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Trained immunity in newborn infants of HBV-infected mothers.

The newborn immune system is characterized by an impaired Th1-associated immune response. Hepatitis B virus (HBV) transmitted from infected mothers to newborns is thought to exploit the newborns’ immune system immaturity by inducing a state of immune tolerance that facilitates HBV persistence. Contrary to this hypothesis, we demonstrate here that HBV exposure in utero triggers a state of trained immunity, characterized by innate immune cell maturation and Th1 development, which in turn enhances the ability of cord blood immune cells to respond to bacterial infection in vitro. These training effects are associated with an alteration of the cytokine environment characterized by low IL-10 and, in most cases, high IL-12p40 and IFN-α2. Our data uncover a potentially symbiotic relationship between HBV and its natural host, and highlight the plasticity of the fetal immune system following viral exposure in utero.

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Contrasting expression patterns of coding and noncoding parts of the human genome upon oxidative stress.

Oxidative stress (OS) is caused by an imbalance between pro- and anti-oxidant reactions leading to accumulation of reactive oxygen species within cells. We here investigate the effect of OS on the transcriptome of human fibroblasts. OS causes a rapid and transient global induction of transcription characterized by pausing of RNA polymerase II (PolII) in both directions, at specific promoters, within 30 minutes of the OS response. In contrast to protein-coding genes, which are commonly down-regulated, this novel divergent, PolII pausing-phenomenon leads to the generation of thousands of long noncoding RNAs (lncRNAs) with promoter-associated antisense lncRNAs transcripts (si-paancRNAs) representing the major group of stress-induced transcripts. OS causes transient dynamics of si-lncRNAs in nucleus and cytosol, leading to their accumulation at polysomes, in contrast to mRNAs, which get depleted from polysomes. We propose that si-lncRNAs represent a novel component of the transcriptional stress that is known to determine the outcome of immediate-early and later cellular stress responses and we provide insights on the fate of those novel mature lncRNA transcripts by showing that their association with polysomal complexes is significantly increased in OS.

Stanford, SRI to Support Development of Novel Drugs to Treat Triple-Negative Breast Cancer

On March 24, 2016 SRI International announced a new collaborative project between scientists at SRI International and physician-researchers from Stanford Cancer Institute that will support development of novel drugs for treatment of triple-negative breast cancer (Press release, SRI International, MAR 25, 2016, View Source [SID:1234510020]).

Close to 20 percent of breast cancers are triple-negative, a type of tumor that lacks the three most common receptors that fuel most breast cancer growth. These tumors are unresponsive to hormone therapy or drugs targeting these receptors.

The research collaboration will explore the use of a preclinical drug known as sudemycin D6 that targets a "molecular machine" called the spliceosome. The spliceosome is critical to the basic biological transformation of DNA to RNA to proteins.

It "edits" raw RNA transcribed from DNA, cutting and piecing together stretches of code to form the instructions for creating various functional proteins, much as a film editor crafts a finished movie from raw footage. If this biological editor complex is defective, proteins that ultimately result from its actions can be dysfunctional and lead to various forms of cancer, including triple-negative breast cancer.

The research team will be led by Thomas R. Webb, Ph.D., director of Medicinal Chemistry at SRI Biosciences, a division of SRI International, and George Sledge, M.D., professor and chief of the Division of Oncology at Stanford University Medical Center.

"As both a medicinal chemist and cancer survivor, I know that new treatments are desperately needed for cancer," said Webb.

"It is my greatest hope that we can combine the unique strengths of SRI Biosciences and the Stanford Cancer Institute to make long-lasting impact in the treatment of triple-negative breast cancer, where unfortunately there are currently few effective therapeutic options. The strategy may also work for a range of other cancers, including lymphoma, melanoma, and certain brain and colon cancers."

"Stanford and SRI both have unique strengths, and together we can create something wonderful for patients with cancer: new treatments that are more effective and less toxic," said Dr. Sledge.

Webb’s research group designed sudemycin D6 to neutralize the SF3B1 protein of the spliceosome with enhanced activity and duration of action as well as less toxicity than previous spliceosome targeting agents. The team has also developed a marker tumor cell line that fluorescently glows when treated with sudemycin D6. This advance enables real-time monitoring of the drug’s activity, which will support translation to the clinical setting.

