Rice University and Baylor College of Medicine researchers have shown they can seradicate advanced-stage mesothelioma tumor in mice in just a few days with a treatment combining Rice’s cytokine “drug factory” implants and a checkpoint inhibitor drug.

The researchers administered the drug-producing beads, which are no larger than the head of a pin, next to tumors where they could produce continuous, high doses of interleukin-2 (IL-2), a natural compound that activates white blood cells to fight cancer. The study, published online today in Clinical Cancer Research, is the latest in a string of successes for the drug-factory technology invented in the lab of Rice bioengineer Omid Veiseh, including Food and Drug Administration (FDA) approval to begin clinical trials of the technology this fall in ovarian cancer patients.

“From the beginning, our objective was to develop a platform therapy that can be used for multiple different types of immune system disorders or different types of cancers,” said Rice graduate student Amanda Nash, who spent several years developing the implant technology with study co-lead author Samira Aghlara-Fotovat, a fellow student in Veiseh’s lab.

The cytokine factories consist of alginate beads loaded with tens of thousands of cells that are genetically engineered to produce natural IL-2, one of two cytokines the FDA has approved for treatment of cancer. The factories are just 1.5 millimeters wide and can be implanted with minimally invasive surgery to deliver high doses of IL-2 directly to tumors. In the mesothelioma study, the beads were placed beside tumors and inside the thin layer of tissue known as the pleura, which covers the lungs and lines the interior wall of the chest.

“I take care of patients who have malignant pleural mesothelioma,” said Dr. Bryan Burt, professor and chief of Baylor’s Division of Thoracic Surgery in the Michael E. DeBakey Department of Surgery. “This is a very aggressive malignancy of the lining of the lungs. And it’s very hard to treat completely by surgical resection. In other words, there is often residual disease that is left behind. The treatment of this residual disease with local immunotherapy — the local delivery of relatively high doses of immunotherapy to that pleural space — is a very attractive way to treat this disease.”

Veiseh said the mesothelioma study began when Burt and Baylor surgeon and associate professor Dr. Ravi Ghanta heard about the early results of ovarian cancer animal tests Veiseh’s team was conducting with collaborators at the University of Texas MD Anderson Cancer Center. In March, Veiseh and MD Anderson collaborators published a study showing IL-2-producing beads could eradicate advanced-stage ovarian and colorectal tumors in mice in less than a week.

“They were really impressed by the preclinical data we had in ovarian cancer,” Veiseh said of Burt and Ghanta. “And they asked the question, ‘Could we actually leverage the same system for mesothelioma?’”

Source: https://blogs.bcm.edu/

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 cells. Whitehead’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/

Rice University bioengineers have shown they can eradicate advanced-stage ovarian and colorectal cancer in mice in as little as six days with a treatment that could be ready for human clinical trials later this year. The researchers used implantable “drug factories” the size of a pinhead to deliver continuous, high doses of interleukin-2, a natural compound that activates white blood cells to fight cancer. The drug-producing beads can be implanted with minimally invasive surgery. Each contains cells engineered to produce interleukin-2 that are encased in a protective shell.

The treatment and animal test results are described online today in a Science Advances study co-authored by Omid Veiseh, Amanda Nash and colleagues from Rice, the University of Texas MD Anderson Cancer Center, the University of Virginia and others.

Veiseh, an assistant professor of bioengineering whose lab produced the treatment, said human clinical trials could begin as soon as this fall because one of his team’s key design criteria was helping cancer patients as quickly as possible. The team chose only components that had previously proven safe for use in humans, and it has demonstrated the safety of the new treatment in multiple tests.

Rice University bioengineers Amanda Nash (left) and Omid Veiseh with vials of bead-like “drug factories” they created to treat cancer. The beads are designed to continuously produce natural compounds that program the immune system to attack tumors. 

“We just administer once, but the drug factories keep making the dose every day, where it’s needed until the cancer is eliminated,” Veiseh said. “Once we determined the correct dose — how many factories we needed — we were able to eradicate tumors in 100% of animals with ovarian cancer and in seven of eight animals with colorectal cancer.”

In the newly published study, researchers placed drug-producing beads beside tumors and within the peritoneum, a sac-like lining that supports intestines, ovaries and other abdominal organs. Placement within this cavity concentrated interleukin-2 within tumors and limited exposure elsewhere. “A major challenge in the field of immunotherapy is to increase tumor inflammation and anti-tumor immunity while avoiding systemic side effects of cytokines and other pro-inflammatory drugs,” said study co-author Dr. Amir Jazaeri, professor of gynecologic oncology and reproductive medicine at MD Anderson. “In this study, we demonstrated that the ‘drug factories’ allow regulatable local administration of interleukin-2 and eradication of tumor in several mouse models, which is very exciting. This provides a strong rationale for clinical testing.”

