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Drug Resistance In Cancer Immunotherapy: New Strategies To Improve Checkpoint Inhibitor Therapies
J. Rodríguez-Pascual, A. Ayuso-Sacido, C. Belda-Iniesta
Published 2019 · Medicine
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Recent advances in pharmacological immune modulation against tumor cells has dramatically changed the paradigm of cancer treatment. Checkpoint inhibitor therapy is a form of cancer immunotherapy already in clinical setting but also under active basic and clinical investigation. Nevertheless, some patients are primary unresponsive or develop ulterior resistance to these family of drugs. This review aims to update the basic molecular mechanism of resistance as well as the current strategies for checkpoint inhibitor selection in order to propose new approaches to individualize the use of these novel therapies.
This paper references
Enhanced antitumor activity induced by adoptive T-cell transfer and adjunctive use of the histone deacetylase inhibitor LAQ824.
Dan D Vo (2009)
Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study
E. Cohen (2019)
Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial.
H. Kaufman (2016)
Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors.
P. Linsley (1994)
Durvalumab after chemoradiotherapy in stage III non-small cell lung cancer.
P. Tomasini (2018)
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma.
J. Larkin (2015)
Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1
Dong-Ming Kuang (2009)
Microsatellite instability in colorectal cancer.
C. Boland (2010)
A phase I dose escalation trial of tremelimumab (CP-675,206) in combination with gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer.
M. Aglietta (2014)
Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity
Stefani Spranger (2015)
Fundamental Mechanisms of Immune Checkpoint Blockade Therapy.
S. Wei (2018)
Molecular and Genetic Properties of Tumors Associated with Local Immune Cytolytic Activity
M. Rooney (2015)
Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial.
P. Sharma (2017)
Ipilimumab plus dacarbazine for previously untreated metastatic Page 12 Rodriguez-Pascual et al. Cancer Drug Resist 2019;2:[Online First] I http://dx.doi.org/10.20517/cdr.2019.61 melanoma
C Robert (2011)
Hereditary Colorectal Cancer
H. Lynch (1990)
and immune tolerance
A Tanaka (2008)
Efficacy and Safety of Durvalumab in Locally Advanced or Metastatic Urothelial Carcinoma: Updated Results From a Phase 1/2 Open-label Study
T. Powles (2017)
Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm
S. Biswas (2010)
Clinical Outcomes of Patients with Advanced Cancer and Pre-Existing Autoimmune Diseases Treated with Anti-Programmed Death-1 Immunotherapy: A Real-World Transverse Study.
A. Cortellini (2019)
Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy
P. Sharma (2017)
Safety and Efficacy of Durvalumab With or Without Tremelimumab in Patients With PD-L1–Low/Negative Recurrent or Metastatic HNSCC: The Phase 2 CONDOR Randomized Clinical Trial
L. Siu (2018)
PD-1 blockade induces responses by inhibiting adaptive immune resistance
P. Tumeh (2014)
Regulatory T Cells and Immune Tolerance
S. Sakaguchi (2008)
Avelumab plus Axitinib versus Sunitinib for Advanced Renal‐Cell Carcinoma
R. Motzer (2019)
Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma.
A. Ribas (2013)
Anti-cytotoxic T-lymphocyte antigen-4 antibody: the first in an emerging class of immunomodulatory antibodies for cancer treatment.
L. Fong (2008)
Frequencies of circulating MDSC correlate with clinical outcome of melanoma patients treated with ipilimumab
C. Meyer (2013)
A human promyelocytic-like population is responsible for the immune suppression mediated by myeloid-derived suppressor cells.
S. Solito (2011)
CTLA-4 is a second receptor for the B cell activation antigen B7
P. Linsley (1991)
History of myeloid-derived suppressor cells
J. Talmadge (2013)
Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial.
M. Patel (2018)
BRAF Inhibition Increases Tumor Infiltration by T cells and Enhances the Antitumor Activity of Adoptive Immunotherapy in Mice
C. Liu (2012)
Safety and Efficacy of Durvalumab (MEDI4736), an Anti-Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor, in Patients With Advanced Urothelial Bladder Cancer.
C. Massard (2016)
Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial.
