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Synergistic Effect Of CTLA-4 Blockade And Cancer Chemotherapy In The Induction Of Anti-Tumor Immunity
W. Lesterhuis, Joanne Salmons, A. Nowak, Esdy N. Rozali, Andrea Khong, I. Dick, Julie A. Harken, B. Robinson, R. Lake
Published 2013 · Medicine
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Several chemotherapeutics exert immunomodulatory effects. One of these is the nucleoside analogue gemcitabine, which is widely used in patients with lung cancer, ovarian cancer, breast cancer, mesothelioma and several other types of cancer, but with limited efficacy. We hypothesized that the immunopotentiating effects of this drug are partly restrained by the inhibitory T cell molecule CTLA-4 and thus could be augmented by combining it with a blocking antibody against CTLA-4, which on its own has recently shown beneficial clinical effects in the treatment of patients with metastatic melanoma. Here we show, using two non-immunogenic murine tumor models, that treatment with gemcitabine chemotherapy in combination with CTLA-4 blockade results in the induction of a potent anti-tumor immune response. Depletion experiments demonstrated that both CD4(+) and CD8(+) T cells are required for optimal therapeutic effect. Mice treated with the combination exhibited tumor regression and long-term protective immunity. In addition, we show that the efficacy of the combination is moderated by the timing of administration of the two agents. Our results show that immune checkpoint blockade and cytotoxic chemotherapy can have a synergistic effect in the treatment of cancer. These results provide a basis to pursue combination therapies with anti-CTLA-4 and immunopotentiating chemotherapy and have important implications for future studies in cancer patients. Since both drugs are approved for use in patients our data can be immediately translated into clinical trials.
This paper references
Ipilimumab in Combination With Paclitaxel and Carboplatin As First-Line Treatment in Stage IIIB/IV Non–Small-Cell Lung Cancer: Results From a Randomized, Double-Blind, Multicenter Phase II Study
A. Tsao (2012)
A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naïve patients with advanced melanoma
E. Hersh (2009)
Gemcitabine depletes regulatory T‐cells in human and mice and enhances triggering of vaccine‐specific cytotoxic T‐cells
Lorna Rettig (2011)
Immunotherapy and chemotherapy — a practical partnership
R. Lake (2005)
Cancer immunotherapy – revisited
W. Lesterhuis (2011)
Anti-CTLA-4 and Cancer Chemotherapy PLOS ONE | www.plosone
Restoration of the immunogenicity of cisplatin-induced cancer cell death by endoplasmic reticulum stress
I. Martins (2011)
Induction of Tumor Cell Apoptosis In Vivo Increases Tumor Antigen Cross-Presentation, Cross-Priming Rather than Cross-Tolerizing Host Tumor-Specific CD8 T Cells1
A. Nowak (2003)
Synergy between chemotherapy and immunotherapy in the treatment of established murine solid tumors.
A. Nowak (2003)
Ipilimumab: controversies in its development, utility and autoimmune adverse events
J. Weber (2008)
Pre-treatment with chemotherapy can enhance the antigenicity and immunogenicity of tumours by promoting adaptive immune responses
W. Liu (2010)
CTLA-4 blockade in combination with xenogeneic DNA vaccines enhances T-cell responses, tumor immunity and autoimmunity to self antigens in animal and cellular model systems.
P. Gregor (2004)
Calreticulin exposure dictates the immunogenicity of cancer cell death
M. Obeid (2007)
The ICOS/ICOSL pathway is required for optimal antitumor responses mediated by anti-CTLA-4 therapy.
T. Fu (2011)
Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice.
R. Ramakrishnan (2010)
Realization of the therapeutic potential of CTLA-4 blockade in low-dose chemotherapy-treated tumor-bearing mice.
M. B. Mokyr (1998)
Platinum-based drugs disrupt STAT6-mediated suppression of immune responses against cancer in humans and mice.
W. Lesterhuis (2011)
The combined activation of positive costimulatory signals with modulation of a negative costimulatory signal for the enhancement of vaccine-mediated T-cell responses
M. Chakraborty (2007)
Gemcitabine exerts a selective effect on the humoral immune response: implications for combination chemo-immunotherapy.
A. Nowak (2002)
CTLA-4 Blockade Expands Infiltrating T Cells and Inhibits Cancer Cell Repopulation during the Intervals of Chemotherapy in Murine Mesothelioma
Licun Wu (2012)
CTLA-4 blockade increases IFNγ-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients
C. Liakou (2008)
Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.
