Ultrasound guides supercharged immune cells to only attack cancer

Bioengineers at the University of California San Diego have developed a cancer immunotherapy that pairs ultrasound with cancer-killing immune cells to destroy malignant tumors while sparing normal tissue. The new experimental therapy significantly slowed down the growth of solid cancerous tumors in mice. The team, led by the labs of UC San Diego bioengineering professor Peter Yingxiao Wang and bioengineering professor emeritus Shu Chien, detailed their work in a paper published Aug. 12 in Nature Biomedical Engineering.

The work addresses a longstanding problem in the field of cancer immunotherapy: how to make chimeric antigen receptor (CAR) T-cell therapy safe and effective at treating solid tumors. CAR T-cell therapy is a promising new approach to treat cancer. It involves collecting a patient’s T cells and genetically engineering them to express special receptors, called CAR, on their surface that recognize specific antigens on cancer cells. The resulting CAR T cells are then infused back into the patient to find and attack cells that have the cancer antigens on their surface.

This therapy has worked well for the treatment of some blood cancers and lymphoma, but not against solid tumors. That’s because many of the target antigens on these tumors are also expressed on normal tissues and organs. This can cause toxic side effects that can kills cells—these effects are known as on-target, off-tumor toxicity.

CAR T cells are so potent that they may also attack normal tissues that are expressing the target antigens at low levels,” said first author Yiqian (Shirley) Wu, a project scientist in Wang’s lab.

The problem with standard CAR T cells is that they are always on—they are always expressing the CAR protein, so you cannot control their activation,” explained Wu.

To combat this issue, the team took standard CAR T cells and re-engineered them so that they only express the CAR protein when ultrasound energy is applied. This allowed the researchers to choose where and when the genes of CAR T cells get switched on.

We use ultrasound to successfully control CAR T cells directly in vivo for cancer immunotherapy,” said Wang, who is a faculty member of the Institute of Engineering in Medicine and the Center for Nano-ImmunoEngineering, both at UC San Diego. What’s exciting about the use of ultrasound, noted Wang, is that it can penetrate tens of centimeters beneath the skin, so this type of therapy has the potential to non-invasively treat tumors that are buried deep inside the body.

The team’s approach involves injecting the re-engineered CAR T cells into tumors in mice and then placing a small ultrasound transducer on an area of the skin that’s on top of the tumor to activate the CAR T cells. The transducer uses what’s called focused ultrasound beams to focus or concentrate short pulses of ultrasound energy at the tumor. This causes the tumor to heat up moderately—in this case, to a temperature of 43 degrees Celsius (109 degrees Fahrenheit)—without affecting the surrounding tissue. The CAR T cells in this study are equipped with a gene that produces the CAR protein only when exposed to heat. As a result, the CAR T cells only switch on where ultrasound is applied.

The research was published in the journal Nature Biomedical Engineering.

How To Intercept Coronavirus Infection

Nanoparticles cloaked in human lung cell membranes and human immune cell membranes can attract and neutralize the SARS-CoV-2 virus in cell culture, causing the virus to lose its ability to hijack host cells and reproduce. The first data describing this new direction for fighting COVID-19 were published on June 17, 2020 in the journal Nano Letters. The “nanosponges” were developed by engineers at the University of California San Diego (UC San Diego) and tested by researchers at Boston University. The UC San Diego researchers call their nano-scale particlesnanosponges” because they soak up harmful pathogens and toxins.

In lab experiments, both the lung cell and immune cell types of nanosponges caused the SARS-CoV-2 virus to lose nearly 90% of its “viral infectivity” in a dose-dependent manner. Viral infectivity is a measure of the ability of the virus to enter the host cell and exploit its resources to replicate and produce additional infectious viral particles.

Instead of targeting the virus itself, these nanosponges are designed to protect the healthy cells the virus invades.

Nanosponges attacking and neutralizing the SARS-COV-2 virus

Traditionally, drug developers for infectious diseases dive deep on the details of the pathogen in order to find druggable targets. Our approach is different. We only need to know what the target cells are. And then we aim to protect the targets by creating biomimetic decoys,” said Liangfang Zhang, a nanoengineering professor at the UC San Diego Jacobs School of Engineering.

