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Nivolumab plus Ipilimumab in Advanced Melanoma

TLDR
Conurrent therapy with nivolumab and ipilimumab had a manageable safety profile and provided clinical activity that appears to be distinct from that in published data on monotherapy, with rapid and deep tumor regression in a substantial proportion of patients.
Abstract
A total of 53 patients received concurrent therapy with nivolumab and ipilimumab, and 33 received sequenced treatment. The objective-response rate (according to modified World Health Organization criteria) for all patients in the concurrent-regimen group was 40%. Evidence of clinical activity (conventional, unconfirmed, or immune-related response or stable disease for ≥24 weeks) was observed in 65% of patients. At the maximum doses that were associated with an acceptable level of adverse events (nivolumab at a dose of 1 mg per kilogram of body weight and ipilimumab at a dose of 3 mg per kilogram), 53% of patients had an objective response, all with tumor reduction of 80% or more. Grade 3 or 4 adverse events related to therapy occurred in 53% of patients in the concurrent-regimen group but were qualitatively similar to previous experience with monotherapy and were generally reversible. Among patients in the sequenced-regimen group, 18% had grade 3 or 4 adverse events related to therapy and the objective-response rate was 20%. CONCLUSIONS Concurrent therapy with nivolumab and ipilimumab had a manageable safety profile and provided clinical activity that appears to be distinct from that in published data on monotherapy, with rapid and deep tumor regression in a substantial proportion of patients. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; ClinicalTrials.gov number, NCT01024231.)

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CTLA-4 and PD-1 Pathway Blockade: Combinations in the Clinic

TL;DR: Checkpoint blocking antibodies targeting regulatory molecules on T cells such as CTLA-4 and PD-1 have reinvigorated the field of cancer immunotherapy and the field is moving in the direction of testing novel combinations.
Journal ArticleDOI

Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) Interaction via Transiently Induced Protein States and Dimerization of PD-L1

TL;DR: NMR and X-ray characterization is presented for the two classes of small-molecule PD-1/PD-L1 inhibitors that carry a number of disadvantages such as the high cost of the antibodies, their limited half-life, and immunogenicity.
Journal ArticleDOI

Beyond CTLA-4 and PD-1, the Generation Z of Negative Checkpoint Regulators

TL;DR: The current knowledge is described on the recently discovered negative checkpoint regulators, future targets for immunotherapy, and how to achieve durable tolerance for treatment of autoimmune diseases and transplantation.
Journal ArticleDOI

Time to abandon single-site irradiation for inducing abscopal effects

TL;DR: This Perspective provides a biological rationale supporting the abandonment of the abscopal approach, and advocates exploring comprehensive irradiation of multiple/all lesions in order to enhance the likelihood of obtaining meaningful clinical outcomes.
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PD-1/PD-L1 Blockade: Have We Found the Key to Unleash the Antitumor Immune Response?

TL;DR: Improve understanding of the efficacy of PD-1/PD-L1 blockade immunotherapy, as well as enhance the development of therapeutic strategies to overcome the resistance mechanisms and unleash the antitumor immune response to combat cancer.
References
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Journal ArticleDOI

Hallmarks of cancer: the next generation.

TL;DR: Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.
Journal ArticleDOI

Toxicity and response criteria of the Eastern Cooperative Oncology Group

TL;DR: The Eastern Cooperative Oncology Group criteria for toxicity and response are presented to facilitate future reference and to encourage further standardization among those conducting clinical trials.
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