Clinically oriented prediction of patient response to targeted and immunotherapies from the tumor transcriptome.

BACKGROUND: Precision oncology is gradually advancing into mainstream clinical practice, demonstrating significant survival benefits. However, eligibility and response rates remain limited in many cases, calling for better predictive biomarkers. METHODS: We present ENLIGHT, a transcriptomics-based computational approach that identifies clinically relevant genetic interactions and uses them to predict a patient's response to a variety of therapies in multiple cancer types without training on previous treatment response data. We study ENLIGHT in two translationally oriented scenarios: personalized oncology (PO), aimed at prioritizing treatments for a single patient, and clinical trial design (CTD), selecting the most likely responders in a patient cohort. FINDINGS: Evaluating ENLIGHT's performance on 21 blinded clinical trial datasets in the PO setting, we show that it can effectively predict a patient's treatment response across multiple therapies and cancer types. Its prediction accuracy is better than previously published transcriptomics-based signatures and is comparable with that of supervised predictors developed for specific indications and drugs. In combination with the interferon-γ signature, ENLIGHT achieves an odds ratio larger than 4 in predicting response to immune checkpoint therapy. In the CTD scenario, ENLIGHT can potentially enhance clinical trial success for immunotherapies and other monoclonal antibodies by excluding non-responders while overall achieving more than 90% of the response rate attainable under an optimal exclusion strategy. CONCLUSIONS: ENLIGHT demonstrably enhances the ability to predict therapeutic response across multiple cancer types from the bulk tumor transcriptome. FUNDING: This research was supported in part by the Intramural Research Program, NIH and by the Israeli Innovation Authority.

Fibrolamellar carcinoma transcriptomic-based treatment prediction: complete response after nivolumab and ipilimumab.

Fibrolamellar carcinoma (FLC) is a rare cancer of the liver that most commonly affects children and young adults. There is no clear standard of care for the disease, whose response to treatment seems to be very different from that of hepatocellular carcinoma. We present a case of FLC in a patient in her mid 30s that recurred and persisted despite resection and multiple lines of treatment. Following transcriptomic analysis, a combination of ipilimumab (anti-CTLA4) and nivolumab (anti-PD-1) led to complete remission, although common biomarkers for immune checkpoint blockade were all negative in this case. The patient is still in remission. Here, combined checkpoint blockade guided by novel transcriptomic analysis led to complete remission after failure of several lines of treatment.

Globally defining the effects of mutations in a picornavirus capsid.

The capsids of non-enveloped viruses are highly multimeric and multifunctional protein assemblies that play key roles in viral biology and pathogenesis. Despite their importance, a comprehensive understanding of how mutations affect viral fitness across different structural and functional attributes of the capsid is lacking. To address this limitation, we globally define the effects of mutations across the capsid of a human picornavirus. Using this resource, we identify structural and sequence determinants that accurately predict mutational fitness effects, refine evolutionary analyses, and define the sequence specificity of key capsid-encoded motifs. Furthermore, capitalizing on the derived sequence requirements for capsid-encoded protease cleavage sites, we implement a bioinformatic approach for identifying novel host proteins targeted by viral proteases. Our findings represent the most comprehensive investigation of mutational fitness effects in a picornavirus capsid to date and illuminate important aspects of viral biology, evolution, and host interactions.

A virus is made up of genetic material that is encased with a protective protein coat called the capsid. The capsid also helps the virus to infect host cells by binding to the host receptor proteins and releasing its genetic material. Inside the cell, the virus hitchhikes the infected cell's machinery to grow or replicate its own genetic material. Viral capsids are the main target of the host's defence system, and therefore, continuously change in an attempt to escape the immune system by introducing alterations (known as mutations) into the genes encoding viral capsid proteins. Mutations occur randomly, and so while some changes to the viral capsid might confer an advantage, others may have no effect at all, or even weaken the virus. To better understand the effect of capsid mutations on the virus' ability to infect host cells, Mattenberger et al. studied the Coxsackievirus B3, which is linked to heart problems and acute heart failure in humans. The researchers analysed around 90% of possible amino acid mutations (over 14,800 mutations) and correlated each mutation to how it influenced the virus' ability to replicate in human cells grown in the laboratory. Based on these results, Mattenberger et al. developed a computer model to predict how a particular mutation might affect the virus. The analysis also identified specific amino acid sequences of capsid proteins that are essential for certain tasks, such as building the capsid. It also included an analysis of sequences in the capsid that allow it to be recognized by another viral protein, which cuts the capsid proteins into the right size from a larger precursor. By looking for similar sequences in human genes, the researchers identified several ones that the virus may attack and inactivate to support its own replication. These findings may help identify potential drug targets to develop new antiviral therapies. For example, proteins of the capsid that are less likely to mutate will provide a better target as they lower the possibility of the virus to become resistant to the treatment. They also highlight new proteins in human cells that could potentially block the virus in cells.

Full genome viral sequences inform patterns of SARS-CoV-2 spread into and within Israel.

Full genome sequences are increasingly used to track the geographic spread and transmission dynamics of viral pathogens. Here, with a focus on Israel, we sequence 212 SARS-CoV-2 sequences and use them to perform a comprehensive analysis to trace the origins and spread of the virus. We find that travelers returning from the United States of America significantly contributed to viral spread in Israel, more than their proportion in incoming infected travelers. Using phylodynamic analysis, we estimate that the basic reproduction number of the virus was initially around 2.5, dropping by more than two-thirds following the implementation of social distancing measures. We further report high levels of transmission heterogeneity in SARS-CoV-2 spread, with between 2-10% of infected individuals resulting in 80% of secondary infections. Overall, our findings demonstrate the effectiveness of social distancing measures for reducing viral spread.