‘Masked’ Cancer Drug Sneaks Through Body

Many cancer treatments are notoriously savage on the body; they attack healthy cells at the same time as tumor cells, causing a plethora of side effects. Now, researchers at the University of Chicago’s Pritzker School of Molecular Engineering (PME) have designed a method to keep one promising cancer drug from wreaking such havoc. The team has engineered a new “masked” version of the immunotherapy drug interleukin-12 that is activated only when it reaches a tumor.

Researchers have long suspected that interleukin-12 could be a powerful cancer treatment, but it caused dangerous side effects. Now, Pritzker Molecular Engineering researchers have developed a version of the molecule not activated until it reaches a tumor, where it eradicates cancer cells.

Our research shows that this masked version of IL-12 is much safer for the body, but it possesses the same anti-tumor efficacy as the original,” said Aslan Mansurov, a postdoctoral research fellow and first author of the new paper. He carried out the IL-12 engineering work with Jeffrey Hubbell, the Eugene Bell Professor in Tissue Engineering, who co-leads PME’s Immunoengineering research theme with professor Melody Swartz.

Researchers know that IL-12 potently activates lymphocytes, immune cells with the potential to destroy tumor cells. But, in the 1990s, early clinical trials of IL-12 were halted because of severe, toxic side effects in patients. The same immune activation that started a cascade of events killing cancer cells also led to severe inflammation throughout the body. IL-12, at least in its natural form, was shelved.
The research on the molecule, also known as IL-12, is described in the journal Nature Biomedical Engineering.

But Mansurov, Hubbell, Swartz, and colleagues had an idea to reinvigorate the possibility of IL-12. What if the drug could slip through the body without activating the immune system? They designed a “masked molecule with a cap covering the section of IL-12 which normally binds immune cells. The cap can be removed only by tumor-associated proteases, a set of molecular scissors found in the vicinity of tumors to help them degrade surrounding healthy tissue. When the proteases chop off the cap, the IL-12 becomes active, able to spur an immune response against the tumor.

The masked IL-12 is largely inactive everywhere in the body except at the site of the tumor, where these proteases can cleave off the mask,” explained Mansurov.

Source: https://pme.uchicago.edu/

CRISPR to Boost Tomatoes’ Vitamin D Levels

By making a few genetic tweaks using CRISPR technology, scientists have designed a special sun-dried tomato packed to the leaves with vitamin D. The flesh and peel of the fruit were genetically engineered to contain the same vitamin D levels as two eggs or 28 grams of tuna, both of which are currently recommended sources of the vital nutrient.

Researchers used gene editing to turn off a specific molecule in the plant’s genome which increased provitamin D3 in both the fruit and leaves of tomato plants. It was then converted to vitamin D3 through exposure to UVB lightVitamin D is created in our bodies after skin’s exposure to UVB light, but the major source is food. This new biofortified crop could help millions of people with vitamin D insufficiency, a growing issue linked to higher risk of cancer, dementia, and many leading causes of mortality. Studies have also shown that vitamin D insufficiency is linked to increased severity of infection by Covid-19.

Tomatoes naturally contain one of the building blocks of vitamin D3, called provitamin D3 or 7-dehydrocholesterol (7-DHC), in their leaves at very low levels. Provitamin D3, does not normally accumulate in ripe tomato fruits. Researchers in Professor Cathie Martin’s group at the John Innes Centre (in UK) used CRISPR-Cas9 gene editing to make revisions to the genetic code of tomato plants so that provitamin D3 accumulates in the tomato fruit. The leaves of the edited plants contained up to 600 ug of provitamin D3 per gram of dry weight. The recommended daily intake of vitamin d is 10 ug for adults. When growing tomatoes leaves are usually waste material, but those of the edited plants could be used for the manufacture of vegan-friendly vitamin D3 supplements, or for food fortification.

We’ve shown that you can biofortify tomatoes with provitamin D3 using gene editing, which means tomatoes could be developed as a plant-based, sustainable source of vitamin D3,” said Professor Cathie Martin, corresponding author of the study which appears in Nature Plants. “Forty percent of Europeans have vitamin D insufficiency and so do one billion people world-wide. We are not only addressing a huge health problem, but are helping producers, because tomato leaves which currently go to waste, could be used to make supplements from the gene-edited lines.”

