New frontier in cancer care: Turning blood into living drugs

Immune therapy is the hottest trend in cancer care and its next frontier is creating ‘living drugs’ that grow inside the body into an army that seeks and destroys tumours. Picture: Elaine Thompson

KEN Shefveland’s body was swollen with cancer, treatment after treatment failing until doctors gambled on a radical approach: They removed some of his immune cells, engineered them into cancer assassins and unleashed them into his bloodstream.

Immune therapy is the hottest trend in cancer care and this is its next frontier — creating “living drugs” that grow inside the body into an army that seek and destroy tumours.

Looking in the mirror, Shefveland saw “the cancer was just melting away.”

A month later doctors at the Fred Hutchinson Cancer Research Center couldn’t find any signs of lymphoma in the man’s body.

“Today I find out I’m in full remission — how wonderful is that?” said Shefveland with a wide grin, giving his physician a quick embrace. This experimental therapy marks an entirely new way to treat cancer — if scientists can make it work, safely. Early-stage studies are stirring hope as one-time infusions of supercharged immune cells help a remarkable number of patients with intractable leukaemia or lymphoma.

“It shows the unbelievable power of your immune system,” said Dr David Maloney, Fred Hutch’s medical director for cellular immunotherapy who treated Shefveland with a type called CAR-T cells.

David Maloney of the Fred Hutchinson Cancer Research Center is greeted by patient Ken Shefveland, whose lymphoma was successfully treated with CAR-T cell therapy. Picture: Elaine ThompsonSource:AP

“We’re talking, really, patients who have no other options, and we’re seeing tumours and leukaemia disappear over weeks,” added immunotherapy scientific director Dr Stanley Riddell. But, “there’s still lots to learn.”

T cells are key immune system soldiers. But cancer can be hard for them to spot, and can put the brakes on an immune attack. Today’s popular immunotherapy drugs called “checkpoint inhibitors” release one brake so nearby T cells can strike. The new cellular immunotherapy approach aims to be more potent: Give patients stronger T cells to begin with.

Currently available only in studies at major cancer centres, the first CAR-T cell therapies for a few blood cancers could hit the market later this year in the US.

The country’s Food and Drug Administration is evaluating one version developed by the University of Pennsylvania and licensed to Novartis, and another created by the National Cancer Institute and licensed to Kite Pharma.

CAR-T therapy “feels very much like it’s ready for prime time” for advanced blood cancers, said Dr Nick Haining of the Dana-Farber Cancer Institute and Broad Institute of MIT and Harvard, who isn’t involved in the development.

Now scientists are tackling a tougher next step, what Haining calls “the acid test”: Making T cells target far more common cancers — solid tumours like lung, breast or brain cancer.

Cancer kills about 600,000 Americans a year, including nearly 45,000 from leukaemia and lymphoma. In Australia, cancer is estimated to the cause of more than 47,000 deaths in 2017, according to Cancer Australia statistics.

In this photo taken March 29, 2017, cell production associate Herley Beyene places containers of immune cells in a centrifuge at the Fred Hutchinson Cancer Research Center in Seattle. Researchers are genetically reprogramming patients’ immune cells to create “living drugs” that better seek and destroy cancer. Picture: Elaine ThompsonSource:AP

“There’s a desperate need,” said NCI immunotherapy pioneer Dr Steven Rosenberg, pointing to queries from hundreds of patients for studies that accept only a few. But for all the excitement, there are formidable challenges.

Scientists still are unravelling why these living cancer drugs work for some people and not others.

Doctors must learn to manage potentially life-threatening side effects from an overstimulated immune system. Also concerning is a small number of deaths from brain swelling, an unexplained complication that forced another company, Juno Therapeutics, to halt development of one CAR-T in its pipeline; Kite recently reported a death, too.

And, made from scratch for every patient using their own blood, this is one of the most customised therapies ever and could cost hundreds of thousands of dollars.

“It’s a Model A Ford and we need a Lamborghini,” said CAR-T researcher Dr Renier Brentjens of New York’s Memorial Sloan Kettering Cancer Center, which, like Hutch, has a partnership with Juno.

In Seattle, Fred Hutch offered a behind-the-scenes peek at research underway to tackle those challenges. At a recently opened immunotherapy clinic, scientists are taking newly designed T cells from the lab to the patient and back again to tease out what works best.

“We can essentially make a cell do things it wasn’t programmed to do naturally,” explained immunology chief Dr Philip Greenberg.

“Your imagination can run wild with how you can engineer cells to function better.”

The cell processing facility at the Fred Hutchinson Cancer Research Center where workers create customised cellular immunotherapies for patients.Source:AP

Child living with HIV maintains remission without drugs since 2008

A nine-year-old South African child who was diagnosed with HIV infection at one month of age and received anti-HIV treatment during infancy has suppressed the virus without anti-HIV drugs for eight and a half years, scientists reported today at the 9th IAS Conference on HIV Science in Paris. This case appears to be the third reported instance of sustained HIV remission in a child after early, limited anti-HIV treatment.


