Stem cell stories that caught our eye: better heart muscle, first patient with eye cell patch, brain cross talk and gut bugs

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Growing better heart muscle in the lab. While researchers have been able to grow beating heart cells from stem cells in a dish for many years, those beating blobs of cells have not looked or acted much like the long strong muscle fibers found in a normal heart. A team at Stanford, with collaborators at the Gladstone Institutes have spent much of the past five years looking for ways to make lab-grown heart muscle more like the real thing.

Heart muscle matured from stem cells functions better when grown in long, thin shapes.

Heart muscle matured from stem cells functions better when grown in long, thin shapes.

They published a couple of solutions in the Proceedings of the National Academy of Sciences this week. One of the keys was to make the stem cells feel more like they are in their natural environment, which is full of physical tension. When they grew the stem cells on substrates that provided that type of tension they got stronger heart muscle better able to beat in a synchronized rhythm. They also found that stem cells grown in long, narrow chambers produced heart muscle closer in appearance and function to the narrow muscle fibers found in normal hearts.

The press release, written by our former colleague Amy Adams who now works for the University, was picked up by Medical Express.

First patient in trial for blindness. Doctors at the Moorfields Eye Hospital in London have used specialized eye cells derived from embryonic stem cells and grown on a synthetic scaffold to try to reverse blindness caused by age-related macular degeneration(AMD). Prior clinical trials have injected similar cells but without the supporting structure of the patch to hold them in place.

Also, prior trials have aimed to halt the progressive loss of vision in the dry form of macular degeneration. This trial is trying to reverse damage already done by the wet form of AMD. Each of the groups use embryonic stem cells and first mature the cells into a type of cell found in the back of the eye’s retina, retinal pigmented epithelium (RPE) cells.

“The reason we are very excited is that we have been able to create these very specific cells and we have been able to transfer them to the patient,” lead researcher Lyndon Da Cruz told a writer for the Huffington Post. “It’s the combination of being able to create the cells that are missing and demonstrate that we can safely transplant them.”

CIRM funds a team at the University of Southern California and the University of California, Santa Barbara that has collaborated with the London team and plans to use a similar patch system on a trial set to begin in the next few weeks.

The London news got broad pick up in the media, including this BBC Video.

Cross-talk in the brain linked to success. The National Institutes of Health issued a press release this week describing two early results of its major Brain Initiative. One team from the University of California, San Francisco, provided an explanation about why primate brains are so much bigger than other mammals, and a team from Oxford and Washington University in St. Louis mapped cross talk between different parts of the brain to various personality traits.

The second group collected data on 280 measures such as IQ, language performance, rule-breaking behavior and anger that they mined from the initiative’s Connectome Project. Their analysis of 461 people found a strong correlation to sections of the brain talking to each other when in a resting state and positive personality and demographic traits. Those included high performance on memory tests, life satisfaction, years of education and income.

The UCSF team showed that brain stem cells during early development produce as much as 1,000-fold more neurons in primates than in lower mammals. More important, they isolated a reason for this strong performance. As the brain gets bigger the stem cells don’t have to continually migrate greater distance from their homes, called the stem cell niche. Instead they seem to pack their bags and take the niche with them.

“It is great to see data from large investments like the Human Connectome Project and the BRAIN Initiative result in such interesting science so quickly,” said Greg Farber of the National Institute of Mental Health in the release.

Have to agree.

The interplay of bugs and genes in our gut. The consumer press spends a considerable amount of time talking about the bacteria in our digestive tract, and now a team a Baylor College of Medicine in Houston has produced some data that suggests these microbial cohabitants of our bodies, called the microbiome, become important early in our development.

In research published in the journal Genome Biology and in a press release picked up by Medical Express, the researchers showed that the microbiome in mice during the period they are nursing helps determine which genes are turned on or turned off, and those settings, called epigenetics, follow the mice through their adult life. Specifically, they found that the gut microbiome impacted the function of gut stem cells that we rely on to replace the lining of our digestive system approximately every four days.

“This promises some exciting opportunities to understand how we might be able to tailor one’s microbiome exposure during infancy to maximize health and reduce gastrointestinal disease throughout life,” said one member of the team, Robert Waterland.

Three teams empower patients’ immune systems to oust cancer

Immuno-oncology is all the rage now in biotech publications, with due cause. It is producing some pretty impressive results in patients who failed other therapies. Most of what gets written about involves strengthening or unlocking the action of one immune cell, the T cell. But our immune systems are armed with many types of ammunition; we have multiple kinds of cells that can initiate or follow through in getting rid of unwanted invaders or cancers. CIRM funds three clinical trials that test these lesser-traveled routes to juicing up our immune response to cancer.

