Overcoming resistance to targeted therapy with immunotherapy and combination therapy for metastatic melanoma

Hilary R. Keller, Xin Zhang, Li Li, Helmut Schaider and James W. Wells _

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Oncotarget. 2017; 8:75675-75686. https://doi.org/10.18632/oncotarget.18523

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Hilary R. Keller1,2,3,4, Xin Zhang4, Li Li4, Helmut Schaider5 and James W. Wells3

1The University of Queensland School of Medicine, Ochsner Clinical School, Brisbane, QLD, Australia

2The University of Queensland School of Medicine, Ochsner Clinical School, New Orleans, LA, USA

3The University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia

4Laboratory of Translational Cancer Research, Ochsner Clinic Foundation, New Orleans, LA, USA

5Dermatology Research Centre, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia

Correspondence to:

James W. Wells, email: [email protected]

Keywords: metastatic melanoma, immunotherapy, targeted therapy, therapy resistance, immune inhibitory receptors

Received: March 17, 2017     Accepted: June 05, 2017     Published: June 16, 2017


Resistance to targeted therapy is an ongoing problem for the successful treatment of Stage IV metastatic melanoma. For many patients, the use of targeted therapies, such as BRAF kinase inhibitors, were initially promising yet resistance inevitably occurred. Even after combining BRAF kinase inhibitors with MEK pathway inhibitors to offset re-activation of the MAP kinase pathway, resistance is still documented. Similarly, outcomes with immune checkpoint inhibitors as monotherapy were optimistic for some patients without relapse or progression, yet the majority of patients undergoing monotherapy have progressive disease. Will immunotherapy and combination therapy trials overcome resistance in metastatic melanoma? In an effort to treat resistant disease, new clinical trials evaluating the combination of immunotherapy with other therapies, such as kinase inhibitors, adoptive cell therapy, chimeric CD40 ligand to boost costimulation, or a tumor-specific oncolytic virus enhancing granulocyte macrophage colony-stimulating factor (GM-CSF) expression, are currently underway. Updated studies on the mechanisms of resistance, immune escape and options to reinvigorate immune cells support the continued discovery of new and improved forms of therapy.

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