Previously, the “Mississippi Baby,” born with HIV in 2010, received anti-HIV treatment beginning 30 hours after birth, stopped therapy around 18 months of age, and controlled the virus without drugs for 27 months before it reappeared in her blood. In 2015, researchers reported that a French child who was born with HIV in 1996, started anti-HIV therapy at age 3 months, and stopped treatment sometime between ages 5.5 and 7 years continued to control the virus without drugs more than 11 years later.

“Further study is needed to learn how to induce long-term HIV remission in infected babies,” said Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). “However, this new case strengthens our hope that by treating HIV-infected children for a brief period beginning in infancy, we may be able to spare them the burden of life-long therapy and the health consequences of long-term immune activation typically associated with HIV disease.”

NIAID funded the clinical trial in which the child received treatment and follow-up monitoring.

The South African child whose case was reported today was definitively diagnosed with HIV infection in 2007 at 32 days of age, and then was enrolled in the NIAID-funded Children with HIV Early Antiretroviral Therapy (CHER) clinical trial. HIV-infected infants in the trial were assigned at random to receive either deferred antiretroviral therapy (ART) or early, limited ART for 40 or 96 weeks. The current child was assigned to the group of 143 infants who received early ART for 40 weeks.

Before starting treatment, the child had very high levels of HIV in the blood (viral load), but after beginning ART at about 9 weeks of age, treatment suppressed the virus to undetectable levels. Investigators halted treatment after 40 weeks and closely monitored the infant’s immune health, and the child has remained in good health during years of follow-up examinations. Although it was not standard practice in South Africa to monitor viral load in people who were not on ART, recent analyses of stored blood samples taken during follow-up showed that the child has maintained an undetectable level of HIV.

When the child was 9-and-a-half years old, investigators conducted thorough laboratory and clinical studies to assess the child’s immune health and the presence of HIV. The scientists detected a reservoir of virus integrated into a tiny proportion of immune cells, but otherwise found no evidence of HIV infection. The child had a healthy level of key immune cells, a viral load that was undetectable by standard assays, and no symptoms of HIV infection. The researchers detected a trace of immune system response to the virus, but found no HIV capable of replicating. The scientists also confirmed that the child does not have genetic characteristics associated with spontaneous control of HIV, suggesting that the 40 weeks of ART provided during infancy may have been key to achieving HIV remission.

“To our knowledge, this is the first reported case of sustained control of HIV in a child enrolled in a randomized trial of ART interruption following treatment early in infancy,” said Avy Violari, F.C.Paed. Dr. Violari co-led the study of the case reported today as well as the CHER trial with Mark Cotton, M.Med., Ph.D. Dr. Violari is head of pediatric research at the Perinatal HIV Research Unit, part of the University of the Witwatersrand in Johannesburg. Dr. Cotton is head of the division of pediatric infectious diseases and director of the family infectious diseases clinical research unit at Stellenbosch University, South Africa.

“We believe there may have been other factors in addition to early ART that contributed to HIV remission in this child,” said Caroline Tiemessen, Ph.D., whose laboratory is studying the child’s immune system. “By further studying the child, we may expand our understanding of how the immune system controls HIV replication.” Dr. Tiemessen is head of cell biology at the Centre of HIV and STIs of the National Institute of Communicable Diseases (NICD) in Johannesburg.

An ongoing NIH clinical trial called IMPAACT P1115 is testing the hypothesis that giving ART to HIV-infected newborns beginning within 48 hours of birth may permit long-term control of HIV replication after treatment is stopped, potentially leading to HIV remission. IMPAACT P1115 began in 2014 and has enrolled close to 400 HIV-exposed infants, 42 of whom are HIV infected, in Argentina, Brazil, Haiti, Malawi, South Africa, Uganda, the United States, Zambia and Zimbabwe. The first children may become eligible to stop ART in late 2017.

NIAID provided funding for the CHER trial as part of a Comprehensive International Program for Research on AIDS-South Africa grant. Additional support was provided by the Medical Research Council Clinical Trials Unit at University College London, the Departments of Health of the Western Cape and Gauteng in South Africa, and ViiV Healthcare. The Eunice Kennedy Shriver National Institute of Child Health and Human Development, also part of NIH, supported continued observation of the children in CHER after the study ended. The EPIICAL Consortium funded the recent analysis of viral load in the children who participated in CHER. The South African Research Chairs Initiative of the Department of Science and Technology and the National Research Foundation of South Africa funded the laboratory studies of the child whose case was reported today.

Reference: A Violari et al. Viral and host characteristics of a child with perinatal HIV-1 following a prolonged period after ART cessation in the CHER trial. 9th IAS Conference on HIV Science, Paris (2017).

Particles That Carry Three Or More Drugs Hold Potential For Targeted Cancer Therapy

Nanoparticles offer a promising way to deliver cancer drugs in a targeted fashion, helping to kill tumors while sparing healthy tissue. However, most nanoparticles that have been developed so far are limited to carrying only one or two drugs.

