Major Advance In Cancer Therapy

Immune checkpoint inhibitors such as Keytruda and Opdivo work by unleashing the immune system’s T cells to attack tumor cells. Their introduction a decade ago marked a major advance in cancer therapy, but only 10% to 30% of treated patients experience long-term improvement. In a paper published online today in The Journal of Clinical Investigation (JCI), scientists at Albert Einstein College of Medicine describe findings that could bolster the effectiveness of immune-checkpoint therapyRather than rally T cells against cancer, the Einstein research team used different human immune cells known as natural killer (NK) cells—with dramatic results.

“We believe the novel immunotherapy we’ve developed has great potential to move into clinical trials involving various types of cancer,” said study leader Xingxing Zang, M.Med., Ph.D., Professor of microbiology  at Einstein and a member of the Cancer Therapeutics Program of the Montefiore Einstein Cancer Center.

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Inhaled Nanobodies Effective Against COVID-19

In a paper published today in Science Advances, researchers from the University of Pittsburgh School of Medicine showed that inhalable nanobodies targeting the spike protein of the SARS-CoV-2 coronavirus can prevent and treat severe COVID-19 in hamsters. This is the first time the nanobodies–which are similar to monoclonal antibodies but smaller in size, more stable and cheaper to produce–were tested for inhalation treatment against coronavirus infections in a pre-clinical model.

The scientists showed that low doses of an aerosolized nanobody named Pittsburgh inhalable Nanobody-21 (PiN-21) protected hamsters from the dramatic weight loss typically associated with severe SARS-CoV-2 infection and reduced the number of infectious virus particles in the animals’ nasal cavities, throats and lungs by a million-fold, compared to placebo treatment with a nanobody that doesn’t neutralize the virus.

By using an inhalation therapy that can be directly administered to the infection site–the respiratory tract and lungs–we can make treatments more efficient,” said co-senior author Yi Shi, Ph.D., assistant professor of cell biology at Pitt. “We are very excited and encouraged by our data suggesting that PiN-21 can be highly protective against severe disease and can potentially prevent human-to-human viral transmission.

Previously, Shi and colleagues discovered a large repertoire of over 8,000 high-affinity SARS-CoV-2 nanobodies. From this repertoire, the scientists selected an ultrapotent nanobody (Nb21) and bioengineered it into a rimeric form to further maximize its antiviral activity. The resulting PiN-21 is by far the most potent antiviral nanobody that has been identified, according to the researchers’ review of published studies.

Source: https://www.eurekalert.org/

Self-Assembling Nanofibers Prevent Damage from Inflammation

Biomedical engineers at Duke University have developed a self-assembling nanomaterial that can help limit damage caused by inflammatory diseases by activating key cells in the immune system. In mouse models of psoriasis, the nanofiber-based drug has been shown to mitigate damaging inflammation as effectively as a gold-standard therapy. One of the hallmarks of inflammatory diseases, like rheumatoid arthritis, Crohn’s disease and psoriasis, is the overproduction of signaling proteins, called cytokines, that cause inflammation. One of the most significant inflammatory cytokines is a protein called TNF. Currently, the best treatment for these diseases involves the use of manufactured antibodies, called monoclonal antibodies, which are designed to target and destroy TNF and reduce inflammation.

Although monoclonal antibodies have enabled better treatment of inflammatory diseases, the therapy is not without its drawbacks, including a high cost and the need for patients to regularly inject themselves. Most significantly, the drugs also have uneven efficacy, as they may sometimes not work at all or eventually stop working as the body learns to make antibodies that can destroy the manufactured drug. To circumvent these issues, researchers have been exploring how immunotherapies can help teach the immune system how to generate its own therapeutic antibodies that can specifically limit inflammation.

The graphic shows the peptide nanofiber bearing complement protein C3dg (blue) and key components of the TNF protein, which include B-cell epitopes (green), and T-cell epitopes (purple)

We’re essentially looking for ways to use nanomaterials to induce the body’s immune system to become an anti-inflammatory antibody factory,” said Joel Collier, a professor of biomedical engineering at Duke University. “If these therapies are successful, patients need fewer doses of the therapy, which would ideally improve patient compliance and tolerance. It would be a whole new way of treating inflammatory disease.”

In their new paper, which appeared online in the Proceedings of the National Academy of Sciences (PNAS), Collier and Kelly Hainline, a graduate student in the Collier lab, describe how novel nanomaterials could assemble into long nanofibers that include a specialized protein, called C3dg. These fibers then were able to activate immune system B-cells to generate antibodies. “C3dg is a protein that you’d normally find in your body,” said Hainline. “The protein helps the innate immune system and the adaptive immune system communicate, so it can activate specific white blood cells and antibodies to clear out damaged cells and destroy antigens.”