Robert Dillman has worked to bring immune therapy to cancer patients for 25 years.

Robert Dillman has worked to bring immune therapy to cancer patients for 25 years.

While this field is hot now, it is not new. It has been elusive; researchers have tried for decades to harness our multi-talented immune system in the war on cancer. One of those researchers, Robert Dillman, who has been working on it for 25 years, now leads a CIRM-funded clinical trial in Phase 3, which is the last leg in a long journey to having a therapy approved for any patient with metastatic melanoma.

Another CIRM-funded team is also in a Phase 3 trial, in this case a therapy for the brain cancer glioblastoma developed by ImmunoCellular Therapeutics. The third CIRM-funded team at Stanford is in the middle of an early phase trial testing for safety and early signs of effectiveness with a therapy that could become an off-the-shelf therapy for many different cancers.

25-year effort getting results

Dillman now works for Caladrius Biosciences, the company conducting the Phase 3 trial in many medical centers around the U.S. He heads the clinical trial team funded by CIRM to conduct the California portion of the trial. But he has been working on the concept behind the therapy since the 1990s, most of the time at Hoag Hospital in Orange County. His mom was diagnosed with cancer when he was 14, and she died of the disease when he was an undergraduate at Stanford. His entire career has been focused on immuno-oncology.

The current effort uses a part of the immune system called dendritic cells that are derived from the patient’s blood. A patient’s tumor cells from a cell line and their dendritic cells are exposed to each other in a lab culture flask. What dendritic cells are really good at is gobbling up the cancer cells, then presenting pieces of the destroyed cancer cells to the immune cells responsible for getting rid of tumors. So, when given back to the patient the dendritic cells present the cancer bits, or antigens, like road maps to the immune cells that can then seek out and kill the cancer stem cells. The company produced a great video explaining the process.

Unlike most of the other immunotherapies that generally only present or target one CSC antigen, the Caladrius strategy presents a multitude of CSC antigens through the dendritic cells. The therapy has been associated with minimal side effects and theoretically should be more effective than other therapeutic cancer vaccine approaches. With so many specific targets, the cells are less likely to cause immune attack on healthy cells and more likely to find all the renegade tumor cells. This therapy is also a bit slower acting, which is actually a good thing. Many of the other immune therapies trigger such a strong immune response, they cause flu like symptoms that sometimes require the therapy to be halted. The dendritic cell therapy has few side effects reported so far.

Caladrius plans to conduct the trial at 32 locations, with 20 of them recruiting patients currently. The first patient was dosed in June, and a total of 250

Norm Beegun was treated in an earlier phase of the Caladrius trial.

Norm Beegun was treated in an earlier phase of the Caladrius trial.

patients will be randomly selected to get the therapy or not, with two thirds getting the therapy. The researchers plan to review the interim results as early as the end of 2017.

One patient from the earlier phase trials of the therapy, Norm Beegun, believes he definitely benefited from the treatment and told his story to our board in May.

Other approaches to ousting cancer

The CIRM-funded team at Stanford began an early phase trial in August 2014 using an antibody that blocks a receptor on the surface of CSCs called CD47. One of the researchers on the team, Irving Weissman, has dubbed that gene the “don’t eat me gene(video)” because it tells the immune system cells responsible for getting rid of tumors to not do their job. When CD47 is blocked, the immune system cells called macrophages are able to destroy—in essence eat—the CSCs.

The initial study primarily seeks to determine safety and the best dose for moving forward. It is enrolling patients with advanced-stage solid tumors. So far 12 patients have been treated with five different doses, and the team continues to screen patients for higher doses to be treated in the coming months. The trial is open only at Stanford Cancer Center under the leadership of Branimir Sikic.

The team at ImmunoCellular plans to enroll 400 brain cancer patients at 120 clinical trial sites around the U.S., Canada and Europe. They are also developing a way to turn a patient’s dendritic cells into a vaccine that helps the immune system target cancer stem cells.

One man’s story points to hope against a deadly skin cancer

At our May Board meeting a gentleman presented his story, which exemplifies being a patient and patient advocate. His name is Norm Beegun. And this is his story.

Norm Beegun was treated in an early phase of the Caladrius trial.