Previous research has studied the biochemical pathway of how 7-DHC is used in the fruit to make molecules and found that a particular enzyme Sl7-DR2 is responsible for converting this into other molecules. To take advantage of this the researchers used CRISPR-Cas 9 to switch off this Sl7-DR2 enzyme in tomato so that the 7DHC accumulates in the tomato fruit. The researchers then tested whether the 7-DHC in the edited plants could be converted to vitamin D3 by shining UVB light on leaves.

After treatment with UVB light to turn the 7-DHC into Vitamin D3, one tomato contained the equivalent levels of vitamin D as two medium sized eggs or 28g tuna – which are both recommended dietary sources of vitamin D. The study says that vitamin D in ripe fruit might be increased further by extended exposure to UVB, for example during sun-drying.

Source: https://www.jic.ac.uk/

Lasers and Ultrasound Combine to Pulverize Arterial Plaque

Lasers are one of the tools physicians can lean on to tackle plaque buildup on arterial walls, but current approaches carry a risk of complications and can be limited in their effectiveness. By bringing ultrasound into the mix, scientists at the University of Kansas have demonstrated a new take on this treatment that relies on exploding microbubbles to destroy plaque with greater safety and efficiency, while hinting at some unique long-term advantages.

Scientists have demonstrated a new technique to take out arterial plaque, using low-power lasers and ultrasound to break it apart with tiny bubbles

The novel ultrasound-assisted laser technique builds off what’s known as laser angioplasty, an existing treatment designed to improve blood flow in patients suffering from plaque buildup that narrows the arteries. Where more conventional treatments such as stents and balloon angioplasty expand the artery and compress the plaque, laser angioplasty destroys it to eliminate the blockage.

The laser is inserted into the artery with a catheter, and the thermal energy it generates turns water in the artery into a vapor bubble that expands, collapses and breaks up the plaque. Because this technique calls for high-power lasers, it has the potential to perforate or dissect the artery, something the scientists are looking to avoid by using low-power lasers instead.

They were able to do so in pork belly samples and ex vivo samples of artery plaque with the help of ultrasound. The method uses a low-power nanosecond pulsed laser to generate microbubbles, and applying ultrasound to the artery then causes these microbubbles to expand, collapse and disrupt the plaque.

In conventional laser angioplasty, a high laser power is required for the entire cavitation process, whereas in our technology, a lower laser power is only required for initiating the cavitation process,” said team member Rohit Singh. “Overall, the combination of ultrasound and laser reduces the need for laser power and improves the efficiency of atherosclerotic plaque removal.

The mix of lasers and ultrasound has shown potential in other areas of medicine, with Singh and his colleagues pursuing similar therapies to tackle abnormal microvessels in the eye that cause blindness and blood clots in the veins. We’ve also seen ultrasound used to explode tiny bubbles in cancer research, providing a way of wiping out cancerous cells within a tumor.

Source: https://newatlas.com/

Revolutionary Cancer-Killing Virus Tested

Scientists have injected the first human patient with a new ‘cancer-killing virus‘ that has been shown to shrink solid tumours in animals. The virus, known as Vaxinia, has been genetically engineered to infect, replicate in and kill cancer cells, while sparing healthy cells. Tests on animals have shown it is able to reduce the size of colon, lung, breast, ovarian and pancreatic cancer tumours.

While other immunotherapies such as checkpoint inhibitors have been effective in certain cancers, patients often relapse and eventually stop responding to or develop resistance to this type of treatment, according to the researchers. In contrast, Vaxinia can prime the patient’s immune system and increase the level of a protein called PD-L1 in tumours, making immunotherapy more effective against cancerVaxinia, (full name CF33-hNIS VAXINIA), is a type of ‘oncolytic virus‘ – a virus found in nature that has been genetically modified specifically to fight cancer. It is being developed by Imugene Limited, a company specialising in novel therapies that activate the immune system against cancer.