MIT chemists have now shown that they can package three or more drugs into a novel type of nanoparticle, allowing them to design custom combination therapies for cancer. In tests in mice, the researchers showed that the particles could successfully deliver three chemotherapy drugs and shrink tumors.

In the same study, which appears in the Sept. 14 issue of the Journal of the American Chemical Society, the researchers also showed that when drugs are delivered by nanoparticles, they don’t necessarily work by the same DNA-damaging mechanism as when delivered in their traditional form.

That is significant because most scientists usually assume that nanoparticle drugs are working the same way as the original drugs, says Jeremiah Johnson, the Firmenich Career Development Associate Professor of Chemistry and the senior author of the paper. Even if the nanoparticle version of the drug still kills cancer cells, it’s important to know the underlying mechanism of action when choosing combination therapies and seeking regulatory approval of new drugs, he says.

“People tend to take it as a given that when you put a drug into a nanoparticle it’s the same drug, just in a nanoparticle,” Johnson says. “Here, in collaboration with Mike Hemann, we conducted detailed characterization using an RNA interference assay that Mike developed to make sure the drug is still hitting the same target in the cell and doing everything that it would if it weren’t in a nanoparticle.”

The paper’s lead authors are Jonathan Barnes, a former MIT postdoc; and Peter Bruno, a former MIT graduate student. Other authors are grad students Hung Nguyen and Jenny Liu, former postdoc Longyan Liao, and Michael Hemann, an associate professor of biology and member of MIT’s Koch Institute for Integrative Cancer Research.

Precise control

The new nanoparticle production technique, which Johnson’s lab first reported in 2014, differs from other methods that encapsulate drugs or chemically attach them to a particle. Instead, the MIT team creates particles from building blocks that already contain drug molecules. They can join the building blocks together in a specific structure and precisely control how much of each drug is incorporated.

“We can take any drug, as long as it has a functional group [a group of atoms that allows a molecule to participate in chemical reactions], and we can load it into our particles in exactly the ratio that we want, and have it release under exactly the conditions that we want it to,” Johnson says. “It’s very modular.”

A key advantage is that this approach can be used to deliver drugs that normally can’t be encapsulated by traditional methods.

Using the new particles, the researchers delivered doses of three chemotherapy drugs — cisplatin, doxorubicin, and camptothecin — at concentrations that would be toxic if delivered by injection throughout the body, as chemotherapy drugs usually are. In mice that received this treatment, ovarian tumors shrank and the mice survived much longer than untreated mice, with few side effects.

“Performing combination chemotherapy using these new designer polymer nanoparticles is an exciting new approach to chemotherapeutics, and this polymer platform is particularly promising for its ability to carry a large load of drugs and deliver them in a triggered, controlled manner,” says Todd Emrick, a professor of polymer science and engineering at the University of Massachusetts at Amherst who was not involved in the study.

Unexpected mechanism

Using a method developed by Hemann’s lab, the researchers then investigated how their nanoparticle drugs affect cells. The technique measures cancer drugs’ effects on eight genes that are involved in the programmed cell death often triggered by cancer drugs. This allows scientists to classify the drugs based on which clusters of genes they affect.

“Drugs that damage DNA get clustered into DNA damage-inducing agents, and drugs that inhibit topoisomerases cluster together in another region,” Johnson says. “If you have a drug that you don’t know the mechanism of, you can do this test and see if the drug clusters with other drugs whose actions are known. That lets you make a hypothesis about what the unknown drug is doing.”

The researchers found that nanoparticle-delivered camptothecin and doxorubicin worked just as expected. However, cisplatin did not. Cisplatin normally acts by linking adjacent strands of DNA, causing damage that is nearly impossible for the cell to repair. When delivered in nanoparticle form, the researchers found that cisplatin acts more like a different platinum-based drug known as oxaliplatin. This drug also kills cells, but by a different mechanism: It binds to DNA but induces a different pattern of DNA damage.

The researchers hypothesize that after cisplatin is released from the nanoparticle, via a reaction that kicks off a group known as a carboxylate, the carboxylate group then reattaches in a way that makes the drug act more like oxaliplatin. Many other researchers attach cisplatin to nanoparticles the same way, so Johnson suspects this could be a more widespread issue.

His lab is now working on a new version of the cisplatin nanoparticle that operates according to the same mechanism as regular cisplatin. The team is also developing nanoparticles with different combinations of drugs to test against pancreatic and other types of cancers.

UFC confirms that Jon Jones failed a USADA drugs test before his title fight with Daniel Cormier

The light-heavyweight’s career has been left in tatters by the news Getty
Jon Jones failed a US Anti-Doping Agency test ahead of his light-heavyweight title fight with Daniel Cormier at UFC 214, it has been revealed.

In the early hours of Wednesday morning, the UFC released a statement confirming a story broken on TMZ that Jones, 30, had failed a USADA test for the second time in his career.

