The lancet oncology
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The lancet oncology · Nov 2015
ReviewMultifunctional receptor-targeting antibodies for cancer therapy.
During the past decade, monospecific antibodies targeting cell-surface receptors in different tumour types have achieved substantial success and have been at the forefront of cancer treatment. However, redundant signalling and crosstalk between different pathways within tumour cells and between tumour cells and their microenvironment can limit the efficacy of receptor-targeted monospecific-based therapies. ⋯ In this Review, we discuss the rationales and strategies for the use of multifunctional receptor-targeting antibodies, their mechanisms of action, and the promises and challenges they hold as cancer therapeutics. This knowledge provides opportunities to improve current targeted therapy outcomes for patients with cancer.
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Melanoma is a leading cause of lost productivity due to premature cancer mortality. Melanoma frequently spreads to the brain and is associated with rapid deterioration in quality and quantity of life. ⋯ New challenges arise, including how to integrate or sequence multiple treatment modalities, and current practice varies widely. In this Review, we summarise evidence for the treatment of melanoma brain metastases, and discuss the rationale and evidence for combination modalities, highlighting areas for future research.
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The lancet oncology · Oct 2015
ReviewRadiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy.
Checkpoint blockade immunotherapy has received mainstream attention as a result of striking and durable clinical responses in some patients with metastatic disease and a reasonable response rate in many tumour types. The activity of checkpoint blockade immunotherapy is not restricted to melanoma or lung cancer, and additional indications are expected in the future, with responses already reported in renal cancer, bladder cancer, and Hodgkin's lymphoma among many others. Additionally, the interactions between radiation and the immune system have been investigated, with several studies describing the synergistic effects on local and distant tumour control when radiation therapy is combined with immunotherapy. ⋯ Herein, we discuss the biological and mechanistic rationale behind combining radiation with checkpoint blockade immunotherapy, with a focus on the preclinical data supporting this potentially synergistic combination. We explore potential hypotheses and important considerations for clinical trial designs. Finally, we reintroduce the notion of radiosensitising immunotherapy, akin to radiosensitising chemotherapy, as a potential definitive therapeutic modality.
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The lancet oncology · Oct 2015
ReviewDisease kinetics for decision-making in advanced melanoma: a call for scenario-driven strategy trials.
In the past 5 years, the treatment of metastatic melanoma has changed from almost no effective treatment to the use of targeted and immune therapies with proven improvements in survival. The time has now come to define the optimal drug combinations, sequence of treatment, and drug regimens (intermittent vs continuous dosing) in the treatment of patients with metastatic melanoma. In view of the prevalence of advanced melanoma, finite resources, and the heterogeneity of disease characteristics, not all possibilities can be tested in therapeutic trials starting from an unselected population of patients with metastatic melanoma. ⋯ The realistic goals of therapy are different in each scenario. We recommend that these scenarios are incorporated into clinical trials as either patient inclusion criteria or stratification factors. This approach is not only feasible but is also the only way to generate evidence for more effective and individualised treatment strategies for patients with metastatic melanoma.
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The lancet oncology · Oct 2015
ReviewTargeting brain metastases in ALK-rearranged non-small-cell lung cancer.
The incidence of brain metastases has increased as a result of improved systemic control and advances in imaging. However, development of novel therapeutics with CNS activity has not advanced at the same rate. ⋯ In this Review, we discuss potential pathways to target ALK-rearranged brain metastases, including next generation ALK inhibitors with greater CNS penetration and mechanisms to overcome resistance. Other important mechanisms to control CNS disease include targeting pathways downstream of ALK phosphorylation, increasing the permeability of the blood-brain barrier, modifying the tumour microenvironment, and adding concurrent radiotherapy.