Norm Beegun was treated in an early phase of the Caladrius trial.

Norm lives in Los Angeles. In 2002 he went to see his regular doctor, an old high school friend, who suggested that since it had been almost ten years since he’d had a chest x-ray it might be a good idea to get one. At first Norm was reluctant. He felt fine, was having no health problems and didn’t see the need. But his friend persisted and so Norm agreed. It was a decision that changed, and ultimately saved, his life.

The x-ray showed a spot on his lung. More tests were done. They confirmed it was cancer; stage IV melanoma. They did a range of other examinations to see if they could spot any signs of the cancer on his skin, any potential warnings signs that they had missed. They found nothing.

Norm underwent surgery to remove the tumor. He also tried several other approaches to destroy the cancer. None of them worked; each time the cancer returned; each time to a different location.

Decided to try a new approach

Then a nurse who was working with him on these treatments suggested he see someone named Dr. Robert Dillman, who was working on a new approach to treating metastatic melanoma, one involving cancer stem cells.

Norm got in touch with Dr. Dillman and learned what the treatment involved; he was intrigued and signed up. They took some cells from Norm’s tumor and processed them, turning them into a vaccine, a kind of personalized therapy that would hopefully work with Norm’s own immune system to destroy the cancer.

That was in 2004. Once a month for the next six months he was given injections of the vaccine. Unlike the other therapies he had tried this one had no side effects, no discomfort, no pain or problems. All it did was get rid of the cancer. Regular scans since then have shown no sign that the melanoma has returned. Theoretically that could be because the new therapy destroyed the standard tumor cells as well as the cancer stem cells that lead to recurrence.

Didn’t miss one of son’s football games

Norm says when you are diagnosed with an incurable life-threatening disease, one with a 5-year survival rate of only around 15%, you will try anything; so he said it wasn’t a hard decision to take part in the clinical trial, he felt he had nothing to lose.

“I didn’t know if it would help me. I didn’t think I’d be cured. But I wanted to be a guinea pig and perhaps help others.”

When he was diagnosed his son had just won a scholarship to play football at the University of California, Berkeley. Norm says he feared he would never be able to see his son play. But thanks to cleverly scheduling surgery during the off-season and having a stem cell therapy that worked he not only saw his son play, he never missed a game.

Norm returned to Berkeley on May 21st, 2015. He came to address the CIRM Board in support of an application by a company called NeoStem (which has just changed its name to Caladrius Biosciences). This was the company that had developed the cell therapy for metastatic melanoma that Norm took.

“Talking about this is still very emotional. When I got up to talk to the CIRM Board about this therapy, and ask them to support it, I wanted to let them know my story, the story of someone who had their life saved by this treatment. Because of this I am here today. Because of this I was able to see my son play. But just talking about it left me close to tears.”

It left many others in the room close to tears as well. The CIRM Board voted to fund the Caladrius application, investing $17.7 million to help the company carry out a Phase 3 clinical trial, the last hurdle it needs to clear to prove to the Food and Drug Administration that this should be approved for use in metastatic melanoma.

Norm says he is so grateful for the extra years he has had, and he is always willing to try and support others going through what he did:

“I counsel other people diagnosed with metastatic melanoma. I feel that I want to help others, to give them a sense of hope. It is such a wonderful feeling, being able to show other people that you can survive this disease.”

CIRM Fights Cancer: Two teams develop therapies to stop and eliminate cancer stem cells

Six out of the ten best selling drugs are proteins called monoclonal antibodies. But the prospect for monoclonal antibodies was not always so bright. It took a decade after their discovery in 1975 before they found any clinical use, even then it was very limited use for organ transplant rejection. It was a full twenty years before their first wide spread use in cancer. One of the first cancer therapies using antibodies, Herceptin approved in 1998, keeps many breast cancer patients alive today.

UCLA's Dennis Slamon

UCLA’s Dennis Slamon

Dennis Slamon, worked for more than a decade in his lab at the University of California, Los Angeles, to get Herceptin tested, approved and marketed by Genentech. That story, told in “The Emperor of All Maladies,” shows him working against skeptics and critics often with scant financial support. Now, he has turned that laser focus on finding a therapy that can seek out and destroy cancer stem cells from a broad array of cancers—an effort he began in earnest some five years ago with an early disease team grant from CIRM.

