mRNA Vaccine to Prevent Colorectal Cancer Recurrence

The COVID-19 vaccines mark the first widespread use of mRNA technology. They work by using synthetic genetic code to instruct the patient’s cells to recognize the coronavirus and activate the immune system against the virus. But researchers began exploring how to use mRNA vaccines as a new way to treat cancer long before this technology was used against the coronavirus.

A B-cell displaying antibodies created in response to foreign protein fragments produced from a personalized mRNA vaccine recognizes a colorectal cancer cell and signals killer T-cells to destroy it

We’ve known about this technology for a long time, well before COVID-19,” says Van Morris, M.D. Here, he explains how mRNA vaccines work and how a team of MD Anderson colorectal cancer experts led by Scott Kopetz, M.D., Ph.D., are testing the technology in a Phase II clinical trial, following high-risk patients with stage II or stage III colorectal cancer who test positive for circulating tumor DNA after surgery.

The presence of circulating tumor DNA is checked with a blood test. “If there is ctDNA present, it can mean that a patient is at higher risk for the cancer coming back,” Morris says. The opposite can also be true: if there is not circulating tumor DNA present, the patient may have a lower risk of recurrence, he adds.

In the Phase II clinical trial, enrolled patients start chemotherapy after the tumor is surgically removed. Tissue from the tumor is sent off to a specialized lab, where it’s tested to look for genetic mutations that fuel the cancer’s growth. Morris explains anywhere from five to 20 mutations specific to that patient’s tumor can be identified during testing. The mutations are then prioritized by the most common to the least common, and an mRNA vaccine is created based on that ranking. “Each patient on the trial receives a personalized mRNA vaccine based on their individual mutation test results from their tumor.

As with the COVID-19 vaccines, the mRNA instructs the patient’s cells to produce protein fragments based off tumor’s genetic mutations identified during testing. The immune system then searches for other cells with the mutated proteins and clears out any remaining circulating tumor cells.We’re hopeful that with the personalized vaccine, we’re priming the immune system to go after the residual tumor cells, clear them out and cure the patient,” says Morris.

Source: https://www.mdanderson.org/

Targeted delivery of therapeutic RNAs directly to cancer cells

Tel Aviv University‘s groundbreaking technology may revolutionize the treatment of cancer and a wide range of diseases and medical conditions. In the framework of this study, the researchers were able to create a new method of transporting RNA-based drugs to a subpopulation of immune cells involved in the inflammation process, and target the disease-inflamed cell without causing damage to other cells.

The study was led by Prof. Dan Peer, a global pioneer in the development of RNA-based therapeutic delivery. He is Tel Aviv University‘s Vice President for Research and Development, head of the Center for Translational Medicine and a member of both the Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, and the Center for Nanoscience and Nanotechnology. The study was published in the prestigious scientific journal Nature Nanotechnology.

Our development actually changes the world of therapeutic antibodies. Today we flood the body with antibodies that, although selective, damage all the  that express a specific receptor, regardless of their current form. We have now taken out of the equation  that can help us, that is, uninflamed cells, and via a simple injection into the bloodstream can silence, express or edit a particular gene exclusively in the cells that are inflamed at that given moment,” explains Prof. Peer.

As part of the study, Prof. Peer and his team were able to demonstrate this groundbreaking development in animal models of inflammatory bowel diseases such as Crohn’s disease and colitis, and improve all inflammatory symptoms, without performing any manipulation on about 85% of the immune system cells. Behind the innovative development stands a simple concept, targeting to a specific receptor conformation. “On every cell envelope in the body, that is, on the , there are receptors that select which substances enter the cell,” explains Prof. Peer. “If we want to inject a drug, we have to adapt it to the specific receptors on the , otherwise it will circulate in the bloodstream and do nothing. But some of these receptors are dynamic—they change shape on the membrane according to external or internal signals. We are the first in the world to succeed in creating a drug delivery system that knows how to bind to receptors only in a certain situation, and to skip over the other identical cells, that is, to deliver the drug exclusively to cells that are currently relevant to the disease.”

Source: https://phys.org/

Early Cancer Detection Test

Mayo Clinic today recognized the debut of a groundbreaking multi-cancer early detection (MCED) test called Galleri™ that can detect more than 50 types of cancers through a simple blood draw. The  Galleri test is intended  to complement U.S. guideline-recommended cancer screenings.

Mayo Clinic Oncologist Minetta Liu, M.D. was involved in the development of the new test. “Today, many cancers are found too late, leading to poor outcomes,” says Dr. Liu. “The ability to detect cancer early is critical to successful treatment.”