“The UFC organization was notified today that the U.S. Anti-Doping Agency (USADA) has informed Jon Jones of a potential Anti-Doping Policy violation stemming from an in-competition sample collected following his weigh-in on July 28, 2017,” the UFC confirmed in a short statement.

“USADA, the independent administrator of the UFC Anti-Doping Policy, will handle the results management and appropriate adjudication of this case involving Jones, as it relates to the UFC Anti-Doping Policy and future UFC participation.

“Under the UFC Anti-Doping Policy, there is a full and fair legal process that is afforded to all athletes before any sanctions are imposed.

“The California State Athletic Commission (CSAC) also retains jurisdiction over this matter as the sample collection was performed the day before Jones’ bout at UFC 214 in Anaheim, CA, and USADA will work to ensure that the CSAC has the necessary information to determine its proper judgment of Jones’ potential anti-doping violation.”

This is not the first time Jones has failed a USADA test (Getty)
TMZ broke the story and claimed that Jones will be stripped of his belt following a positive test for Turinabol, an anabolic steroid.

This is the second time that Jones has failed a USADA drugs test, having tested for banned substances in the build-up to UFC 200, when he was scheduled to fight Cormier for a second time.

Jones was pulled from the event and banned for one year. He could now face a ban four-times that in length, which would likely leave his MMA career in tatters.

Nootropics and Smart Drugs: Brain Boosting Substances?

Throughout human history there seems to be a constant search for a silver bullet or pill that will make us faster, stronger and smarter. Sure, there are more difficult ways of accomplishing all of these goals (through various types of training), but humans seem fascinated with the search for a substance or “hack” that will make the process easier.

While this is an age-old search, new options have emerged and gained popularity in the form of smart drugs and nootropics, though many are still not aware of the benefits (and risks) of these substances.

The movie “Limitless” increased interest in these substances as the main character finds a smart drug that allows him to become cognitively superhuman, but then faces the unintended consequences of the drug.

What are Nootropics and Smart Drugs?

In short, these are substances that enhance cognitive performance in some way. Some are natural, in the form of herbs or high-dose vitamins, while others are man-made and pharmaceutical. Technically, while “smart drugs” typically refer to any pharmaceutical (or nutritional substance) that increase brain performance, nootropics must fulfill five criteria defined by the man who coined the term, Dr. Corneliu E. Giurgea:

The substance should enhance the brain in some way.
It should improve cognitive performance under stress (such as electrical shock or oxygen deprivation)
The substance should have protective properties that protect the brain against harmful substances.
The substance should “increase the efficacy of neuronal firing control mechanisms in cortical and sub-cortical regions of the brain.” (1)
It should be non-toxic and have no harmful side effects.
Tall order, huh?

As you can imagine, this limits the number of substances that technically meet the definition of “nootropics,” and as Bradley Cooper’s character found in the movie “Limitless,” substances that offer incredible benefit and seem too good to be true often are.

In common conversation, the terms “nootropic” and “smart drug” are often used to define any substance, supplement or chemical that improves cognitive performance in some way, though many of these substances do have side effects and do not meet all of the technical criteria for a “nootropic.”

Additionally, while the two terms are often used interchangeably, there are important differences in their mechanisms and safety.

“Smart” Drugs?

Smart drugs are typically pharmaceutical substances (prescribed medications or off-label drugs) that are used to improve cognition in some way. Popular options include off-label use of the ADD/ADHD drugs Adderall or Ritalin to increase cognitive performance in someone who doesn’t struggle with these conditions.

In the highly-competitive honors program at the university I attended, I often saw use (and mis-use) of these substances as they enabled students to sleep less, study more, and focus under extreme conditions. Unfortunately, I also saw the negative side effects in my fellow students, including sleep problems and irritability.

More recently, the drug Modafinil has gained popularity in a similar way:

A popular atypical stimulant “smart drug” includes the narcolepsy agents Modafinil / Adrafinil, although their effects on cognition beyond wakefulness are unproven, and side effects – while rare – can be life threatening. If attention problems are already present the side effect risk appears to be significant increased, as well. (Kumar, (2008), Approved and Investigational Uses, Drugs. 68(13):1803-39.). (2)

While the cinema perception may be that college students are using illegal drugs recreationally, I never saw this when I was in school and instead saw rampant off-label use of potentially dangerous but legal pharmaceuticals by students to keep up with demanding academic programs.

Benefits of Nootropics

Personally, I’ve always stayed away from smart drugs because while they offer some potentially impressive benefits, they also tend to come with side effects and I’ve always preferred natural options whenever possible. Call me old-fashioned, but I’ve also always thought the best way to improve cognitive performance is to regularly challenge the mind (without the need for pharmaceutical assistance!).

At the same time, I can honestly say I’m probably more stressed and sleep deprived now as a mom of six than I was in college and over the last few years I have researched and evaluated several natural types of nootropics for their effect on cognitive performance (without the negative side effects of smart drugs).