Our previous research demonstrated that oncolytic viruses can stimulate the immune system to respond to and kill cancer, as well as stimulate the immune system to be more responsive to other immunotherapies, including checkpoint inhibitors,‘ said Daneng Li MD, principal investigator and assistant professor of City of Hope‘s Department of Medical Oncology & Therapeutics Research. ‘Now is the time to further enhance the power of immunotherapy, and we believe CF33-hNIS has the potential to improve outcomes for our patients in their battle with cancer.’

The Phase 1 clinical trial aims to recruit 100 cancer patients with metastatic or advanced solid tumours across approximately 10 trial sites in the United States and Australia. It is anticipated to run for approximately 24 months. Patients will begin by receiving a low dose of Vaxinia, either as an injection directly into tumours or intravenously. Once the safety of Vaxina has been demonstrated, some participants will also receive an immunotherapy drug called pembrolizumab, which improves the immune system’s ability to fight cancer-causing cells.

Interestingly, the same characteristics that eventually make cancer cells resistant to chemotherapy or radiation treatment actually enhance the success of oncolytic viruses, such as CF33-hNIS,’ said Yuman Fong MD, the Sangiacomo Family Chair in Surgical Oncology at City of Hope and the key developer of the genetically modified virus.

Source: https://www.cityofhope.org/
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Drug Prevents Breast Cancer Recurrence and Metastasis

Even when detected early, some cancers are more aggressive and more fatal than others. This is the case, for example, with triple negative breast cancer which accounts for 10 to 15% of all breast cancers. This cancer affects 1,000 patients per year in Belgium, while the figure worldwide is 225,000. Around half of the patients will develop local recurrences and metastases, regardless of the treatment they receive. No specific treatment is currently capable of preventing these two events. Patients suffering from pervasive triple negative breast cancer have only a one-in-ten chance of a cure. In 2014, Pierre Sonveaux, a researcher at the University of Louvain (UCLouvain) Institute for experimental and clinical research, succeeded in demonstrating the principle that it was possible to prevent the appearance of melanoma tumour metastases in mice. However, the experimental molecules used at the time were far from being drugs.

Since then, the UCLouvain researcher and his team, including post-doctoral researcher Tania Capeloa, have continued their work thanks in particular to sponsorship obtained by the UCLouvain Foundation. They have now succeeded in establishing that a drug developed for diseases other than cancer, MitoQ, avoids the appearance of metastases in 80% and local recurrences of human breast cancer in 75% of cases in mice. Conversely, most of the mice not treated suffered a recurrence of their cancer, which spread.

To do this, the researchers treated mice affected by human breast cancer. They treated them as hospital patients are treated, i.e. by combining surgery with a carefully dosed cocktail of standard chemotherapies. However, the UCLouvain researchers supplemented this standard treatment with the new molecule, MitoQ. They not only demonstrated that the administration of MitoQ is compatible with standard chemotherapies, but also that this innovative treatment prevents both relapses and metastases of breast cancer in mice. “We expected to be able to block the metastases, says Pierre Sonveaux enthusiastically. But preventing the recurrence of the cancer was totally unexpected. Getting this type of result is a huge motivation for us to carry on.” In short, this is a giant step given that the three main causes of cancer mortality are recurrences, the spread of the cancer caused by metastasis and resistance to treatment. And that there is currently no other known molecule capable of acting like MitoQ.

How does it work? Cancers consist of two types of cancerous cells: those that proliferate and are sensitive to clinical treatments and those that are dormant and that bide their time. Such cells are more harmful. The problem? These cancerous stem cells are resistant to clinical treatments. They result in metastases and if, unfortunately, cancer surgery fails to remove them all, they cause recurrences. These relapses are currently treated using chemotherapy. However, this tends to be relatively ineffective owing to the resistance to treatment developed by the tumorous cells . This is where the important discovery of the UCLouvain scientists comes in: the molecule MitoQ stops cancerous stem cells from awakening.