Cancer is expected to become the leading cause of death in the U.S. this year. Currently recommended cancer screening tests only cover five cancer types and screen for a single cancer at a time. In fact, there are no recommended early detection screening tests for other cancers, which account for 71% of cancer deaths.

Researchers used the Galleri test in the Circulating Cell-free Genome Atlas (CCGA) Study, a prospective, observational, longitudinal study designed to characterize the landscape of genomic cancer signals in the blood of people with and without cancer. In the study, the Galleri test demonstrated the ability to detect more than 50 types of cancers — over 45 of which have no recommended screening tests today — with a low false-positive rate of less than 1%.

According to Dr. Liu, when a cancer signal is detected, the Galleri test can identify where in the body the cancer is located with high accuracy — a critical component to help enable health care providers to direct diagnostic next steps and care.

We are grateful to Mayo Clinic for its dedication to advancing new technologies for early cancer detection and for playing a pivotal role in the development of Galleri,” says Dr. Josh Ofman, chief medical officer and head of external affairs at GRAIL.“A simple blood test capable of detecting more than 50 cancers is a ground-breaking advancement and could have a tremendous human and economic benefit.

Initial results from the interventional PATHFINDER Study, which involved the return of Galleri test results to providers to communicate to participants, were presented today at the 2021 American Society of Clinical Oncology Annual Meeting. They demonstrate Galleri’s performance in the clinical setting was consistent with findings from previous observational studies, underscoring the potential real-world ability of Galleri to find deadly cancers earlier.

Source: https://individualizedmedicineblog.mayoclinic.org/

Nkarta and CRISPR Therapeutics Develop Natural Killer Cell Cancer Treatments

Biopharmaceutical company CRISPR Therapeutics has entered into a strategic research, development and commercialization partnership with cancer-focused Nkarta. The new collaboration will be geared toward advancing CRISPR/Cas9 gene-edited cell therapies for certain cancers.

In a statement on the collaboration, the companies state “their complementary cell therapy engineering and manufacturing capabilities” will join forces to advance “the development of a novel NK+T product candidate harnessing the synergies of the adaptive and innate immune systems.” Financial details of the agreement were not publicly disclosed.

According to terms of the agreement, both CRISPR Therapeutics and Nkarta plan to jointly develop and commercialize up to two CAR NK cell product candidates. One candidate will target the CD70 tumor antigen, while no specific target has been set for the additional product. Nkarta has obtained a license to CRISPR gene-editing technology under the agreement. This license will allow Nkarta to edit up to five gene targets using “an unlimited number” of the company’s own NK cell therapy products.

Additionally, the two companies will share equally the research and development costs as well as global profits related to the products born from the collaboration. While Nkarta will retain global rights to a product candidate using a CRISPR Therapeuticsgene editing target but not developed through the collaboration, Nkarta will provide CRISPR Therapeutics milestone payments as well as royalties on all net sales of the non-collaboration product.

There is a three-year exclusivity on the new agreement, according to the announcement of the collaboration. Overall, the exclusivity agreement covers the research, development as well as commercialization of allogeneic, gene-edited, and donor-derived NK cells and NK+T cells. “This collaboration broadens the scope of our efforts in oncology cell therapy, and expands our efforts to discover and develop novel cancer therapies for patients,” according to a statement made by CRISPR Therapeutics’ Chief Executive Officer (CEO), Samarth Kulkarni, Ph.D.

Uniting the best-in-class gene editing solution and allogeneic T cell therapy expertise of CRISPR with Nkarta’s best-in-class CAR NK cell therapy platform will be a major advantage to advancing the next wave of transformative cancer cell therapies,” said Nkarta’s CEO, Paul J. Hastings, in a statement. Hastings added that the partnership will enable the company to harness CRISPR’s deep knowledge of CD70 biology as well as experience in the clinical development of allogeneic T cell candidates, which may ultimately “deliver innovative treatments to patients that much faster.

https://www.biospace.com/

RNA Could Be The Future of Cancer Treatment

Cells are the basic building blocks of all living things. So, in order to treat or cure almost any disease or condition – including cancer – you first need to have a fundamental understanding of cell biology. While researchers have a pretty good understanding of what each component of a cell does, there are still things we don’t know about them – including the role that some RNAs molecules play in a cell.

Finding the answer to this may be key in developing further cancer treatments, which is what our research has sought to uncover. Three types of molecules carry information in a cell, and each of these molecules performs its own important function. The first is DNA, which contains hard-wired genetic information (like a book of instructions). . The second, RNA, is a temporary copy of one particular instruction that is derived from DNA. Last are the proteins produced thanks to the information provided by the RNA. These proteins are the “workhorses” of the cells, which perform specific functions, such as helping cells move, reproduce, and generate energy.