That early CIRM grant let his team test several different compounds alone and in combination with standard therapies to settle upon one drug that targets a protein called PLK-4, a specific kinase that is found in many cancer stem cells. CIRM now funds an early phase clinical trial testing that drug in several different solid tumors. The University Health Network in Toronto, partnered with CIRM in supporting the early work, and now also funds another clinic site for the same trial at the Princess Margaret Hospital in Toronto.

All doses safe so far

So far, seven groups of patients made up of three patients each, have been given increasing doses of the drug. The Slamon team suspected that the early doses administered in the trial were likely to be too small to be effective but the Food and Drug Administration appropriately insists on the demonstration of safety first for new

Trial Patient Frank Gonzalez tells his story in his own words

Trial Patient Frank Gonzalez tells his story in his own words

therapies. So far in the study none of the groups have shown any toxicity and Slamon thinks, based on the animal data that they are now near a dose where they could see patient tumors responses. Since each group has to be monitored for four weeks before the next group can be treated it has been nearly a year since the trial began, but Herceptin showed Slamon has the stamina to stick with a therapy that makes sense.

One of the early participants in the trial, Frank Gonzalez, knew he would probably be getting a dose too low to be effective, but felt it was valuable to participate for the potential long term outcomes of the therapy. (link to his story and video)

Second trial targets leukemia stem cells

CIRM funds a second clinical trial that targets a protein broadly found on cancer stem cells, with the current trial treating leukemia. This therapy, an antibody being tested at the University of California, San Diego, targets a protein called ROR1. When the antibody blocks that protein it prevents the cancer stem cells from proliferating and encourages them to die. We at CIRM are proud of the name the team gave the antibody, Cirmtuzumab. This trial, too, was required to start at a very low dose to guarantee safety and has slowly escalated the dose with the expectation of the trial continuing for another year. One of the lead researchers on that trial, Catriona Jamieson, also thinks they may be near a therapeutic dose where they may see tumor response.

Many companies have jumped into the field developing traditional drugs and antibodies targeting cancer stem cells. As always it is nice to have colleagues working on many different routes to the same goal. It makes sense that some of these should work. Patients fearful of their doctor telling them “it’s back” deserve nothing less.

Pioneering patients heroes of early clinical trials

When Frank Gonzales was diagnosed with colorectal cancer in November 2010 it was the start of a long fight against the disease.

Chemotherapy helped keep the cancer in check, but it wasn’t a cure. So when Frank heard about a new experimental treatment, that seeks out and destroys cancer stem cells, he was intrigued.

Frank talked to UCLA’s Dr. Zev Wainberg, who is running the clinical trial funded by CIRM: “I knew it was a study and everybody wasn’t getting the same dosage but after having gone through all the other treatments this was easy.”

Frank took a single pill every day, and says he experienced no side effects. After six months he had to drop out of the trial to receive radiation.

Frank’s cancer is now in remission and he’s been able to go back to work. He doesn’t know if the pills helped but he’s proud of being a stem cell pioneer and hopes the first-in-human therapy proves effective so that one day many others will be as lucky as he is.

“It is pretty amazing. I hope they close in on it. Figure this thing out, because there’s a lot of need for it.”

CIRM fights cancer: $56 million for 5 clinical trials to vanquish tumors for good

target on CSC[This is the first of three stories on CIRM’s Cancer Fight that we will post this week. Tomorrow’s will discuss two projects that attack cancer stem cells directly and Thursday’s will describe three projects that help our immune system wipe out the traitorous cells.]

It’s back—two words we would like to remove from the cancer caregivers’ vocabulary. Many researchers blame cancer stem cells for this too common occurrence, saying cancer stem cells have ways of avoiding most traditional therapies and trigger the tumor’s return. Others prefer the term “tumor initiating cells.” But whatever you call them they need to be dealt with if we are going to make major improvements in cancer patient survival.

Cancer_stem_cellsCIRM is investing $56 million in five clinical trials targeting cancer stem cells (CSCs), the most advanced projects in our over $200 million commitment so far, to fighting cancer. Two of these trials use agents that target the cancer stem cells directly and three use agents that enable a person’s immune system to do a better job of getting rid of the CSCs.

Trials that target cancer stem cells directly

 One of the clinical trials directly targeting CSCs uses a type of protein called an antibody to seek out the renegade stem cells and initiate their demise. Antibodies home to specific proteins on the surface of cells called antigens. Researchers have been able to identify a few antigens that seem to be almost exclusively on the surface of CSCs and they have become targets for therapy.