M. Maio (2017)
Loss of IFN-γ Pathway Genes in Tumor Cells as a Mechanism of Resistance to AntiCTLA-4 Therapy. Cell 2016;167:397-404.e9
J Gao (2016)
Cdk5 disruption attenuates tumor PD-L1 expression and promotes antitumor immunity
R. D. Dorand (2016)
Nivolumab for recurrent squamous-cell carcinoma of the head and neck
J. Radford (2016)
Microsatellite instability status determined by next‐generation sequencing and compared with PD‐L1 and tumor mutational burden in 11,348 patients
A. VanderWalde (2018)
The role of an immune checkpoint score in resected non-small cell lung cancer patients' prognosis.
Rossana Berardi (2017)
Phase I/II trial of tremelimumab in patients with metastatic melanoma.
L. Camacho (2009)
Loss of IFN-γ Pathway Genes in Tumor Cells as a Mechanism of Resistance to Anti-CTLA-4 Therapy
J. Gao (2016)
Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN Solid Tumor study
L. Dirix (2017)
Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis.
Li Yang (2004)
Five-Year Overall Survival for Patients With Advanced Non‒Small-Cell Lung Cancer Treated With Pembrolizumab: Results From the Phase I KEYNOTE-001 Study
E. Garon (2019)
A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C.
B. Sangro (2013)
NCCN Guidelines Updates: New Immunotherapy Strategies for Improving Outcomes in Non-Small Cell Lung Cancer.
M. Gubens (2019)
T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer.
Eric Tran (2016)
Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial.
L. Calabrò (2013)
Avelumab, an Anti–Programmed Death-Ligand 1 Antibody, In Patients With Refractory Metastatic Urothelial Carcinoma: Results From a Multicenter, Phase Ib Study
A. Apolo (2017)
Pembrolizumab as Second‐Line Therapy for Advanced Urothelial Carcinoma
J. Bellmunt (2017)
Tumor-associated macrophages in cancers
W. Hu (2015)
Foxp 3 exploits a pre - existent enhancer landscape for regulatory T
Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors.
E. Akbay (2013)
Oncogenic Signaling Pathways in The Cancer Genome Atlas
F. Sánchez-Vega (2018)
MYC regulates the antitumor immune response through CD47 and PD-L1
S. Casey (2016)
S Sakaguchi (2012)
Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes.
Y. Agata (1996)
Loss of PTEN Promotes Resistance to T Cell-Mediated Immunotherapy.
W. Peng (2016)
Perspectives of Induction With Chemo and/or Immune Check Point Inhibition in Head and Neck Organ Preservation Treatment
S. Wiegand (2019)
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.
S. Topalian (2012)
Pembrolizumab for the treatment of non-small cell lung cancer
S. H. Lim (2016)
Foxp3 Exploits a Pre-Existent Enhancer Landscape for Regulatory T Cell Lineage Specification
R. Samstein (2012)
Regulatory T cells in cancer immunotherapy
A. Tanaka (2017)
Targeting cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4)
S. O’Day (2007)
Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.
C. Robert (2011)
Improved survival with ipilimumab in patients with metastatic melanoma.
F. S. Hodi (2010)
Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients
R. Herbst (2014)
Summary Of product characteristics. Available from: https://www.ema.europa.eu/en/documents/product-information/ keytruda-epar-product-information_en.pdf
I. Annex (2019)
Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma.
Jesse M. Zaretsky (2016)
Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma.
M. Green (2010)
Immune Checkpoint Targeting in Cancer Therapy: Toward Combination Strategies with Curative Potential
P. Sharma (2015)
Control of PD-L1 Expression by Oncogenic Activation of the AKT-mTOR Pathway in Non-Small Cell Lung Cancer.
Kristin J. Lastwika (2016)
Immunostimulatory monoclonal antibodies for cancer therapy
I. Melero (2007)
Summary of product characteristics
H. Andrew (2016)
Safety and Clinical Activity of the Programmed Death-Ligand 1 Inhibitor Durvalumab in Combination With Poly (ADP-Ribose) Polymerase Inhibitor Olaparib or Vascular Endothelial Growth Factor Receptor 1-3 Inhibitor Cediranib in Women's Cancers: A Dose-Escalation, Phase I Study.
J. Lee (2017)
A Phase III Study of Durvalumab (MEDI4736) With or Without Tremelimumab for Previously Treated Patients With Advanced NSCLC: Rationale and Protocol Design of the ARCTIC Study.
D. Planchard (2016)
Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial.
T. Seiwert (2016)
Summary Of product characteristics. Available from: https://www.ema.europa.eu/en/documents/product-information/ tecentriq-epar-product-information_en.pdf
I. Annex (2019)
Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial
A. Balar (2017)
Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study.
S. Antonia (2016)
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