Source: https://news.rice.edu/

In 2010, three patients received an experimental form of immunotherapy for leukemia through a clinical trial at the University of Pennsylvania. Two of the patients went into complete remission—and stayed that way.  The treatment, known as CAR T-cell therapy, is now FDA-approved to treat certain blood cancers. It involves engineering a patient’s own white blood cells to attack cancerous cells and then returning them to the body. Since clinical trials and FDA approval, CAR T-cell therapy has already been used to successfully treat and clear certain cancers. However, CAR T-cell therapy doesn’t lead to lasting remissions for every patient, and it can cause serious side effects. A new report offers clues about why the treatment is sometimes remarkably effective.

The two patients who responded well to CAR T-cell therapy in 2010 remained disease free for over a decade. One of the men, a Californian named Doug Olson, is now 75. The other, William Ludwig, died early last year of COVID-19. Researchers were able to detect CAR T-cells lingering in Olson and Ludwig’s bloodstreams long after their cancers disappeared, although the types of immune cells that persisted were slightly different than anticipated, the team reported in Nature.

Two T-cells (red) attack an oral squamous cancer cell (white)—a fight that’s part of the natural immune response. Clinical researchers are developing a new type of therapy that modifies a patient’s T-cells to better attack cancer

“Now we can finally say the word ‘cure’ with CAR T-cells,” Carl June, the principal investigator for the University of Pennsylvania trial, told The New York Times.

Olson and Ludwig were among the earliest recipients of CAR T-cell therapy, allowing clinicians a chance to track the patients’ cells and condition over the past decade. “To use the word ‘cure,’ you really need a long time to follow up to make sure people don’t relapse,” says David Maloney, the medical director of cellular immunotherapy at the Immunotherapy Integrated Research Center at the Fred Hutchinson Cancer Research Center in Seattle. “When we get these people out to 10 and 11 years post-treatment, that encourages us to be a little more forceful in saying that perhaps patients are cured in some cases.”

Source: https://www.popsci.com/

Brigham and Women’s Hospital will test the safety and efficacy of a nasal vaccine aimed at preventing and slowing Alzheimer’s disease, the Boston hospital announced Tuesday. The start of the small, Phase I clinical trial comes after nearly 20 years of research led by Howard L. Weiner, MD, co-director of the Ann Romney Center for Neurologic Diseases at the hospital.

The trial will include 16 participants between the ages of 60 and 85, all with early symptomatic Alzheimer’s but otherwise generally healthy. They will receive two doses of the vaccine one week apart, the hospital said in a press release. The participants will enroll from the Ann Romney Center.

A Phase I clinical trial is designed to establish the safety and dosage for a potential new medication. If it goes well, a much larger trial would be needed to test its effectiveness. The vaccine uses a substance called Protollin, which stimulates the immune system. “Protollin is designed to activate white blood cells found in the lymph nodes on the sides and back of the neck to migrate to the brain and trigger clearance of beta amyloid plaques — one of the hallmarks of AD [Alzheimer’s disease],” the hospital explains. It notes that Protollin has been found to be safe in other vaccines.

“The launch of the first human trial of a nasal vaccine for Alzheimer’s is a remarkable milestone,” said Weiner in the hospital’s press release. “Over the last two decades, we’ve amassed preclinical evidence suggesting the potential of this nasal vaccine for AD. If clinical trials in humans show that the vaccine is safe and effective, this could represent a nontoxic treatment for people with Alzheimer’s, and it could also be given early to help prevent Alzheimer’s in people at risk.”

The researchers say they aim to “determine the safety and tolerability of the nasal vaccine” in the trial and observe how Protollin affects participants’ immune response, including how it affects their white blood cells.

“The immune system plays a very important role in all neurologic diseases,” Weiner added. “And it’s exciting that after 20 years of preclinical work, we can finally take a key step forward toward clinical translation and conduct this landmark first human trial.”

Source: brighamandwomens.org
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https://www.cbsnews.com/

White blood cells called eosinophils can be “summoned” in order to fight cancer by both destroying the cancer cells directly as well as recruiting the immune system’s cancer-fighting T-cells, according to a new study published in the journal of the American Association for Cancer Research.

Eosinophils produce powerful destructive proteins intended for fighting parasites. However, in the modern Western world, where high levels of hygiene have significantly reduced the risk of many parasites, eosinophils can be harmful, inducing allergies and asthma. Considering the destructive power of eosinophils, the researchers decided to test the potential benefits of these white blood cells if turned against cancer cells.

Examining tissue samples of lung metastases taken from breast cancer patients, the researchers found that eosinophils reach the lungs and penetrate cancerous tissues, where they often release their destructive proteins and summon T-cells for reinforcement. Ultimately, T-cells gather in the affected lungs, slowing the growth of tumors. In the absence of eosinophils, lung metastases were much larger than those exposed to the white blood cells. These findings led to the conclusion that eosinophils could serve as a basis for improved immunotherapeutic medications to fight cancer effectively.