A team at the University of California, San Diego uses an antibody named after our agency Cirmtuzumab to fight chronic lymphocytic leukemia. It targets the protein ROR1 that is abundant on CSC in the leukemia but not on normal blood-forming stem cells. Once bound on the cells Cirmtuzumab seems to prevent them from proliferating and migrating to other parts of the body and promotes them to go through a form of cell death called apoptosis.

The second trial directly attacking CSCs, at the University of California, Los Angeles, targets various solid tumors. They use a drug that affects the CSCs ability to replicate. It binds to and inhibits a protein, called a kinase, that the CSCs use when they divide.

Trials that activate the immune system

 A third clinical trial, at Stanford, also uses an antibody, but in this case it blocks a protein the CSCs use to fend off the cells in our immune system that routinely destroy emergent cancers in all of us. Immuno-oncology, the process of juicing up our immune response to cancer, is one of the hottest areas in cancer research and on Wall Street right now. But most of those efforts target a part of the immune system called the T cell. The Stanford team mobilizes a different immune cell, the macrophage, which routinely gobbles up dying, damaged or cancerous cells.

One beautiful thing about all three of these therapies is they could reverse a decade-long trend of new cancer therapies being targeted to increasingly narrow populations of cancer patients, resulting in extremely high costs per patient. Because the proteins targeted by these therapies seem to be shared across a great many types of tumors, they could be broad-spectrum cancer strategies that could be delivered at a lower cost.

CIRM currently funds five clinical trials targeting cancer stem cells.

An additional five cancer clinical trials have been undertaken based on early research funded by CIRM.

The fourth CIRM-funded clinical trial also seeks to increase our natural immune response, in this case in notoriously hard to treat metastatic melanoma. Like the Stanford team, this project by researchers at the firm Caladrius Biosciences targets a type of cell different from most immuno-oncology. In this case they derive cells called dendritic cells from the patients’ blood and establish a cell line from their tumor. In the lab they mix the cell types together and the dendritic cells gobble up the tumor cells including the cancer’s antigens, those surface proteins that act as identification tags. When re-infused into the patient the dendritic cells do what they are really good at: presenting antigens to the immune cells responsible for getting rid of tumors. Dendritic cells display the antigens like road maps to the immune cells that can then seek out and kill the cancer stem cells.

The fifth CIRM-funded trial uses a similar concept activating a patient’s dendritic cells with antigens from their brain cancers, known as glioblastomas. That trial is being conducted by ImmunoCellular Therapeutics

The first three trials are all early phase studies looking to test safety and determine what is the best dose to use going forward. The last two trials are more advanced, so-called Phase 3 studies of a dose already having shown signs of benefit in earlier trials.

Calling for a cure for HIV/AIDS

Larry Kramer - Photo by David Shankbone

Larry Kramer – Photo by David Shankbone

Larry Kramer is a pivotal figure in the history of HIV/AIDS. His activism on many fronts has been widely credited with changing public health policy and speeding up access to experimental medications for people infected with the virus. So when he says that the fight for treatment is not enough but “The battle cry now must be one word — cure, cure, cure!” People pay attention.

A few years ago it might have been considered dangerously optimistic to use the word “cure” in any conversation about HIV/AIDS, but that’s no longer the case. In fact cure is something that is becoming not just a wildly ambitious dream, but something that scientists are working hard to achieve right now.

On Tuesday, October 6th, we are going to hold an HIV/AIDS Cure Town Hall meeting in Palm Springs. This will be the third event we’ve held and the previous two, in San Francisco and Los Angeles, were hugely successful. It’s not hard to understand why. Our experts are going to be talking about their work in trying to eradicate the AIDS virus from people infected with it.

This includes clinical trials run by Calimmune and City of Hope/Sangamo, plus some truly cutting edge research by Dr. Paula Cannon of the University of Southern California.

The clinical trials are both taking similar, if slightly different, approaches to reach the same goal; functionally curing people with HIV. They take the patient’s own blood stem cells and genetically modify them so that the AIDS virus is no longer able to infect them. They also help boost the patient’s T cells, a key part of a healthy immune system and the virus’ main target, so that they can fight back against the virus. It’s a kind of one-two punch to block and eventually evict the virus.

Timothy Brown; photo courtesy

Timothy Brown; photo courtesy

This work is based on the real-life experiences of Timothy Ray Brown, the “Berlin Patient”. He became the first person ever cured of HIV/AIDS when he got a bone marrow transplant from a person with a natural resistance to HIV. This created a new blood supply and a new immune system both of which were resistant to HIV.