What next? MitoQ has already come through the first clinical phase successfully. It has been tested on healthy patients, both men and women, and proves to be only slightly toxic (nausea, vomiting). In addition, its behaviour is known. What next? The discovery made by the UCLouvain scientists opens wide the path for the clinical 2 phase, intended to demonstrate the efficacy of the new treatment in cancer patients.

Source: https://uclouvain.be/
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Cancer of the Blood and Bone Marrow Healed by Immunotherapy

Emily Whitehead was diagnosed with acute lymphoblastic leukemia (ALL) when she was just five years old. Acute lymphoblastic leukemia is a type of cancer of the blood and bone marrow that affects white blood cells, and is most common in children ages three to five. Whitehead needed chemotherapy, but after two years, it was unsuccessful. Her health was rapidly declining, and the local hospital told them to go home and enjoy the days they had left with her. But Whitehead’s parents refused to give up on their daughter and turned to the Children’s Hospital of Philadelphia (CHOP) for help.. There, they learned about a clinical trial that had just started involving CAR T-cell therapy, which genetically alters a patient’s white blood cells to fight cancer cellsWhitehead’s doctor, Dr. Grub, says this therapy is a game-changer for blood cancers and is a great option for those who relapsed and don’t have their cancer under control. In 2012, Whitehead became the first pediatric patient in the world to receive this type of therapy. Today, she is 17 years old and just celebrated being ten years cancer-free!

I’m feeling great. I’m really healthy. I’m driving now, I got my driver’s license in January.”

Not all patients who receive CAR T for relapsed ALL reach the same outcome as Emily. Currently, more than 90% of patients who receive CAR T-cell therapy for relapsed ALL go into remission; approximately 50% of those patients will remain cancer free. Researchers are continuing to advance the field so that more patients never relapse. Because CHOP is the pediatric oncology program with the most CAR T experience — having to date treated more than 440 patients, who have come to CHOP from across the globe — the program remains poised to further improve those outcomes.

In addition, Dr. Grupp says there has been a change in thinking surrounding enrollment in clinical trials for cancer patients. Rather than waiting until a patient is nearly out of options to consider experimental treatment options, oncologists are recognizing patients who might qualify for CAR T-cell therapy and other clinical trials earlier in the process. While CAR T-cell therapy is good for blood cancers, doctors and researchers will be spending the next five to ten years trying to figure out how to make this work for other types of cancers such as breast cancer and lung cancer.

Source: https://www.chop.edu/

mRNA Breakthrough Offers a Potential Heart Attack Cure

King’s College London researchers are turning to the same technology behind the mRNA COVID-19 vaccines to develop the first damage-reversing heart attack cure. They used mRNA to deliver the genetic instructions for specific proteins to damaged pig hearts, sparking the growth of new cardiac muscle cells. “The new cells would replace the dead ones and instead of forming a scar, the patient has new muscle tissue,” lead researcher Mauro Giacca said. Researchers are turning to the same technology behind Pfizer and Moderna’s vaccines to develop the first damage-reversing heart attack cure.

Diseases of the heart are the leading cause of death around the world; the WHO estimates that 17.9 million people died from cardiovascular disease in 2019, representing almost a third of all deaths. Of those, 85% are ultimately killed by heart attacks and strokes. Heart attacks occur when blood flow to parts of the heart is blocked, often due to fat or cholesterol build up. The cardiac muscle cells — marvelous little powerhouses that keep you beating throughout your entire life — are starved of oxygen and can be damaged or killed. Left in its wake is not the smoothly pumping cardiac muscle, but instead scar tissue.

We are all born with a set number of muscle cells in our heart and they are exactly the same ones we will die with. The heart has no capacity to repair itself after a heart attack,” explained Giacca.

At least, until now. To develop their heart attack cure, the researchers turned to mRNA, which delivers the instructions for protein creation to cells. Whereas the Pfizer and Moderna vaccines instruct cells to make the spike protein of SARS-CoV-2, priming the immune system against the virus, the same technology can deliver a potential heart attack cure by carrying the code for proteins that stimulate the growth of new heart cellsPharmaTimes reported. In an experiment with pigs (a close match for the human heart), the mRNA treatment stimulated new heart cells to grow after a heart attackregenerating the damaged tissues and creating new, functional muscle rather than a scar.