C. Robert (2011)
Restoration of the immunogenicity of cisplatininduced cancer cell death by endoplasmic reticulum stress
I Martins (2011)
Myeloid-derived suppressor cell inhibition of the IFN response in tumor-bearing mice.
Bethany L. Mundy-Bosse (2011)
Single dose of anti–CTLA-4 enhances CD8+ T-cell memory formation, function, and maintenance
Virginia Pedicord (2010)
Improved survival with ipilimumab in patients with metastatic melanoma.
F. S. Hodi (2010)
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.
S. Topalian (2012)
This paper is referenced by
Tumor abolition and antitumor immunostimulation by physico-chemical tumor ablation.
Y. Keisari (2017)
Targeting the inhibitory receptor CTLA-4 on T cells increased abscopal effects in murine mesothelioma model
Licun Wu (2015)
Understanding the checkpoint blockade in lung cancer immunotherapy.
M. D. Dal Bello (2017)
Tumor‐infiltrating dendritic cells exhibit defective cross‐presentation of tumor antigens, but is reversed by chemotherapy
A. McDonnell (2015)
Neoadjuvant anti-tumor vaccination prior to surgery enhances survival
Scott A Fisher (2014)
Exploiting the Immunomodulatory Properties of Chemotherapeutic Drugs to Improve the Success of Cancer Immunotherapy
K. Kersten (2015)
The Prognostic Landscape of Tumor-Infiltrating Immune Cells and Immune Checkpoints in Glioblastoma
Shiman Wu (2019)
Enhancing antitumor response by combining immune checkpoint inhibitors with chemotherapy in solid tumors
K. Heinhuis (2019)
Efficacy and biomarker analysis of nivolumab plus gemcitabine and cisplatin in patients with unresectable or metastatic biliary tract cancers: results from a phase II study
K. Feng (2020)
Breast cancer and immunology: biomarker and therapeutic developments
C. Santa-Maria (2015)
Recent Technological Advances in Using Mouse Models to Study Ovarian Cancer
C. House (2014)
Implication des cellules myéloïdes immunosuppressives (MDSC) et des lymphocytes TH17 dans l’efficacité des chimiothérapies et de l’immunothérapie
E. Limagne (2017)
Immunotherapy for malignant pleural mesothelioma. Current status and future prospects.
R. Wong (2014)
Immunotherapy advances for glioblastoma.
D. Reardon (2014)
Immune Stimulatory Features of Classical Chemotherapy
W. Joost Lesterhuis (2013)
82 – Pleural Tumors
V. Broaddus (2016)
Chemotherapy and immunotherapy: mapping the road ahead.
A. Cook (2016)
Enhancing immunity against melanoma using Type I interferon
Rachael M. Zemek (2013)
Chemoimmunotherapy: still waiting for the magic to happen.
A. Nowak (2014)
Prognostic and predictive aspects of the tumor immune microenvironment and immune checkpoints in malignant pleural mesothelioma
E. Marcq (2017)
The efficacy of tumor debulking surgery is improved by adjuvant immunotherapy using imiquimod and anti-CD40
Andrea Khong (2014)
Novel insights into the pathophysiology and treatment of malignant pleural mesothelioma
Alistair M. Cook (2015)
Sensitization to immune checkpoint blockade through activation of a STAT1/NK axis in the tumor microenvironment
Rachael M. Zemek (2019)
Modulation of Determinant Factors to Improve Therapeutic Combinations with Immune Checkpoint Inhibitors
Magalie Dosset (2020)
Immune response profiling of malignant pleural mesothelioma for diagnostic and prognostic biomarkers
J. Creaney (2016)
Centre for Microscopy, Characterisation and Analysis
Sorting Pre-Sort (2013)
Immunogenic effects of chemotherapy-induced tumor cell death
Y. Wang (2018)
Association of Cytotoxic T-lymphocyte Antigen-4 Polymorphisms with Malignant Bone Tumor Risk: A Meta-analysis.
C. Zhang (2016)
Mouse models of mesothelioma: strengths, limitations and clinical translation
C. Robinson (2014)
Nivolumab Immunotherapy in Malignant Mesothelioma: A Case Report Highlighting a New Opportunity for Exceptional Outcomes
R. G. Jones (2018)
Dynamic versus static biomarkers in cancer immune checkpoint blockade: unravelling complexity
W. Lesterhuis (2017)
Identification of Nrf2/STAT3 axis in induction of apoptosis through sub‐G 1 cell cycle arrest mechanism in HT‐29 colon cancer cells
Issa Tajmohammadi (2019)See more