I stuck to substances that seemed to meet the actual definition of “nootropics,” offering benefits and cognitive protection without the negative side effects and I found several that seemed to be very effective. I realized that many of us moms use substances that affect the brain daily anyway, especially caffeine and sugar, and I wanted to see if there were other natural ways to improve energy and brain performance.

It is important to note that even natural substances that improve cognition do have an effect of some kind of the brain. While there isn’t a single way that they work, most affect the brain by changing the neurochemicals or hormones in the brain. It goes without saying that it is vitally important to ensure the safety of any substance and check with a doctor before using anything that may affect the mind in this way (especially if pregnant or nursing) and many are not recommended at all during pregnancy/nursing.

Types of Nootropics

Many types of substances get lumped into the broad category of “nootropics” or “smart drugs,” though as explained above, not all of them technically meet the criteria. That said, there are several classes of herbs and supplements that seem to improve cognition.

Adaptogens

These are natural substances that help the body handle stress and that as a byproduct may improve cognition. Examples include herbs like ginseng, maca and cordyceps.

Unlike caffeine, which is a stimulant that encourages a specific response within the body, adaptogenic herbs help the body adapt to stress by nudging it toward balance. To put it a different way, if caffeine is like a map from point A (sleepy) to point B (alert), adaptogens are more like a GPS system that figures out where you are and helps you get where you need to go (balanced). (3)

Since stress and exhaustion are two factors that can greatly decrease cognitive ability, it makes sense that adaptogens may improve brain performance by balancing the body and reducing stress. Some of the most common adaptogens are:

Rhodiola
Ginseng
Tulsi
Ginkgo
Cordyceps
Maca
What I did: I personally tried Maca and Cordyceps (when I wasn’t pregnant or nursing) with good results. I drank a coffee that contained Cordyceps Extract and used a Maca and Greens powder.

Food Based Nootropics

Nature provides many natural foods and herbs that support the body in various ways, including supporting brain health (with or without side effects). Popular substances that we know affect the brain include caffeine and high doses of certain amino acids or herbs.

These are my go-to brain boosters, as most foods are generally considered safe (even while pregnant/nursing) and they support and nourish the body in other ways as well. The best option for ensuring optimal brain performance (and overall health) is consuming a nourishing and varied diet, though I try to include these foods and herbs specifically when I need a brain boost:

Sources of DHA and EPA like oily fish and supplements
High antioxidant foods like berries and brightly colored vegetables
Healthy fats like coconut oil, ghee and MCT oil
Vitamin K from leafy greens and supplements
Coffee (because motherhood)
Alpha Brain

Much less often, I’ve used specific nootropic supplements designed to improve mental performance. I tried quite a few and only saw results without side effects from a couple of them. The first is called Alpha Brain, an herbal nootropic supplement designed to increase focus and concentration. I noticed that it helped my energy and focus much more than coffee without making me jittery like coffee can at times.

CILTEP

Dave Asprey introduced me to this supplement and I was amazed at how effective it was for me. It is essentially a “nootropic stack” meaning a combination of herbs that are designed specifically to support the brain. I would take this supplement on days that I needed to be able to concentrate on writing or meet deadlines and noticed a big difference in focus and concentration. When I wasn’t pregnant or nursing, I would often alternate these supplements a couple of times a week with good results.

The Bottom Line

Nootropics aren’t a magic bullet and they won’t create superhuman abilities like they seem to in movies, but there are some natural substances that may help improve brain performance. Smart drugs, on the other hand, have potentially dangerous side effects (especially when used off-label or by someone they were not prescribed to) and should generally be avoided, especially without the oversight of a trained doctor or medical professional.

Ever tried any Nootropics or smart drugs? What did you think? Share below!

Magnetic Bacteria Show Promise As Efficient Vehicle For Delivering Tumor-Fighting Drugs

 Researchers funded by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) have found that magnetic bacteria can act as a possible tool for efficiently transporting drugs to tumors in the human body.

One of the largest issues in cancer treatment is being able to deliver a sufficient amount of chemotherapy drugs to tumors without damaging healthy cells in the process. Researchers have tried using nanocarriers, extremely small particles packed with drugs, which are specifically designed so that only cancer cells absorb them (1). While they do a good job of protecting healthy tissue, only a small amount of drugs actually reach centers of tumor activity, characterized by low oxygen content.

Attempting to create nanocarriers that would travel to areas of the human body where cancerous cells typically develop, researchers discovered nature might have the solution. A bacteria named magnetococcus marinus thrives in deep waters where oxygen is scarce by using system of sensors to help detect changes in oxygen levels and also possess a chain of magnetic nanocrystals that direct the bacteria to swim north using Earth’s magnetic fields. Dr. Martel believes the bacteria’s unique navigation system could be capitalized on to easily deliver drugs to tumors (1).