In line with this model, RNA has long been seen as nothing more than an intermediary between DNA and proteins. But researchers are starting to discover that RNA is much more than an intermediary. In fact, this overlooked molecule may hold the secret to cancer progression. The scientists group recently discovered a new type of RNA that drives cancer progression without producing any protein. We think that this type of discovery may pave the way for an entirely new way of targeting cancer cells. But to understand how this is possible, it’s first important to know the different types of RNA we have in our body. Only about 1% of DNA is copied into RNAs that make proteins. Other RNAs help the production of proteins. The rest (known as non-coding RNAs) were long assumed to serve no function in the human body. But recent studies are challenging these assumptions, showing these “uselessRNAs actually performvery specific purpose. In fact, these “non-coding” RNAs regulate the functions of many genes, thereby controlling key aspects of the cells’ lives (such as their ability to move around).

The most abundant type of non-coding RNAs are long non-coding RNAs (lncRNAs). These are long molecules which interact with many different molecules in the cell. And, as researchers have now discovered, these complex structures allow many different functions to take place between cells.

For example, some lncRNAsgrab” different proteins and gather them to work in a specific cellular space – such as the same gene segment. This function is essential for controlling the inactivation of some genes during development.

Source: https://nationalinterest.org/

How to Completely Wipe out Colon Cancer in Anybody Who Gets Screened

Michael Wallace has performed hundreds of colonoscopies in his 20 years as a gastroenterologist. He thinks he’s pretty good at recognizing the growths, or polyps, that can spring up along the ridges of the colon and potentially turn into cancer. But he isn’t always perfect. Sometimes the polyps are flat and hard to see. Other times, doctors just miss them. “We’re all humans,” says Wallace, who works at the Mayo Clinic. After a morning of back-to-back procedures that require attention to minute details, he says, “we get tired.”

Colonoscopies, if unpleasant, are highly effective at sussing out pre-cancerous polyps and preventing colon cancer. But the effectiveness of the procedure rests heavily on the abilities of the physician performing it. Now, the Food and Drug Administration has approved a new tool that promises to help doctors recognize precancerous growths during a colonoscopy: an artificial intelligence system made by Medtronic. Doctors say that alongside other measures, the tool could help improve diagnoses.

 

We really have the opportunity to completely wipe out colon cancer in anybody who gets screened,” says Wallace, who consulted with Medtronic on the project.

The Medtronic system, called GI Genius, has seen the inside of more colons than most doctors. Medtronic and partner Cosmo Pharmaceuticals trained the algorithm to recognize polyps by reviewing more than 13 million videos of colonoscopies conducted in Europe and the US that Cosmo had collected while running drug trials. To “teach” the AI to distinguish potentially dangerous growths, the images were labeled by gastroenterologists as either normal or unhealthy tissue. Then the AI was tested on progressively harder-to-recognize polyps, starting with colonoscopies that were performed under perfect conditions and moving to more difficult challenges, like distinguishing a polyp that was very small, only in range of the camera briefly, or hidden in a dark spot. The system, which can be added to the scopes that doctors already use to perform a colonoscopy, follows along as the doctor probes the colon, highlighting potential polyps with a green box. GI Genius was approved in Europe in October 2019 and is the first AI cleared by the FDA for helping detect colorectal polyps. “It found things that even I missed,” says Wallace, who co-authored the first validation study of GI Genius. “It’s an impressive system.”

Source: https://www.wired.com/

New Blood Test Could Replace Biopsies

No one enjoys getting a biopsy, in which a tissue sample is surgically taken and analyzed in a lab for signs of disease, such as cancer. It’s not only unpleasant for the patient, but has clinical drawbacks: A biopsy doesn’t always extract the diseased tissue and isn’t helpful in detecting disease at early stages. These concerns have encouraged researchers to find less invasive and more accurate diagnostic methods. Prof. Nir Friedman and Ronen Sadeh of the Hebrew University of Jerusalem have developed a blood test that enables lab technicians to diagnose cancer and diseases of the heart and liver by identifying and determining the state of the dead cells throughout the body.

Millions of cells die every day and are replaced by new cells. When cells die, their DNA is fragmented. Some of these DNA fragments reach the blood and can be “read” by advanced DNA sequencing methods.

As a result of these scientific advancements, we understood that if this information is maintained within the DNA structure in the blood, we could use that data to determine the tissue source of dead cells and the genes that were active in those very cells. Based on those findings, we can uncover key details about the patient’s health,” Friedman said.

We are able to better understand why the cells died — whether it’s an infection or cancer — and based on that, be better positioned to determine how the disease is developing,” he said. Co-author Israa Sharkia added the simple blood test could “be administered often and quickly, allowing the medical staff involved to follow the presence or development of a disease more closely.”