His lab first created this biomimetic nanosponge platform more than a decade ago and has been developing it for a wide range of applications ever since. When the novel coronavirus appeared, the idea of using the nanosponge platform to fight it came to Zhang “almost immediately,” he said.

In addition to the encouraging data on neutralizing the virus in cell culture, the researchers note that nanosponges cloaked with fragments of the outer membranes of macrophages could have an added benefit: soaking up inflammatory cytokine proteins, which are implicated in some of the most dangerous aspects of COVID-19 and are driven by immune response to the infection.

Source: https://ucsdnews.ucsd.edu/

CRISPR-Cas9 gene editing could ‘turn off’ HIV virus

HIV treatment has come a long way over the years, due in large part to antiretroviral drugs that stop the HIV virus from replicating in the body. This gives the immune system a chance to repair itself and stop further damage. Thanks to these amazing advances, HIV is no longer the death sentence that it was in previous decades. However, antiretrovirals only keep HIV at bay for as long as they’re taken. Defaulting on the drugs means that the HIV virus comes back. Even worse, it can cause patients to build up resistance to the antiretrovirals so that they do not work so effectively in the future. In other words, there’s still room for improvement when it comes to treatment. Fortunately, researchers from thUniversity of California — San Diego School of Medicine are poised to provide help, courtesy of a new genetic-sequencing approach that could possibly provide a “kill switch” to clear out dormant HIV reservoirs inside cells.

The most exciting part of this discovery has not been seen before,” Tariq Rana, professor of pediatrics and genetics at UC San Diego School of Medicine, said in a statement. “By genetically modifying a long non-coding RNA, we prevent HIV recurrence in T cells and microglia upon cessation of antiretroviral treatment, suggesting that we have a potential therapeutic target to eradicate HIV and AIDS.”

The work is based on the discovery of a recently emerged gene that appears to regulate HIV replication in immune cells, including macrophages, microglia, and T cells. The team refers to this as HIV-1 Enchanced LncRNA (HEAL), and it is elevated in people with HIV. By using CRISPR-Cas9 gene editing, their work suggests that it could stop HIV from recurring in the event that antiretroviral treatment is stopped.

This has the potential for [being a] cure but, [we’ll] have to wait for animal studies,” Rana told Digital Trends. As for the next steps, Rana said that future studies “will determine if turning this regulator HEAL off can remove viral reservoirs, which are the key source for viral rebound when therapies are discontinued.” A paper describing the work was recently published in the journal mBio.

Source: https://mbio.asm.org/
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Micromotors Deliver Oral Vaccines

Researchers are working on new generations of oral vaccines for infectious diseases. But to be effective, oral vaccines must survive digestion and reach immune cells within the intestinal wall. As a step in this direction, UC San Diego nanoengineering researchers have developed oral vaccines powered by micromotors that target the mucus layer of the intestine.

The work appears in the ACS journal Nano Letters. It’s a collaboration between the labs of nanoengineering professors Joseph Wang and Liangfang Zhang at the UC San Diego Jacobs School of Engineering.

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The lack of needles is one reason oral vaccines are attractive. Another reason: oral vaccines can generate a broad immune response by stimulating immune cells within the mucus layer of the intestine to produce a special class of antibody called immunoglobulin A (IgA). The NanoLetters paper documents the team’s efforts to use magnesium particles as tiny motors to deliver an oral vaccine against the bacterial pathogen Staphylococcus aureus. When coated over most of their surfaces with titanium dioxide, magnesium microparticles use water as fuel to generate hydrogen bubbles that power their propulsion.

To develop the oral vaccine, the researchers coated magnesium micromotors with red blood cell membranes that displayed the Staphylococcal α-toxin, along with a layer of chitosan to help them stick to the intestinal mucus. Then, they added an enteric coating that protects drugs from the acidic conditions of the stomach.

The micromotors safely passed through the stomach to the intestine, at which point the enteric coating dissolved, activating the motors. Imaging of mice that had been given the vaccine showed that the micromotors accumulated in the intestinal wall much better than non-motorized particles. The micromotors also stimulated the production of about ten times more IgA antibodies against the Staphylococcal α-toxin than the static particles.

Source: http://jacobsschool.ucsd.edu/