Using mice as test subjects, researchers injected bacteria tagged with cancer-killing drugs into living tissue next to tumor cells (1). They exposed the mice to a magnetic field, aiming to direct the cells into the tumor. Results indicated that live bacterial cells were found deep within the tumor, especially in regions with low oxygen content (2).

Later trials demonstrate that the rate of drug intake in tumor cells increases significantly compared to standard nanocarriers. Researchers estimate that on average, 55% of injected bacterial cells with attached vesicles when exposed to the magnet make it to tumor cells, versus standard nanocarriers that deliver about 2% of the drug load (2). The bacteria harmlessly die within 30 minutes of being injected, suggesting that they be safe in humans.

Dr. Martel’s next goal is to determine the drug-loaded bacterial cells’ effects on shrinking tumor size in the body. They are also interested in examining whether the bacteria can deliver other types of cancer-killing medicines.

References:

  1. National Institute of Biomedical Imaging and Bioengineering. (2016, September 22). Swarms of magnetic bacteria could be used to deliver drugs to tumors. ScienceDaily. Retrieved September 25, 2016 from www.sciencedaily.com/releases/2016/09/160922093326.htm
  2. Felfoul, O., Mohammadi, M., Taherkhani, S., de Lanauze, D., Zhong Xu, Y., & Loghin, D. et al. (2016). Magneto-aerotactic bacteria deliver drug-containing nanoliposomes to tumour hypoxic regions. Nature Nanotechnology. http://dx.doi.org/10.1038/nnano.2016.137

A New Strategy For Choosing Cancer Drugs

Choosing the best treatment for a cancer patient is often an inexact science. Drugs that work well for some patients may not help others, and tumors that are initially susceptible to a drug can later become resistant.

In a new approach to devising more personalized treatments, researchers at MIT and Dana-Farber Cancer Institute have developed a novel way to test tumors for drug susceptibility. Using a device that measures the masses of single cells, they can predict whether a particular drug will kill tumor cells, based on how it affects their growth rates.

The researchers successfully tested this approach with a very aggressive type of brain cancer called glioblastoma and a type of blood cancer known as acute lymphoblastic leukemia. They reported their results in the Oct. 10 issue of Nature Biotechnology.

“We’ve developed a functional assay that can measure drug response of individual cells while maintaining viability for downstream analysis such as sequencing,” says Scott Manalis, the Andrew (1956) and Erna Viterbi Professor in the MIT departments of Biological Engineering and Mechanical Engineering and a member of MIT’s Koch Institute for Integrative Cancer Research, who is one of the paper’s senior authors.

David Weinstock and Keith Ligon of Dana-Farber Cancer Institute are also senior authors of the paper. The lead authors are Mark Stevens, a former MIT graduate student who is now a research scientist at Dana-Farber; MIT graduate student Nigel Chou; and Dana-Farber postdocs Cecile Maire and Mark Murakami.

Measuring cell growth

In recent years, scientists have been trying to identify genetic markers in tumors that suggest susceptibility to targeted cancer drugs. However, useful markers have been found for only a small percentage of cancers so far, and even when there is a predictive test, it is not accurate for all patients with that type of cancer.

The MIT and Dana-Farber researchers took a different approach, inspired in part by a test that has been used for decades to choose antibiotics to treat bacterial infections. The antibiotic susceptibility test involves simply taking bacteria from a patient, exposing them to a range of antibiotics, and observing whether the bacteria grow or die. To translate that approach to cancer, scientists need a way to rapidly measure cell responses to drugs, and to do it with a limited number of cells available.

For the past several years, Manalis’ lab has been developing a device known as a suspended microchannel resonator (SMR), which can measure cell masses 10 to 100 times more accurately than any other technique. This allows the researchers to precisely calculate growth rates of single-cells over short periods of time.

In this study, Manalis’ lab worked with Dana-Farber researchers to determine whether drug susceptibility could be predicted by measuring cancer cell growth rates following drug exposure. The team analyzed different subtypes of glioblastoma or leukemia cells that have previously been shown to be either sensitive or resistant to specific  therapies: For glioblastoma, these are drugs called MDM2 inhibitors, and for acute lymphocytic leukemia, the drugs are known as BCR-ABL inhibitors. This allowed the researchers to test whether their approach would yield accurate predictions.

After exposing cancer cells to the drug, the researchers waited about 15 hours and then measured the cell’s growth rates. Each cell was measured several times over a period of 15 to 20 minutes, giving the researchers enough data to calculate the mass accumulation rate. They found that cells known to be susceptible to a given therapy changed the way they accumulate mass, whereas resistant cells continued growth as if unaffected.

“We’re able to show that cells we know are sensitive to therapy respond by dramatically reducing their growth rate relative to cells that are resistant,” Stevens says. “And because the cells are still alive, we have the opportunity to study the same cells following our measurement.”

One major advantage of this technique is that it can be done with very small numbers of cells. In the experiments with leukemia cells, the researchers showed they could get accurate results with a tiny droplet of blood containing about 1,000 cancer cells.