An eosinophil, a type of white blood cell. A new study shows these cells can be “summoned” to fight cancer

“We chose to focus on lung metastases for two main reasons. First, metastases, and not the primary tumors, are often the main problem in treating cancer, and the lungs are a major target for the metastasis of many types of cancer,” said lead researcher, professor Ariel Munitz of Tel Aviv University’s department of microbiology and clinical immunology.
“Second, in a preliminary study we demonstrated that eosinophils gather in tumors developing in mucous tissues like the lungs, and therefore assumed that they would be found in lung metastases as well,”  he said.  Compared to traditional techniques, immunotheraphy generally leads to longer protection from cancer and fewer side effects. This new discovery may contribute to the development of new methods of immunotherapy. “Enhancing the number and power of T-cells is one of the main targets of immunotherapy treatments administered to cancer patients today,” said Munitz.

Source: https://www.zenger.news

The aging global population is the greatest challenge faced by 21st-century healthcare systems. Even COVID-19 is, in a sense, a disease of aging. The risk of death from the virus roughly doubles for every nine years of life, a pattern that is almost identical to a host of other illnesses. But why are old people vulnerable to so many different things?

It turns out that a major hallmark of the aging process in many mammals is inflammation. By that, I don’t mean intense local response we typically associate with an infected wound, but a low grade, grinding, inflammatory background noise that grows louder the longer we live. This “inflammaging” has been shown to contribute to the development of atherosclerosis (the buildup of fat in arteries), diabetes, high blood pressure , frailty, cancer and cognitive decline.

Now a new study published in Nature reveals that microglia — a type of white blood cells found in the brain — are extremely vulnerable to changes in the levels of a major inflammatory molecule called prostaglandin E2 (PGE2). The team found that exposure to this molecule badly affected the ability of microglia and related cells to generate energy and carry out normal cellular processes.

Fortunately, the researchers found that these effects occurred only because of PGE2’s interaction with one specific receptor on the microglia. By disrupting it, they were able to normalize cellular energy production and reduce brain inflammation. The result was improved cognition in aged mice. This offers hope that the cognitive impairment associated with growing older is a transient state we can potentially fix, rather than the inevitable consequence of aging of the brain. Levels of PGE2 increase as mammals age for a variety of reasons — one of which is probably the increasing number of cells in different tissues entering a state termed cellular senescence. This means they become dysfunctional and can cause damage to tissue by releasing PGE2 and other inflammatory molecules.

But the researchers also found that macrophages — another type of white blood cells related to microglia — from people over the age of 65 made significantly more PGE2 than those from young people. Intriguingly, exposing these white blood cells to PGE2 suppressed the ability of their mitochondria — the nearest thing a cell has to batteries — to function. This meant that the entire pattern of energy generation and cellular behavior was disrupted.

Although PGE2 exerts its effects on cells through a range of receptors, the team were able to narrow down the effect to interaction with just one type (the “EP2 receptor” on the macrophages). They showed this by treating white blood cells, grown in the lab, with drugs that either turned this receptor on or off. When the receptor was turned on, cells acted as if they had been exposed to PGE2. But when they were treated with the drugs that turned it off, they recovered. That’s all fine, but it was done in a petri dish. What would happen in an intact body?

The researchers took genetically modified animals in which the EP2 receptor had been removed and allowed them to grow old. They then tested their learning and memory by looking at their ability to navigate mazes (something of a cliche for researchers) and their behavior in an “object location test.” This test is a bit like someone secretly entering your house, swapping your ornaments around on the mantelpiece and then sneaking out again. The better the memory, the longer the subject will spend looking suspiciously at the new arrangement, wondering why it has changed.

It turned out that the old genetically modified mice learned and remembered just as well as their young counterparts. These effects could be duplicated in normal old mice by giving them one of the drugs that could turn the EP2 receptor off for one month. So it seems possible that inhibiting the interaction of PGE2 with this particular receptor may represent a new approach to treating late-life cognitive disorders.

Source: https://www.theconversation.com/

White blood cells, which release a toxic potion of proteins to kill cancerous and virus-infected cells, are protected from any harm by the physical properties of their cell envelopes, find scientists from UCL and the Peter MacCallum Cancer Centre in Melbourne. Until now, it has been a mystery to scientists how these white blood cells – called cytotoxic lymphocytes – avoid being killed by their own actions and the discovery could help explain why some tumours are more resistant than others to recently developed cancer immunotherapies.

The research, published in Nature Communications, highlights the role of the physical properties of the white blood cell envelope, namely the molecular order and electric charge, in providing such protection.