Timothy is going to be joining us at the event in Palm Springs to share his story and show that cure is not just a word it’s a goal; one that we can now think of as being possible.

The HIV/AIDS Cure Town Hall event will be held on Tuesday, October 6th in the Sinatra Auditorium at the Desert Regional Medical Center in Palm Springs. Doors open at 6pm and the program starts at 6.30pm. And of course, it’s free.

Stem cell stories that caught our eye: lab-grown kidneys that work, finding blood stem cells’ home and colitis

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Lab grown kidneys able to take a leak. While a few teams have been able to grow parts of kidneys in the lab using stem cells, they could never show full function because kidneys are not a closed system. They need connecting plumbing and a shutterstock_251360653bladder to collect fluid before urine can be expelled. Now, a team in Japan has built kidneys as well as those other parts in the lab. When they were implanted in rats and pigs and connected to the animals’ own plumbing the man-made organs successfully peed.

The BBC ran a story on the work that included a quote from noted stem cell expert Chris Mason of University College, London:

”This is an interesting step forward. The science looks strong and they have good data in animals. But that’s not to say this will work in humans. We are still years off that. It’s very much mechanistic. It moves us closer to understanding how the plumbing might work.”

The team published the research in the U.S. Proceedings of the National Academy of Sciences.

Seeing through bone to track stem cells. Yes we know blood-forming stem cells reside in bone marrow, but that is a pretty big base of operations. We really haven’t known where in the marrow they tend to hang out and in what sort of groupings. A team at Children’s Research Institute at the University of Texas Southwestern published research this week using new imaging techniques to map the home of all the blood stem cells in marrow and it showed some surprising results.

“The bone marrow and blood-forming stem cells are like a haystack with needles inside. Researchers in the past have been able to find a few stem cells, but they’ve only seen a small percentage of the stem cells that are there, so there has been some controversy about where exactly they’re located,” said UT’s Sean Morrison in a press release posted by Technology Networks.

“We developed a technique that allows us to digitally reconstruct the entire haystack and see all the needles – all the blood-forming stem cells that are present in the bone marrow – and to know exactly where they are and how far they are from every other cell type.”

They found the blood-forming stem cells clustered in the center of the bone marrow rather than near the edges of the bone as was presumed. This improved understanding of the stem cells’ natural environment should make it easier to replicate the cells behavior in the lab and, in turn, lead to improved stem cell therapies.

Help for colitis patients resistant to therapy. About two-thirds of patients with colitis and Crohn’s disease do not respond to one of the leading medications that blocks a protein considered key to the inflammatory process, Tumor Necrosis Factor (TNF). A CIRM-funded team at the Children’s Hospital Los Angeles published research this week suggesting why and offering possible new options for treatment.

“Understanding this mechanism allows us to target new therapeutic approaches for patients who don’t respond to current therapies,” said principal investigator Brent Polk in a university press release posted at Eurekalert.

The mechanism surprised his team. They found that TNF in these patients actually protected against inflammation by inhibiting one type of the immune system’s T cells. The interplay between TNF and those culprit T cells now becomes a target to therapeutic intervention.

Funding a clinical trial for deadly cancer is a no brainer

The beast of cancers
For a disease that is supposedly quite rare, glioblastoma seems to be awfully common. I have lost two friends to the deadly brain cancer in the last few years. Talking to colleagues and friends here at CIRM, it’s hard to find anyone who doesn’t know someone who has died of it.


Imagery of glioblastoma, a deadly brain cancer,  from ImmunoCellular’s website

So when we got an application to fund a Phase 3 clinical trial to target the cancer stem cells that help fuel glioblastoma, it was really a no brainer to say yes. Of course it helped that the scientific reviewers – our Grants Working Group or GWG – who looked at the application voted unanimously to approve it. For them, it was great science for an important cause.

Today our Board agreed with the GWG and voted to award $19.9 million to LA-based ImmunoCellular Therapeutics to carry out a clinical trial that targets glioblastoma cancer stem cells. They’re hoping to begin the trial very soon, recruiting around 400 newly diagnosed patients at some 120 clinical sites around the US, Canada and Europe.

There’s a real urgency to this work. More than 50 percent of those diagnosed with glioblastoma die within 15 months, and more than 90 percent within three years. There are no cures and no effective long-term treatments.

