Genetic Engineering & Biotechnology News

JUL 2018

Genetic Engineering & Biotechnology News (GEN) is the world's most widely read biotech publication. It provides the R&D community with critical information on the tools, technologies, and trends that drive the biotech industry.

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GENengnews.com | Genetic Engineering & Biotechnology News | JULY 2018 | 15 therapeutic strategy to promote immune in- filtration into tumors, reduce mesenchymal suppression, and enhance the antitumor ef- fects of immunotherapy." Modulating Regulatory T Cells Ubiquitination, which encompasses far- reaching signaling pathways, provides a key degradation mechanism for proteins. Furthermore, reversible protein ubiquitina- tion regulates virtually all known cellular activities. Opportunistic tumors exploit this host system to support their survival and metastasis. "Our company targets the ubiquitin- proteasome pathway to develop novel medi- cines for treating cancer, inflammation, and neurodegenerative diseases," said Suresh Kumar, Ph.D., senior director and head of drug discovery at Progenra. The company has developed potent inhibitors of ubiquitin protease 7 (USP7), the most widely studied among the 100 deubiquitinating enzymes. "Recent investigations have demonstrated that USP7 is essential for regulatory T cell (Treg) function in that it regulates Foxp3 and Tip60, which together drive the development and maintenance of Treg cell lineage," Dr. Kumar explained. According to Dr. Kumar, since immune suppressive Tregs in the TME correlate with poor patient prognosis, depletion or impair- ment of Tregs is an attractive cancer immuno- therapy: "Using our UbiPro™ platform, we have developed potent USP7 inhibitors that impair Treg functions and are efficacious in various syngeneic solid tumor models, espe- cially for melanoma and for lung and colon cancers. We will be taking this into clinical studies to evaluate safety and efficacy." Many future cancer therapies may be based on small molecules, Dr. Kumar sug- gested. "The use of exceedingly expensive antibody-based immunotherapies consis- tently shows that only 20–30% of the pa- tients respond to therapy," he said. "We be- lieve that small molecules can better tackle disease processes and solid tumors. The small molecule drug approach will likely change the landscape for checkpoint inhibi- tion therapies." Optimizing CAR T-Cell Therapies T cells equipped with engineered chime- ric antigen receptors (CARs) have success- fully navigated multicenter clinical trials. Now CAR-engineered T cells are beginning to enter clinical practice. Going forward, CAR T-cell treatments may be optimized through the evaluation of associated TME gene signatures, said Adrian Bot, M.D., Ph.D., vice president, translational sciences, Kite Pharma. Although previous studies correlated clin- ical activity of CAR T cells with a range of blood biomarkers, a detailed assessment of how CAR T-cell treatments change the TME has been lacking. Recently, Kite Pharma sci- entists succeeded in identifying a TME gene signature that was related to CAR T-cell treatment. According to Dr. Bot, exploiting IL-15, in conjunction with modulating in- terferon-related pathways and TME check- points, could optimize CAR T-cell prolifera- tive capability and produce more efficacious T-cell interventions. Solving the "Last Mile" Problem Reaching the end of the road to cure can- cer means eliminating every last malignant cell. This is no small task, especially because tumors highjack a natural process that em- bryos use to evade the mother's immune sys- tem…hypoxia. Both embryos and tumors feature an environment that restricts the lam- inar flow of oxygen. "Hypoxia is a fundamental characteris- tic of tumor malignancy that underlies im- mune evasion and metastatic progression," remarked Stephen Cary, Ph.D., co-founder and CEO, Omniox. "Typically, in a tumor environment there is a poor organization of blood vessels such that areas about 100–200 microns away are poorly perfused. Since oxygen perfusion usually ceases beyond 80 microns from blood vessels, these hypoxic areas adapt to survive. They promote im- mune tolerance by altering the recruitment and function of innate and adaptive immune effector and suppressor cells." Reversing tumor hypoxia could be thera- peutic. "Reoxygenating the microenviron- ment could help restore normal tissue biol- ogy," Dr. Cary declared. "The challenge, which no one has yet overcome, is how to get oxygen into the desired neighborhood safely. Our company has engineered a very high af- finity oxygen carrier, OMX-4.80P, using a platform based on heme nitric oxide/oxygen (H-NOX) proteins." H-NOX proteins are a family of gas- sensing proteins in prokaryotes and higher eukaryotes. According to Dr. Cary, OMX- 4.80P can accumulate preferentially in tu- mors through an enhanced permeability and retention effect and can release oxygen only in the presence of severe hypoxia. Oxygenat- ing malignant tissue helps restore the body's natural anticancer immune responses. "An- other advantage," Dr. Cary points out, "is that since radiation therapy relies on oxygen to damage DNA, treatment with oxygenat- ing molecules such as OMX-4.80P can syn- ergize with radiotherapies to enhance tumor treatments." Having successfully used the molecule as a single agent and in combination with im- munotherapies in preclinical testing, Omniox is optimistic about its upcoming clinical tri- als, which are scheduled to begin next year. "Delivering oxygen deep into the hypoxic tumor microenvironment could become a cornerstone therapy against a wide range of solid tumors," Dr. Cary suggested. "The goal is to go the last mile and eliminate every last cancerous cell." Accurate quality assessment of extracted genomic DNA from biobank samples is important prior to long-term storage and critical for some downstream applications. The FEMTO Pulse from AATI measures the size and concentration of extracted genomic DNA, helping you identify the appropriate high molecular weight DNA samples suitable for optical mapping or long-read sequencing. aati-us.com BRING BIOBANK SAMPLES INTO FOCUS See how the FEMTO Pulse can improve your downstream application outcomes when using biobank samples. OMICS

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