The SRI Biosciences and Stanford Cancer Institute collaboration is the first step in determining whether sudemycin D6 may be effective against triple-negative breast cancer. As part of the research, tumor samples from anonymous patients will be analyzed at the molecular level and examined in mouse models.

Nathan Collins Ph.D., vice president of Pharmaceutical and Chemical Technologies in SRI Biosciences and Sanjay Malhotra Ph.D., FRSC, associate professor of radiation oncology at Stanford are co-directors of the SRI Biosciences – Stanford Drug Discovery and Development Program that was announced in January 2016 to combine the translational capabilities of both organizations focused on creating a pipeline of innovative cancer drugs for unmet needs in oncology.

According to Malhotra, "The Webb-Sledge collaboration is an excellent example of how translation of a lab discovery into clinic can be expedited though the Stanford-SRI Drug Discovery and Development program. This is a new program, and we hope our wider research community will benefit from our joint efforts."

"Building on our collaborative program we are delighted to be working with the Stanford Cancer Institute to develop therapies for serious unmet needs in the treatment of cancer," added Collins.

Advances in the Development of Site-Specific Antibody-Drug Conjugation.

Antibody-drug conjugates (ADCs) showed strong anticancer efficacy in the clinic. However, the current conventional technologies generate conjugates with undefined attachment sites and heterogeneous profiles containing different sub-populations, leading to potential off-target toxicity. In order to reduce the variability and heterogeneity associated with the ADCs generated using conventional technologies, several site-specific antibody-drug conjugation strategies were developed for the next generation of ADCs. These strategies include cysteine-targeted conjugation by engineering a free cysteine into the antibody or by placing a thiol bridge on cysteines in hinge disulfides. Glutamine-targeted conjugation was also demonstrated by coupling the drug-linker to glutamine residues through an engineered glutamine tag or a native glutamine, as well as an additionally introduced glutamine residue in aglycosylated antibody mutant using microbial transglutaminase. The site-specific conjugation of drug-linker to antibody carbohydrates was developed either through metabolic engineering or a chemo-enzymatic approach. Other amino acids, such as unnatural amino acids or amino acid derivatives introduced through protein engineering, have also been shown to be efficient targets for site-specific conjugation. The sitespecific ADCs with homogeneous profiles and well-defined conjugation sites were obtained using these second generation ADC methods and showed potent in vitro cytotoxicity and strong in vivo antitumor activity. These results suggest that newly developed site-specific conjugation technologies can potentially be applied in producing the next generation ADC for cancer treatment in the clinic with high therapeutic index.

A phase II, single-arm, multicentre study of coltuximab ravtansine (SAR3419) and rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma.

In this phase II, multicentre, single-arm study, 52 patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) received the anti-CD19 antibody-drug conjugate coltuximab ravtansine (55 mg/m(2) ) and rituximab (375 mg/m(2) ) weekly for 4 weeks, then every 2 weeks for 8 weeks. The primary endpoint was objective response rate (ORR) by International Working Group Criteria. The primary objective was to reject the null hypothesis of an ORR of ≤40%. Among 45 evaluable patients, the ORR was 31·1% (80% confidence interval [CI]: 22·0-41·6%) and the primary objective was not met. The ORR appeared higher in patients with relapsed disease (58·3% [80% CI: 36·2-78·1%]) versus those refractory to their last (42·9% [80% CI: 17·0-72·1%]) or first-line therapy (15·4% [80% CI: 6·9-28·4%]). Median progression-free survival, overall survival and duration of response were 3·9 [80% CI: 3·22-3·98], 9·0 [80% CI: 6·47-13·67] and 8·6 (range: 0-18) months, respectively. The pharmacokinetics of both drugs were unaffected by co-administration. Common adverse events included gastrointestinal disorders (52%) and asthenia (25%). No patients discontinued due to adverse events. In conclusion, coltuximab ravtansine with rituximab was well tolerated and yielded clinical responses in a subset of patients with relapsed/refractory DLBCL.
© 2016 John Wiley &amp; Sons Ltd.