As our President and CEO, Dr. Randy Mills, said in a news release:

 “This kind of deadly disease is precisely why we created CIRM 2.0, our new approval process to accelerate the development of therapies for patients with unmet medical needs. People battling glioblastoma cannot afford to wait years for us to agree to fund a treatment when their survival can often be measured in just months. We wanted a process that was more responsive to the needs of patients, and that could help companies like ImmunoCellular get their potentially life-saving therapies into clinical trials as quickly as possible.”

The science
The proposed treatment involves some rather cool science. Glioblastoma stem cells can evade standard treatments like chemotherapy and cause the recurrence and growth of the tumors. The ImmunoCellular therapy addresses this issue and targets six cell surface proteins that are found on glioblastoma cancer stem cells.

The researchers take immune cells from the patient’s own immune system and expose them to fragments of these cancer stem cell surface proteins in the lab. By re-engineering the immune cells in this way they are then able to recognize the cancer stem cells.

My colleague Todd Dubnicoff likened it to letting a bloodhound sniff a piece of clothing from a burglar so it’s able to recognize the scent and hunt the burglar down.  When the newly trained immune system cells are returned to the patient’s body, they can now help “sniff out” and hopefully kill the cancer stem cells responsible for the tumor’s recurrence and growth.

Like a bloodhound picking up the scent of a burglar, ImmunoCellular's therapy helps the immune system track down brain cancer stem cells (source: wikimedia commons)

Like a bloodhound picking up the scent of a burglar, ImmunoCellular’s therapy helps the immune system track down brain cancer stem cells (source: Wikimedia Commons)

Results from both ImmunoCellular’s Phase 1 and 2 trials using this approach were encouraging, showing that patients given the therapy lived longer than those who got standard treatment and experienced only minimal side effects.

Turning the corner against glioblastoma
There’s a moment immediately after the Board votes “yes” to fund a project like this. It’s almost like a buzz, where you feel that you have just witnessed something momentous, a moment where you may have turned the corner against a deadly disease.

We have a saying at the stem cell agency: “Come to work every day as if lives depend on it, because lives depend on it.” On days like this, you feel that we’ve done something that could ultimately help save some of those lives.

CIRM Scholar Spotlight: Matt Donne on Lung Stem Cells

CIRM has funded a number of educational and research training programs over the past ten years to give younger students and graduate/postdoc scholars the opportunity to explore stem cell science.

Two of the main programs we support are the Bridges and the CIRM Scholars Training Program. These programs fund future scientists from an undergraduate to postdoctoral level with a goal of creating “training programs that will significantly enhance the technical skills, knowledge, and experience of a diverse cohort of… trainees in the development of stem cell based therapies.”

The Stem Cellar team was interested to hear from Bridges and CIRM scholars themselves about their experience with these programs, how their careers have benefited from CIRM funding, and what research accomplishments they have under their belt. We were able to track some of these scholars down, and will be publishing a series of interview-style blogs featuring them over the next few months.

Matt Donne

Matt Donne

We start off with a Matt Donne, a PhD student at the University of California, San Francisco (UCSF) in the Developmental and Stem Cell Biology graduate program. Matt is a talented scientist and has a pretty cool story about his research training path. I sat down with Matt to ask him a few questions.

Q: Tell us how you got into a Stem Cell graduate program at UCSF.

MD: I was fortunate to have Dr. Carmen Domingo from San Francisco State support my application into the CIRM Bridges Program. I’d been working for Dr. Susan Fisher at UCSF for a couple of years and realized that I wanted to get a PhD and go to UCSF. I thought the best way to do that was improve my GPA and get a masters degree in stem cell biology. I applied to the CIRM program at SF State, and was accepted.

The Bridges Program has been a great feeder platform to get students more science experience exposure than they would have otherwise received, and prepares them well to move on to competitive graduate schools.

After receiving my Masters degree, I was admitted into the first year of the Developmental and Stem Cell Biology program at UCSF. When the opportunity to apply for a training grant from CIRM came about between my first and second year of at UCSF, I knew I had to give it a chance and apply. With the help of my mentor, Dr. Jason Rock, I wrote a solid proposal and was awarded the fellowship.

While at SF State, Carmen was extremely supportive and always available for her students. Since then, many of us still keep in touch and more have joined the UCSF graduate school community.

Q: Can you describe your graduate research?

