Agonist anti-GITR antibody significantly enhances the therapeutic efficacy of Listeria monocytogenes-based immunotherapy

Rajeev Kumar Shrimali, Shamim Ahmad, Zuzana Berrong, Grigori Okoev, Adelaida Matevosyan, Ghazaleh Shoja E. Razavi, Robert Petit, Seema Gupta, Mikayel Mkrtichyan, Samir N. Khleif

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Background: We previously demonstrated that in addition to generating an antigen-specific immune response, Listeria monocytogenes (Lm)-based immunotherapy significantly reduces the ratio of regulatory T cells (Tregs)/CD4+ and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. Since Lm-based immunotherapy is able to inhibit the immune suppressive environment, we hypothesized that combining this treatment with agonist antibody to a co-stimulatory receptor that would further boost the effector arm of immunity will result in significant improvement of anti-tumor efficacy of treatment. Methods: Here we tested the immune and therapeutic efficacy of Listeria-based immunotherapy combination with agonist antibody to glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) in TC-1 mouse tumor model. We evaluated the potency of combination on tumor growth and survival of treated animals and profiled tumor microenvironment for effector and suppressor cell populations. Results: We demonstrate that combination of Listeria-based immunotherapy with agonist antibody to GITR synergizes to improve immune and therapeutic efficacy of treatment in a mouse tumor model. We show that this combinational treatment leads to significant inhibition of tumor-growth, prolongs survival and leads to complete regression of established tumors in 60% of treated animals. We determined that this therapeutic benefit of combinational treatment is due to a significant increase in tumor infiltrating effector CD4+ and CD8+ T cells along with a decrease of inhibitory cells. Conclusion: To our knowledge, this is the first study that exploits Lm-based immunotherapy combined with agonist anti-GITR antibody as a potent treatment strategy that simultaneously targets both the effector and suppressor arms of the immune system, leading to significantly improved anti-tumor efficacy. We believe that our findings depicted in this manuscript provide a promising and translatable strategy that can enhance the overall efficacy of cancer immunotherapy.

Original languageEnglish (US)
Article number64
JournalJournal for ImmunoTherapy of Cancer
Volume5
Issue number1
DOIs
StatePublished - Aug 15 2017

Fingerprint

Listeria monocytogenes
Immunotherapy
Anti-Idiotypic Antibodies
Neoplasms
Listeria
Tumor Microenvironment
Therapeutics
Antibodies
Tumor Necrosis Factor Receptors
Histocompatibility Antigens Class II
Regulatory T-Lymphocytes
Growth
Glucocorticoids
Immune System
Immunity
T-Lymphocytes

Keywords

  • Anti-GITR antibody
  • Co-stimulation
  • Immune tolerance
  • Immunotherapy
  • Listeria vaccine
  • Lm-LLO-E7

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

Agonist anti-GITR antibody significantly enhances the therapeutic efficacy of Listeria monocytogenes-based immunotherapy. / Shrimali, Rajeev Kumar; Ahmad, Shamim; Berrong, Zuzana; Okoev, Grigori; Matevosyan, Adelaida; Razavi, Ghazaleh Shoja E.; Petit, Robert; Gupta, Seema; Mkrtichyan, Mikayel; Khleif, Samir N.

In: Journal for ImmunoTherapy of Cancer, Vol. 5, No. 1, 64, 15.08.2017.

Research output: Contribution to journalArticle

Shrimali, RK, Ahmad, S, Berrong, Z, Okoev, G, Matevosyan, A, Razavi, GSE, Petit, R, Gupta, S, Mkrtichyan, M & Khleif, SN 2017, 'Agonist anti-GITR antibody significantly enhances the therapeutic efficacy of Listeria monocytogenes-based immunotherapy', Journal for ImmunoTherapy of Cancer, vol. 5, no. 1, 64. https://doi.org/10.1186/s40425-017-0266-x
Shrimali, Rajeev Kumar ; Ahmad, Shamim ; Berrong, Zuzana ; Okoev, Grigori ; Matevosyan, Adelaida ; Razavi, Ghazaleh Shoja E. ; Petit, Robert ; Gupta, Seema ; Mkrtichyan, Mikayel ; Khleif, Samir N. / Agonist anti-GITR antibody significantly enhances the therapeutic efficacy of Listeria monocytogenes-based immunotherapy. In: Journal for ImmunoTherapy of Cancer. 2017 ; Vol. 5, No. 1.
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abstract = "Background: We previously demonstrated that in addition to generating an antigen-specific immune response, Listeria monocytogenes (Lm)-based immunotherapy significantly reduces the ratio of regulatory T cells (Tregs)/CD4+ and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. Since Lm-based immunotherapy is able to inhibit the immune suppressive environment, we hypothesized that combining this treatment with agonist antibody to a co-stimulatory receptor that would further boost the effector arm of immunity will result in significant improvement of anti-tumor efficacy of treatment. Methods: Here we tested the immune and therapeutic efficacy of Listeria-based immunotherapy combination with agonist antibody to glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) in TC-1 mouse tumor model. We evaluated the potency of combination on tumor growth and survival of treated animals and profiled tumor microenvironment for effector and suppressor cell populations. Results: We demonstrate that combination of Listeria-based immunotherapy with agonist antibody to GITR synergizes to improve immune and therapeutic efficacy of treatment in a mouse tumor model. We show that this combinational treatment leads to significant inhibition of tumor-growth, prolongs survival and leads to complete regression of established tumors in 60{\%} of treated animals. We determined that this therapeutic benefit of combinational treatment is due to a significant increase in tumor infiltrating effector CD4+ and CD8+ T cells along with a decrease of inhibitory cells. Conclusion: To our knowledge, this is the first study that exploits Lm-based immunotherapy combined with agonist anti-GITR antibody as a potent treatment strategy that simultaneously targets both the effector and suppressor arms of the immune system, leading to significantly improved anti-tumor efficacy. We believe that our findings depicted in this manuscript provide a promising and translatable strategy that can enhance the overall efficacy of cancer immunotherapy.",
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AU - Matevosyan, Adelaida

AU - Razavi, Ghazaleh Shoja E.

AU - Petit, Robert

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