Another advantage is the speed at which small changes in cell mass can be measured, says Anthony Letai, an associate professor of medicine at Dana-Farber Cancer Institute, who is working on a different approach to monitoring cancer cells’ reactions to drugs.

“This system is well suited to making rapid measurements,” says Letai, who was not involved in this study. “I look forward to seeing them apply this to many more cancers and many more drugs.”

Understanding resistance

The researchers are now using this technique to test cells’ susceptibility and then isolate the cells and sequence the RNA found in them, revealing which genes are turned on.

“Now that we have a way to identify cells that are not responding to a given therapy, we are excited about isolating these cells and analyzing them to understand mechanisms of resistance,” Manalis says.

In a recent paper in Nature Biotechnology, the researchers reported on a higher throughput version of the SMR device that can do in one day the same number of measurements that took several months with the device used in this study. This is an important step toward making the approach suitable for clinical samples, Manalis says.

The research was funded by the Bridge Project, a partnership between MIT’s Koch Institute and Dana-Farber/Harvard Cancer Center, and the National Cancer Institute.

Compound Derived From Marijuana Interacts With Antiepileptic Drugs

New research published in Epilepsia, a journal of the International League Against Epilepsy (ILAE), suggests that an investigational neurological treatment derived from cannabis may alter the blood levels of commonly used antiepileptic drugs. It is important for clinicians to consider such drug interactions during treatment of complex conditions.

Cannabidiol (CBD), a compound developed from the cannabis plant, is being studied as a potential anticonvulsant, and it has demonstrated effectiveness in animal models of epilepsy and in humans. An ongoing open label study (Expanded Access Program) conducted by investigators at the University of Alabama at Birmingham is testing the potential of CBD as a therapy for children and adults with difficult to control epilepsy. The study includes 39 adults and 42 children, all of whom receive CBD.

Because all of the participants are also taking other seizure drugs while they are receiving the investigational therapy, investigators checked the blood levels of their other seizure drugs to see if they changed. “With any new potential seizure medication, it is important to know if drug interactions exist and if there are labs that should be monitored while taking a specific medication,” said lead author Tyler Gaston, MD.

Dr. Gaston and her colleagues found that there were significant changes in levels of the drugs clobazam (and its active metabolite N-desmethylclobazam), topiramate, and rufinamide in both adults and children, and zonisamide and eslicarbazepine in adults only. Except for clobazam/desmethylclobazam, however, the drug levels did not change outside of the normally accepted range. In addition, adult participants in the study taking clobazam reported sedation more frequently.

Tests also showed that participants taking valproate and CBD had higher ALT and AST (liver function tests) compared with participants not taking valproate. Very high ALT and AST indicate abnormal liver function, but significant ALT and AST elevation occurred only in a mall number of participants (4 children and 1 adult), and the levels returned to normal after discontinuation of valproate and CBD.

“While the interaction between CBD and clobazam has been established in the literature, there are currently no published human data on CBD’s potential interactions with other seizure medications,” said Dr. Gaston. “However, given the open label and naturalistic follow-up design of this study, our findings will need to be confirmed under controlled conditions.”

The findings emphasize the importance of monitoring blood levels of antiepileptic drugs as well as liver function during treatment with CBD. “A perception exists that since CBD is plant based, that it is natural and safe; and while this may be mostly true, our study shows that CBD, just like other antiepileptic drugs, has interactions with other seizure drugs that patients and providers need to be aware of,” said Dr. Gaston.

Child living with HIV maintains remission without drugs since 2008

Researchers have renewed hope to learn how to induce long-term HIV remission in infected babies

A nine-year-old South African child who was diagnosed with HIV infection at one month of age and received anti-HIV treatment during infancy has suppressed the virus without anti-HIV drugs for eight and a half years, scientists reported today at the 9th IAS Conference on HIV Science in Paris. This case appears to be the third reported instance of sustained HIV remission in a child after early, limited anti-HIV treatment.

Previously, the “Mississippi Baby,” born with HIV in 2010, received anti-HIV treatment beginning 30 hours after birth, stopped therapy around 18 months of age, and controlled the virus without drugs for 27 months before it reappeared in her blood. In 2015, researchers reported that a French child who was born with HIV in 1996, started anti-HIV therapy at age 3 months, and stopped treatment sometime between ages 5.5 and 7 years continued to control the virus without drugs more than 11 years later.

“Further study is needed to learn how to induce long-term HIV remission in infected babies,” said Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). “However, this new case strengthens our hope that by treating HIV-infected children for a brief period beginning in infancy, we may be able to spare them the burden of life-long therapy and the health consequences of long-term immune activation typically associated with HIV disease.”

NIAID funded the clinical trial in which the child received treatment and follow-up monitoring.

The South African child whose case was reported today was definitively diagnosed with HIV infection in 2007 at 32 days of age, and then was enrolled in the NIAID-funded Children with HIV Early Antiretroviral Therapy (CHER) clinical trial. HIV-infected infants in the trial were assigned at random to receive either deferred antiretroviral therapy (ART) or early, limited ART for 40 or 96 weeks. The current child was assigned to the group of 143 infants who received early ART for 40 weeks.

