=?22); OSP 50?mg/kg (n?=?16); PV (n?=?6); OSP+PV (n?=?11)], intermittent [control (n?=?10); OSP 10 and 50?mg/kg (n?=?11); PV (n?=?11); combination treatment (n?=?11 each dose)] and pretreatment [control; OSP 100?mg/kg; PV 100?μg; combination treatment (n?=?8 all groups)] ospemifene oral dosing schedules in a total of 317 mixed-sex tumor-bearing and nontumor-bearing mice. RESULTS:: The results showed that ospemifene induced expression of the key TH1 cytokines interferon gamma and interleukin-2 in vitro, which may be mediated by stimulating T-cells through phosphoinositide 3-kinase and calmodulin signaling pathways. In combination with an antigen-specific peptide cancer vaccine, ospemifene increased antigen-specific immune response and increased cytotoxic T-lymphocyte activity in tumor-bearing and nontumor-bearing mice. The pretreatment, intermittent, and chronic dosing schedules of ospemifene activate naive T-cells, modulate antigen-induced tolerance and reduce tumor-associated, pro-inflammatory cytokines, respectively. CONCLUSIONS:: Taken together, ospemifeneʼs dose response and schedule-dependent immune modulating activity offers a method of tailoring and augmenting the efficacy of previously failed antigen-specific cancer vaccines for a wide range of malignancies.

AB - OBJECTIVE:: Ospemifene, an estrogen receptor agonist/antagonist approved for the treatment of dyspareunia and vaginal dryness in postmenopausal women, has potential new indications as an immune modulator. The overall objective of the present series of preclinical studies was to evaluate the immunomodulatory activity of ospemifene in combination with a peptide cancer vaccine. METHODS:: Immune regulating effects, mechanism of action and structure activity relationships of ospemifene and related compounds were evaluated by examining expression of T-cell activating cytokines in vitro, and antigen-specific immune response and cytotoxic T-lymphocyte activity in vivo. The effects of ospemifene (OSP) on the immune response to a peptide cancer vaccine (PV) were evaluated after chronic [control (n?=?22); OSP 50?mg/kg (n?=?16); PV (n?=?6); OSP+PV (n?=?11)], intermittent [control (n?=?10); OSP 10 and 50?mg/kg (n?=?11); PV (n?=?11); combination treatment (n?=?11 each dose)] and pretreatment [control; OSP 100?mg/kg; PV 100?μg; combination treatment (n?=?8 all groups)] ospemifene oral dosing schedules in a total of 317 mixed-sex tumor-bearing and nontumor-bearing mice. RESULTS:: The results showed that ospemifene induced expression of the key TH1 cytokines interferon gamma and interleukin-2 in vitro, which may be mediated by stimulating T-cells through phosphoinositide 3-kinase and calmodulin signaling pathways. In combination with an antigen-specific peptide cancer vaccine, ospemifene increased antigen-specific immune response and increased cytotoxic T-lymphocyte activity in tumor-bearing and nontumor-bearing mice. The pretreatment, intermittent, and chronic dosing schedules of ospemifene activate naive T-cells, modulate antigen-induced tolerance and reduce tumor-associated, pro-inflammatory cytokines, respectively. CONCLUSIONS:: Taken together, ospemifeneʼs dose response and schedule-dependent immune modulating activity offers a method of tailoring and augmenting the efficacy of previously failed antigen-specific cancer vaccines for a wide range of malignancies.

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