“Cytotoxic lymphocytes, or white blood cells, rid the body of disease by punching holes in rogue cells and by injecting poisonous enzymes inside. Remarkably, they can do this many times in a row, without harming themselves. We now know what effectively prevents these white blood cells from committing suicide every time they kill one of their targets,” according to Professor Bart Hoogenboom (London Centre for Nanotechnology, UCL Physics & Astronomy and UCL Structural & Molecular Biology), co-author of the study.

The scientists made the discovery by studying perforin, which is the protein responsible for the hole-punching. They found that perforin’s attachment to the cell surface strongly depends on the order and packing of the molecules – so-called lipids – in the membrane that surrounds and protects the white blood cells.

Source: https://www.ucl.ac.uk/

For the first time in the United States, a gene editing tool has been used to treat advanced cancer in three patients and showed promising early results in a pilot phase 1 clinical trial. So far the treatment appears safe, and more results are expected soon. To develop a safer and more effective treatment for cancer patients, scientists from the University of Pennsylvania, the Parker Institute for Cancer Immunotherapy in San Francisco and Tmunity Therapeutics, a biotech company in Philadelphia, developed an advanced version of immunotherapy. In this treatment, a patient’s own immune cells are removed from the body, trained to recognize specific cancer cells and then finally injected back into the patient where they multiply and destroy them.

Unlike chemotherapy or radiation therapy, which directly kills cancer cells, immunotherapy activates the body’s own immune system to do the work. This team used a gene editing tool called CRISPR to alter immune cells, turning them into trained soldiers to locate and kill cancer cells. By using this technique, the team hoped to develop a more effective form of immunotherapy with minimal side effects.

Better CRISPR-based gene editors for the diagnosis and treatment of cancer and other disorders, . combining chemistry, biology and nanotechnology, are used to engineer, control and deliver gene editing tools more efficiently and precisely.

The first step in making these tumor-killing cells used in the cancer drug trial was to isolate the T-cells – a type of white blood cells that fights pathogens and cancer cells – from the blood of the cancer patients. Two patients with advanced multiple myeloma and one patient with myxoid/round cell liposarcomav were enrolled for this study.

To arm the T-cells and bolster their tumor-fighting skills without harming normal cells, scientists genetically engineered the T-cells – disabling three genes and adding one gene – before returning them to the patients.

The first two of these deleted genes encode T-cell receptors, which are proteins found on the surface of the T-cells that can recognize and bind specific molecules, known as antigens, on cancer cells. When these engineered T-cells bind to these antigens, it allows them to attack and directly kill the cancer cells. But the problem is that a single T-cell can recognize multiple different antigens in the body, making them less focused on finding the cancer cells. By eliminating these two genes, the T-cells are less likely to attack the wrong target or the host, a phenomenon called autoimmunity, In addition, they disrupted a third gene, called programmed cell death protein 1, which slows down the immune response. Disabling the programmed cell death protein 1 gene improves the efficiency of T-cells.

The final step in the transformation of these cells was adding a gene which produces a new T-cell receptor that recognizes and grabs onto a specific marker on the cancer cells called NY-ESO-1. With three genes deleted and one added, the T-cells are now ready to fight cancer.

Source: https://theconversation.com/

Ground-breaking immune therapy promises to deliver vital evidence in the fight against cancer as researchers from the Centre for Cancer Biology in Australia open a new clinical trial using genetically engineered immune cells to treat solid cancers. The phase 1 clinical trial will test the feasibility and safety of CAR-T cells – genetically modified white blood cells harvested from a patient’s own blood with the unique ability to directly attack and kill cancers – to treat advanced solid tumours including small cell lung cancer, sarcomas and triple negative breast cancer.

The new clinical trial will allow researchers to learn more about how CAR-T cells interact with solid tumours in the hope that this form of immune-based therapy may one day treat a wide range of different cancers. Led by the Centre for Cancer Biology – an alliance between University of South Australia (UniSA), the Central Adelaide Local Health Network (CALHN) and the Royal Adelaide Hospital, the trial is funded by Cancer Council’s Beat Cancer Project and sponsored by CALHN.

The research scientist in charge of manufacturing the CAR-T cell product and following the patients’ responses to treatment is UniSA’s Dr Tessa Gargett, a Cancer Council Beat Cancer Project Early Career Fellow from the Centre for Cancer Biology .She says the CAR-T immune therapy shows great potential for developing cancer treatments.

“Chimeric antigen receptor (CAR) T cells are a promising new technology in the field of cancer immunotherapy,” Dr Gargett says. “Essentially, CAR-T cells are super-powered immune cells which work by enlisting and strengthening the power of a patient’s immune system to attack tumours. “They’ve had astounding results in treating some forms of chemotherapy-resistant blood cancers, but similar breakthroughs are yet to be achieved for solid cancers – that’s where this study comes in.”

Source: https://www.unisa.edu.au/