Before starting treatment, the child had very high levels of HIV in the blood (viral load), but after beginning ART at about 9 weeks of age, treatment suppressed the virus to undetectable levels. Investigators halted treatment after 40 weeks and closely monitored the infant’s immune health, and the child has remained in good health during years of follow-up examinations. Although it was not standard practice in South Africa to monitor viral load in people who were not on ART, recent analyses of stored blood samples taken during follow-up showed that the child has maintained an undetectable level of HIV.

When the child was 9-and-a-half years old, investigators conducted thorough laboratory and clinical studies to assess the child’s immune health and the presence of HIV. The scientists detected a reservoir of virus integrated into a tiny proportion of immune cells, but otherwise found no evidence of HIV infection. The child had a healthy level of key immune cells, a viral load that was undetectable by standard assays, and no symptoms of HIV infection. The researchers detected a trace of immune system response to the virus, but found no HIV capable of replicating. The scientists also confirmed that the child does not have genetic characteristics associated with spontaneous control of HIV, suggesting that the 40 weeks of ART provided during infancy may have been key to achieving HIV remission.

“To our knowledge, this is the first reported case of sustained control of HIV in a child enrolled in a randomized trial of ART interruption following treatment early in infancy,” said Avy Violari, F.C.Paed. Dr. Violari co-led the study of the case reported today as well as the CHER trial with Mark Cotton, M.Med., Ph.D. Dr. Violari is head of pediatric research at the Perinatal HIV Research Unit, part of the University of the Witwatersrand in Johannesburg. Dr. Cotton is head of the division of pediatric infectious diseases and director of the family infectious diseases clinical research unit at Stellenbosch University, South Africa.

“We believe there may have been other factors in addition to early ART that contributed to HIV remission in this child,” said Caroline Tiemessen, Ph.D., whose laboratory is studying the child’s immune system. “By further studying the child, we may expand our understanding of how the immune system controls HIV replication.” Dr. Tiemessen is head of cell biology at the Centre of HIV and STIs of the National Institute of Communicable Diseases (NICD) in Johannesburg.

An ongoing NIH clinical trial called IMPAACT P1115 is testing the hypothesis that giving ART to HIV-infected newborns beginning within 48 hours of birth may permit long-term control of HIV replication after treatment is stopped, potentially leading to HIV remission. IMPAACT P1115 began in 2014 and has enrolled close to 400 HIV-exposed infants, 42 of whom are HIV infected, in Argentina, Brazil, Haiti, Malawi, South Africa, Uganda, the United States, Zambia and Zimbabwe. The first children may become eligible to stop ART in late 2017.

NIAID provided funding for the CHER trial as part of a Comprehensive International Program for Research on AIDS-South Africa grant. Additional support was provided by the Medical Research Council Clinical Trials Unit at University College London, the Departments of Health of the Western Cape and Gauteng in South Africa, and ViiV Healthcare. The Eunice Kennedy Shriver National Institute of Child Health and Human Development, also part of NIH, supported continued observation of the children in CHER after the study ended. The EPIICAL Consortium funded the recent analysis of viral load in the children who participated in CHER. The South African Research Chairs Initiative of the Department of Science and Technology and the National Research Foundation of South Africa funded the laboratory studies of the child whose case was reported today.

Reference: A Violari et al. Viral and host characteristics of a child with perinatal HIV-1 following a prolonged period after ART cessation in the CHER trial. 9th IAS Conference on HIV Science, Paris (2017).

Soon, Anti-Diabetes Drugs to Replace Painful Insulin Jabs

Diabetes Mellitus is a condition wherein the body is either unable to produce insulin on its own or is not able to use it properly. Patients with Type 1 diabetes

are required to take insulin injections to keep their blood sugar in control. Insulin jabs are usually required to be taken several times in a day and in some cases more than one type of insulin may be used. A new discovery claims that diabetics will no longer have to go through painful insulin injections as new anti-diabetes drugs will soon be able to do the needful. Researchers led by the University of Adelaide have shown how potential anti-diabetic drugs interact with their target in the body at the molecular level.

“Type two diabetes is characterized by resistance to insulin with subsequent high blood sugar which leads to serious disease. It is usually associated with poor lifestyle factors such as diet and lack of exercise,” said John Bruning, from University of Adelaide.

(Also Read: 7 Things You Should Do Regularly to Reduce the Risk of Diabetes)

The new drug doesn’t act on the liver to reduce glucose product like most commonly prescribed anti-diabetes drugs like Metformin. They target a protein receptor known as PPARgamma found in fat tissue throughout the body, either fully or partially activating it in order to lower blood sugar by increasing sensitivity to insulin and changing the metabolism of fat and sugar.
“People with severe diabetes need to take insulin but having to inject this can be problematic, and it’s difficult to get insulin levels just right,” said Bruning.