Current opinion in oncology
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Immune checkpoint inhibitors, antiprogrammed death receptor 1 (anti-PD-1)/antiprogrammed death-ligand 1 (anti-PD-L1), are new therapeutic regimens for managing advanced nonsmall cell lung cancer patients, giving an overall response rate of approximately 20% as monotherapy in second-line treatment. The use of predictive biomarkers for identifying patients suitable for these therapies is an important issue not only for making treatment decisions, but also from a medical economic point of view. ⋯ Standardized techniques and conditions for evaluating PD-L1 expression (tissue quality and age, percentage positivity threshold, managing heterogeneous and dynamic expression) are critical for establishing the use of this protein as a predictive marker. Care should be also taken when using anti-PD-1/PD-L1 therapies in combination with other therapies, which may impact the predictive value of PD-L1 expression.
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In early 2015 the National Institutes of Health launched a new, national Precision Medicine Initiative with the primary goal of rapidly improving the prevention, diagnosis, and treatment of cancers. The first-stage emphasis on oncology presents unique opportunities for clinical oncology to influence how the ethical challenges of precision medicine are to be articulated and addressed. Thus, a review of recent developments in connection with the Initiative, in particular on core ethics issues in clinical genomics, is a useful starting point. ⋯ The first tests of precision medicine ethics in practice will be in clinical oncology, providing a rare opportunity to shape the agenda and integrate practical ethics considerations. These efforts can benefit from pre-existing research ethics analyses and recommendations from clinical and translational genetics research.
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Antigens recognized by T cells in tumors include differentiation antigens, overexpressed antigens, cancer-testis, and mutated tumor neoantigens. Ionizing radiation causes damage to multiple biomolecules by direct energy deposition or by generation of free radicals, leading to cell death when the damage cannot be repaired. Tumor cell death induced by radiation will generate specific molecular signals that are sensed by antigen-presenting cells and stimulate their maturation and ability to cross-present tumor-derived antigens to T cells. Immunogenic cell death will complement the activity of immune checkpoint inhibitors. We will provide the emerging information coming from preclinical and clinical testing about the combinations of immunotherapies and radiotherapy. ⋯ Radiation therapy is confirmed to be a sensitizer of tumors to immune checkpoint inhibitors in clinical trials, and its application will be easy to implement and widespread. Conversely, many issues need to be addressed before radiotherapy can become such a valid immunogenic tool. An area of increasing importance will be the development of suitable biomarkers that will be able to reliably assess 'immunogenic tumor cell death', immune effector stimulation, and adaptive immunity. Such an immune profile of biomarkers will aid in searching for an optimal combination of radiotherapy and immunomodulation and allows patient selection and response prediction.
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In this review, we focus on the recent findings and future challenges in cancer treatment with immune checkpoint inhibitors. ⋯ The main challenge for the near future will be to predict efficacy of immune checkpoint blockade and to predict and prevent immune-related adverse events. More research should be done in order to find potential biomarkers that predict treatment response and/or toxicity; the optimal administration route, dosage, and frequency; and possible combinations of therapies that have an added or synergetic effect.