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Combinatorial Approaches to the Treatment of Advanced Melanoma.

ABSTRACT: The treatment landscape for patients with advanced melanoma has dramatically improved over the past decade, leading to unprecedented survival. Despite the robust activity of single-agent immune-checkpoint blockade with anti-CTLA-4 or anti-PD-1 agents, and the efficacy of targeted therapies capable of interrupting aberrant signaling resulting from BRAF mutations, the benefit from these therapies is not universal. Advanced understanding of immune and molecular processes underlying melanoma tumorigenesis has demonstrated the promise of combined, multidrug regimens. We discuss the currently available evidence that supports using combinatorial approaches in advanced melanoma treatment and provide insights into promising new combination strategies under investigation.

SUBMITTER: Munhoz RR

PROVIDER: S-EPMC9428831 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Combinatorial Approaches to the Treatment of Advanced Melanoma.

Munhoz Rodrigo Ramella RR Postow Michael Andrew MA

Hematology/oncology clinics of North America 20201026 1

The treatment landscape for patients with advanced melanoma has dramatically improved over the past decade, leading to unprecedented survival. Despite the robust activity of single-agent immune-checkpoint blockade with anti-CTLA-4 or anti-PD-1 agents, and the efficacy of targeted therapies capable of interrupting aberrant signaling resulting from BRAF mutations, the benefit from these therapies is not universal. Advanced understanding of immune and molecular processes underlying melanoma tumorig ...[more]

PMID: 33759771

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Project description:Attenuated viruses have numerous applications, in particular in the context of live viral vaccines. However, purposefully designing attenuated viruses remains challenging, in particular if the attenuation is meant to be resistant to rapid evolutionary recovery. Here we develop and analyze a new attenuation method, promoter ablation, using an established viral model, bacteriophage T7. Ablation of promoters of the two most highly expressed T7 proteins (scaffold and capsid) led to major reductions in transcript abundance of the affected genes, with the effect of the double knockout approximately additive of the effects of single knockouts. Fitness reduction was moderate and also approximately additive; fitness recovery on extended adaptation was partial and did not restore the promoters. The fitness effect of promoter knockouts combined with a previously tested codon deoptimization of the capsid gene was less than additive, as anticipated from their competing mechanisms of action. In one design, the engineering created an unintended consequence that led to further attenuation, the effect of which was studied and understood in hindsight. Overall, the mechanisms and effects of genome engineering on attenuation behaved in a predictable manner. Therefore, this work suggests that the rational design of viral attenuation methods is becoming feasible. IMPORTANCE Live viral vaccines rely on attenuated viruses that can successfully infect their host but have reduced fitness or virulence. Such attenuated viruses were originally developed through trial and error, typically by adaptation of the wild-type virus to novel conditions. That method was haphazard, with no way of controlling the degree of attenuation or the number of attenuating mutations or preventing evolutionary reversion. Synthetic biology now enables rational design and engineering of viral attenuation, but rational design must be informed by biological principles to achieve stable, quantitative attenuation. This work shows that in a model system for viral attenuation, bacteriophage T7, attenuation can be obtained from rational design principles, and multiple different attenuation approaches can be combined for enhanced overall effect.

Dataset Information

Combinatorial Approaches to the Treatment of Advanced Melanoma.

Publications

Combinatorial Approaches to the Treatment of Advanced Melanoma.

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