MD: The field of regenerative medicine is searching for ways to allow us to repair injuries similar to how the Marvel Comic Wolverine can repair his wounds in the movies. One interesting fact which has been known for several decades, but has not been able to be investigated more deeply until now, is the innate ability for the adult lung to regrow lost lung tissue without any sort of intervention. My thesis focuses on defining the molecular mechanisms and stem cell niches that allow for this normal, healthy adult lung tissue growth. The working hypothesis is if we can understand what makes a cell undergo healthy tissue proliferation and differentiation, we could stimulate this response to cure individuals who suffer from diseases such as chronic obstructive pulmonary disease (COPD). Similarly, if we understand how a cell decides to respond in a diseased way, we could stop or revert the disease process from occurring.

One of the models we use in our lab is a “pneumosphere” culture. We essentially grow alveoli, which are the site of gas exchange in the lung, in a dish to attempt to understand how specific alveolar stem cells signal and interact with one another. This information will teach us how these cells behave so we can in turn either promote a healthy response to injury or, potentially, stop the progression of unhealthy cell responses. The technique of growing alveoli in a dish allows us to cut down on the “noise” and focus on major cellular pathways, which we can then more selectively apply to our mouse model systems.

Pneumospheres. (Photo by Matt Donne)

Pneumospheres or “lung cells in a dish”. (Photo by Matt Donne)

Lung cells.

Lung pneumospheres under a microscope. (Photo by Matt Donne)

We are now in the process of submitting a paper demonstrating some of the molecular players that are involved in this regenerative lung response. Hopefully the reviewers will think our paper is as awesome we as believe it to be.

Q: How has being a CIRM scholar benefited your graduate research career?

MD: Starting in my second year at UCSF, I was awarded the CIRM fellowship. I think it helped the lab to have the majority of my stipend covered through the CIRM fellowship, and personally I was very excited about the $5,000 discretionary budget. These monies allowed me to go to conferences every year for the past three years, and also have helped to support the costs of my experiments.

The first conference I attended was a Gordon Conference in Italy on Developmental Biology. There I was able to learn more about the field and also make friends with many professors, students, and postdocs from around the world. Last year, I went to my first lung-specific conference, and attended again this year. That has been one of the highlights of my PhD career. While there, one is able to speak and interact with professors whose names are seen in many textbooks and published papers. I never thought I would be able to so casually interact with them and develop relationships. Since then, I have been able to work on small collaborations with professors from across the US.

It was great that I could go to these conferences and establish important relationships with professors without being a major financial burden to my Professor. Plus, it has been hugely beneficial for my career as I now have professors whom I can reach out to as I look towards my future as a scientist.

Q: What other benefits did the CIRM scholars program provide you?

MD: Dr. Susan Fisher has been in charge of the CIRM program at UCSF. She organized lunch-time research talks that involved both academic as well as non-academic leaders in the field. I enjoyed the extra exposure to new fields of stem cell biology as well as the ability to learn more about the start-up and non-academic world. There are not many programs that offer this type of experience, and I felt fortunate to be a part of it. Also, the free lunches on occasion were a nice perk for a grad student living in San Francisco!

I attended the CIRM organized conferences whenever they happened. It’s always great presenting at or attending poster sessions at these events, seeing familiar faces and meeting new people. I took full advantage of the learning and networking that CIRM allowed me to do. The CIRM elevator pitch competition was really cool too. I didn’t win, came in third, but I enjoyed the challenge of trying to break down my thesis project into a digestible one-minute pitch.

Q: Where do you see the field of lung biology and regenerative medicine heading?

MD: My take away from the research conferences I have attended with the help of CIRM-funding is that we are in a very exciting time for lung stem cell research. The field overall is still young, but there are many labs across the world now working on a “lung mapping project” to better define stem cell populations in the lung. I see this research in the future translating in to regenerative therapies by which diseased cells/tissue will be targeted to actually stop the disease progression, and in turn possibly repair and regenerate healthy new tissue. This research has wide reaching implications as it has the potential to help everyone from a premature baby more quickly develop mature healthy lungs, to adults suffering from COPD brought on by environmental factors, such as air pollution. As many scientists are often quoted, “This is a very exciting time for our field.”

Q: What are your future plans?

MD: I expect to graduate in about a year’s time. In the future, I want to pursue a career focusing on the social impact of science. I aspire to be someone like UCSF’s former chancellor Dr. Susan Desmond-Hellmand. It’s really cool to go from someone who was the president of product development at Genentech, to chancellor at UCSF, to now president of the Bill and Melinda Gates Foundation. Bringing science to impact society in that way is what I hope to do with my future.

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