Due to the protein’s ability to interface between different cells in the immune system and activate the creation of antibodies without causing inflammation, researchers have been exploring how C3dg could be used as a vaccine adjuvant, which is a protein that can help boost the immune response to a desired target or pathogen.

Source: https://pratt.duke.edu/

Two New Trials of Coronavirus Treatment

Drugs used for treating arthritis are being tested as treatments for COVID-19, the disease caused by a new coronavirus, as researchers rush to find ways of helping patients and slowing the number of infectionsSanofi and Regeneron Pharmaceuticals said on Monday they began a clinical trial of their rheumatoid arthritis drug Kevzara as a coronavirus treatment, while in Spain a separate trial is studying if a combination of two drugs can slow down the spread of coronavirus among people. Enrolments for the mid-to-late stage trial of Kevzara, an immune-system modifying drug known as a monoclonal antibody, will begin immediately and test up to 400 patients, Sanofi and Regeneron said in a joint statement. Regeneron in February announced a partnership with the U.S. Department of Health and Human Services to develop a treatment for the new coronavirus, called SARS-CoV2, and said it would focus on monoclonal antibodies.

The virus that emerged in central China in December has now infected more than 179,000 people worldwide, according to the Johns Hopkins University, which is tracking these figures. Doctors have seen that many of those who become critically ill from SARS-CoV2 are experiencing a so-called cytokine storm, which happens when the immune system overreacts and attacks the body’s organs. Some researchers think drugs that can suppress the immune system, including monoclonal antibodies, might be useful for limiting this autoimmune response.

Meanwhile, Barcelona-based researchers said on Monday they would administer a drug used to treat HIV – containing darunavir and cobicistat – to a coronavirusinfected person. The patient’s close contacts would be administered hydroxychloroquine, a drug for malaria and rheumatoid conditions because laboratory experiments suggest it prevents this strain of coronavirus from reproducing. “The goal of our study is to separate the transmission chains,” Oriol Mitja, researcher at Germans Trias i Pujol Research Institute, told a news briefing. Patients with coronavirus can infect between 5% and 15% of the people they come into contact with during the 14 days after starting to show symptoms, he said. The trial’s goal is to reduce that number below 14 days and also to reduce the percentage of contacts infected and researchers plan to analyze the results in 21 days. Around 200 patients with coronavirus and 3,000 of their close contacts will take part in the trial, which has private and public funding.

Source: https://www.reuters.com/

DNA Nanorobots Target Breast Cancer Cells

According to the Mayo Clinic, about 20% of breast cancers make abnormally high levels of a protein called human epidermal growth factor receptor 2 (HER2). When displayed on the surface of cancer cells, this signaling protein helps them proliferate uncontrollably and is linked with a poor prognosis. Now, researchers have developed a DNA nanorobot that recognizes HER2 on breast cancer cells, targeting them for destruction.

Current therapies for HER2-positive breast cancer include monoclonal antibodies, such as trastuzumab, that bind to HER2 on cells and direct it to the lysosome — an organelle that degrades biomolecules. Lowering the levels of HER2 slows cancer cell proliferation and triggers cell death. Although monoclonal antibodies can lead to the death of cancer cells, they have severe side effects and are difficult and expensive to produce. In a previous study, Yunfeng Lin and colleagues identified a short sequence of DNA, called an aptamer, that recognizes and binds HER2, targeting it for lysosomal degradation in much the same way that monoclonal antibodies do. But the aptamer wasn’t very stable in serum. So the researchers wanted to see if adding a DNA nanostructure, called a tetrahedral framework nucleic acid (tFNA), could increase the aptamer‘s biostability and anti-cancer activity.

A DNA NANOROBOT CAN TARGET BREAST CANCER CELLS FOR DESTRUCTION

To find out, the team designed DNA nanorobots consisting of the tFNA with an attached HER2 aptamer. When injected into mice, the nanorobots persisted in the bloodstream more than twice as long as the free aptamer. Next, the researchers added nanorobots to three breast cancer cell lines in petri dishes, showing that they killed only the HER2-positive cell line. The addition of the tFNA allowed more of the aptamer to bind to HER2 than without tFNA, leading to reduced HER2 levels on cell surfaces. Although the nanorobot is much easier and less expensive to make than monoclonal antibodies, it likely needs further improvement before it could be used to treat breast cancer in the clinic, the researchers say.

The findings are published  in the ACS journal Nano Letters.

Source: https://www.eurekalert.org/