A startup company, Senseera, has been established to pursue clinical testing of this innovative approach in partnership with major pharmaceutical companies.

The multi-author study published in Nature Biotechnology explains the test can even identify markers that may differentiate between patients with similar tumors, which could help physicians develop personalized treatments.

Source: https://www.zenger.news/

A Protein that Can Melt Tumors Discovered

For the second time, cancer researchers at Vanderbilt have discovered a protein that—when genetically manipulated to impede it from interacting with a gene responsible for cancer genesis—effectively melts tumors in days. 

William Tansey, professor of cell and developmental biology, is dedicated to understanding how the oncogene MYC, an  highly conserved, noodle-like protein, works. It performs important functions in normal human development, and it often becomes reactivated in the deadliest and most difficult to treat cancers. 

Conducted experiment shows six tumor sizes grow for 15 days, at which point the MYC–HCF1 interaction is broken. After day 15, the tumors shrink and are gone. Cancer cells are dead by four days. 

MYC becomes the nitro in the tank, driving relentless rounds of cell duplication and division,” Tansey said. “The faster the cells grow and divide, they accumulate mutations, which give rise to cancer growth.” 

MYC has been an elusive drug target for at least 30 years, Tansey says, and has been considered “undruggable” because of its lack of structure. To work around this roadblock, Tansey set out to identify MYC’s more structured partner proteins with the goal of engineering mutations that disrupt the partners’ interactions with MYC that cause cancer growth. “If we can validate the physical contact between MYC and a protein, we can go after it therapeutically,” Tansey explained.  

Tansey and his collaborators have identified the protein Host Cell Factor-1 (HCF1) as a definite candidate for this type of therapeutic development. HCF1 is touched by MYC and is important for stimulating protein synthesis. When a cancer cell with MYC is genetically engineered to no longer interact with HCF1, the cancer cell begins to self-destruct. Developing a therapy that limits this interaction is a hugely promising step in cancer treatment 

The article, “MYC regulates ribosome biogenesis and mitochondrial gene expression programs through interaction with Host Cell Factor-1,” was published in the journal eLIFE on Jan. 8. 

Source: https://news.vanderbilt.edu/

How To Reverse Aging in the Brain

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/

Immune System Killer Cells Controlled By Circadian Rhythms

An analysis of an exhaustive dataset on cells essential to the mammalian immune system shows that our ability to fight disease may rely more heavily on daily circadian cycles than previously assumed.

Malfunctions in , the process that keeps our bodies in tune with the day/night cycles, are increasingly associated with diabetes, cancer, Alzheimer’s, and many other diseases. An investigation published today in Genome Research shows that the activity of macrophagescells within us that seek and destroy intruders like bacteria—may time daily changes in their responses to pathogens and stress through the circadian control of metabolism. In this study, Jennifer Hurley, the Richard Baruch M.D. Career Development Assistant Professor of Biological Sciences at Rensselaer Polytechnic Institute and senior author on this study, and her team investigated how the levels of RNA and proteins in macrophages change over two days.

We have shown there is an incredible amount of circadian timing of macrophage behavior, but the clock is timing macrophages in unexpected ways” said Hurley.

The circadian system is comprised of a set of core clock proteins that anticipate the day/night cycle by causing daily oscillations in levels of enzymes and hormones, and ultimately affecting physiological parameters such as body temperature and the immune response. This molecular clock marks time through a self-regulating cycle of  production and decay. The “positive” element proteins of the clock trigger production of the “negative” element proteins, which in turn block production of positive element proteins until the negative element proteins decay, thus creating a negative feedback cycle that occurs once every 24 hours.

Positive element proteins also regulate fluctuations in a substantial number of gene products, known as messenger RNA or mRNA. Genetic instructions are transcribed from DNA to mRNA, which are then used as a recipe for assembling proteins, the functional building blocks of the cell. It has long been assumed that the levels of each subsequent step could be predicted from the previous. If that were the case, oscillating mRNA would correspond with oscillating levels of cellular proteins, and therefore, if one could track mRNA, they would know what proteins the circadian clock controlled in the cell.

However, this investigation showed that this paradigm may not always be true. The analysis of the macrophage dataset revealed that there was a substantial mismatch between the proteins and mRNAs that are controlled by the circadian clock. This data paralleled research published in Cell Systems in 2018 by the Hurley lab, showing that about 40% of oscillating proteins in the fungus and circadian model system, Neurospora crassa, had no corresponding oscillating mRNA.

But the scale of the difference in macrophages really surprised us,” Hurley said. “Eighty percent of the proteins that oscillate don’t have associated oscillating mRNA in macrophages. That means we were really missing how the clock was timing immunity.”

Source: https://medicalxpress.com/