According to BioSpace, harnessing mRNA in this way has been dubbed “genetic tracking,” named for the way the mRNA’s progress is tracked via the new proteins it is creating. The technique is being explored to create vaccines for pathogens like HIV, Ebola, and malaria, as well as cancers and autoimmune and genetic diseases. While thus far their heart attack cure has only been successfully tested in porcine pumpers, the team hopes to begin human clinical trials within the next couple years. “Regenerating a damaged human heart has been a dream until a few years ago,” Giacca said, “but can now become a reality.”

Source: https://www.freethink.com/

Tumors Partially Destroyed with Sound Don’t Come Back

Noninvasive sound technology developed at the University of Michigan (U-M) breaks down liver tumors in rats, kills cancer cells and spurs the immune system to prevent further spread—an advance that could lead to improved cancer outcomes in humans. By destroying only 50% to 75% of liver tumor volume, the rats’ immune systems were able to clear away the rest, with no evidence of recurrence or metastases in more than 80% of animals.

The 700kHz, 260-element histotripsy ultrasound array transducer used in Prof. Xu’s lab

Even if we don’t target the entire tumor, we can still cause the tumor to regress and also reduce the risk of future metastasis,” said Zhen Xu, professor of biomedical engineering at U-M and corresponding author of the study in Cancers. Results also showed the treatment stimulated the rats’ immune responses, possibly contributing to the eventual regression of the untargeted portion of the tumor and preventing further spread of the cancer.

The treatment, called histotripsy, noninvasively focuses ultrasound waves to mechanically destroy target tissue with millimeter precision. The relatively new technique is currently being used in a human liver cancer trial in the United States and Europe. In many clinical situations, the entirety of a cancerous tumor cannot be targeted directly in treatments for reasons that include the mass’ size, location or stage. To investigate the effects of partially destroying tumors with sound, this latest study targeted only a portion of each mass, leaving behind a viable intact tumor. It also allowed the team, including researchers at Michigan Medicine and the Ann Arbor VA Hospital, to show the approach’s effectiveness under less than optimal conditions.

Histotripsy is a promising option that can overcome the limitations of currently available ablation modalities and provide safe and effective noninvasive liver tumor ablation,” said Tejaswi Worlikar, a doctoral student in biomedical engineering. “We hope that our learnings from this study will motivate future preclinical and clinical histotripsy investigations toward the ultimate goal of clinical adoption of histotripsy treatment for liver cancer patients.”

Liver cancer ranks among the top 10 causes of cancer related deaths worldwide and in the U.S. Even with multiple treatment options, the prognosis remains poor with five-year survival rates less than 18% in the U.S. The high prevalence of tumor recurrence and metastasis after initial treatment highlights the clinical need for improving outcomes of liver cancer. Where a typical ultrasound uses sound waves to produce images of the body’s interior, U-M engineers have pioneered the use of those waves for treatment. And their technique works without the harmful side effects of current approaches such as radiation and chemotherapy.

Our transducer, designed and built at U-M, delivers high amplitude microsecond-length ultrasound pulses—acoustic cavitation—to focus on the tumor specifically to break it up,” Xu said. “Traditional ultrasound devices use lower amplitude pulses for imaging.”

Source: https://news.umich.edu/

How to Keep Cancer from Returning after Surgery

After surgery to remove tumors, some cancer cells can be left behind where they can grow back or spread to a new part of the body. Researchers at the University of Wisconsin-Madison have now developed a hydrogel that can be applied post-surgery to prevent or slow tumor regrowth. The gel works by releasing two compounds selected to strategically keep cancer from coming back after surgery. First is a drug called Pexidartinib, which is already in use to inhibit tumor-associated macrophages (TAMs). These are immune cells that have, for unclear reasons, “switched sides” and now contribute to creating a pro-cancer environment. As such, inhibiting these TAMs slows the growth (or regrowth) of cancer.

A microscope image of the hydrogel (teal) containing platelets with antibodies (red) and tumor-fighting drug nanoparticles (green)

The second component is made up of PD-1 antibodies, which help train T cells to recognize and attack cancer cells. These are bound to platelets for stability. Together, the two components prevent the formation of a microenvironment that’s favorable to cancer growth, and help the immune system clear out any cancer cells remaining after surgery. After its work is done, the gel is designed to biodegrade safely in the body.

The researchers tested the gel in mouse models of several different types of cancers, including colon cancer, melanoma, sarcoma, and triple negative breast cancer. The gel significantly reduced recurrence and metastasis of the cancer, and extended the survival rates of the mice – all control animals succumbed within 36 days, while survival rates ranged between 50 and 66 percent for treated mice, depending on the type of cancer.

The local application of the gel also helps prevent side effects that can arise if a drug is delivered system-wide. As such, no major side effects were seen in the test mice. Importantly, the team says that some of these cancers don’t usually respond well to immune therapy, and are prone to metastasizing, so the effectiveness of the gel treatment is encouraging.

We are really glad to see that this local strategy can work against so many different kinds of tumors, especially these non-immunogenic tumors,” said Quanyin Hu, lead researcher on the study. “We are even more glad to see this local treatment can inhibit tumor metastasis.”

Source: https://newatlas.com/

Tiny Bubbles Destroy Tumours in Seven Minutes

Following her diagnosis with liver cancer last June, 68-year-old Sheila Riley braced herself for painful and gruelling treatmentsSurgery, chemotherapy, radio-therapy and even ablation — where heat is used to destroy tumours — are some of medicine’s most effective tools against cancer, but the potential side-effects can be hard to bear. In fact, Sheila was spared these thanks to a radical new form of therapy that uses tiny bubbles of gas to destroy tumours within minutes and doesn’t leave a mark on the body. She was one of the first patients in the UK to undergo histotripsy, where focused ultrasound waves are directed from outside the body to destroy tumours by generating thousands of exploding gas bubbles. So rapid is the procedure that her tumour was obliterated painlessly — in under seven minutes.

It was amazing,’ says the grandmother of eight, who had the treatment last August at St James’s University Hospital in Leeds. ‘I didn’t need any medication — not even painkillers afterwards,’ adds Sheila, who lives in Bradford with her partner Frank, 70. ‘I was able to go shopping the next day, and two days after my treatment I was out with friends. It didn’t even leave a mark on my skin.

It is now hoped the procedure can help those with tumours in other parts of the bodyHistotripsy was pioneered by researchers at the University of Michigan in the U.S. and relies on a process called cavitation — creating an empty space inside something solid — to eradicate cancer. First, a beam of ultrasound energy is directed through the skin to the tumour site. As the beam hits the targeted spot, it activates thousands of pockets of gas that occur naturally in tissue throughout the body, even tumours, as a result of the respiratory process. These tiny pockets of gas are usually dormant, but when blasted with the sound waves, they expand, vibrate and explode, forming a high-energy cloud of microbubbles in the tumour. As they rapidly expand and collapse, the bubbles break up surrounding cancerous tissue, liquifying it into a solution that then gets passed out of the body as waste.

Unlike existing treatments such as microwave ablation, where a heat-generating probe is used to ‘cook’ tumour cells, there is no heat that might damage surrounding healthy tissue, making cavitation potentially safer. This capacity for ultrasound to destroy tissue has been known about for years but was not previously adopted as a cancer treatment because it was too difficult to control the bubble clouds and avoid damaging healthy tissue.

However, the process has now been fine-tuned and the energy source can be better directed inside the tumour, avoiding the risk of nearby healthy tissue or organs being affected. An international trial is now under way looking at histotripsy for liver cancer. The chief investigator, Professor Tze Min Wah, a senior consultant interventional radiologist at St James’s University Hospital, believes cavitation could transform cancer treatment. ‘Rather than using heat, radiation or surgery to remove the tumour, the bubble cloud created by histotripsy is so powerful that it ruptures the tumour but doesn’t damage the tissue around it,’ she says.

Source: https://www.dailymail.co.uk/