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
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
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.
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.”
[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.
CIRM 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.
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.
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.
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 CureAIDSreport.org
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.
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 bladder 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 BBCran 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.
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.
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)
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 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
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 or “lung cells in a dish”. (Photo by Matt Donne)
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.
As we age, so do the cells that make up our bodies. To keep us spry as we get older, our bodies rely on adult stem cells to replace the cells in our tissues and organs. Adult stem cells can only generate cell types specific to the organ or tissue that they live in. For instance, heart stem cells can only help regenerate or repair the heart, same for brain stem cells and the brain, etc.
While adult stem cells have built-in mechanisms to help them avoid the aging process for as long as possible, they can only delay the inevitable for so long. So as the function of our bodies decline, so does adult stem cell function and with it our ability to regenerate damaged tissue.
But now a new study has found out what happens to cause the aging of adult stem cells and points at ways to avoid it and keep these stem cells “forever young.”
Brain stem cells stay youthful
A group from Zurich, Switzerland studied how brain stem cells stay young as the brain ages. In a study published in Science on Friday, they found that young brain stem cells divide in a way that routes damaged proteins and aging-related factors away from the daughter stem cells and into their non-stem cell progeny, thus keeping brain stem cells healthy and youthful.
Brain stem cells divide asymmetrically into a daughter stem cell and a non-stem daughter cell that can differentiate into other brain cells (Image adapted from Berika et al., 2014).
The Zurich group took a closer look at brain stem cells in adult mouse brains and found that they divide asymmetrically. This means that instead of equally dividing its cellular components between two daughter cells, the mother cell instead herds all of the damaged proteins and aging factors into the non-stem daughter cell, leaving the new stem cell unexposed to cell damage. In this way, the new stem cell is protected and is able to maintain its regenerative capacity.
A barrier against aging?
Brain stem cells are able to preferentially shuttle damaged proteins into their non-stem cell progeny by a diffusion barrier called the endoplasmic reticulum (ER). The ER is a membrane structure in cells that has a number of important functions including deciding what factors or proteins end up in which cells.
The authors observed that during the division of brain stem cells, the ER forms a barrier between the non-stem and stem cell progeny that keeps the damaged proteins and aging factors in the non-stem daughter cell. This ER barrier remains intact during the division of young brain stem cells, however, they weren’t sure this was the case with older brain stem cells.
The scientists watched older brain stem cells to see if this anti-aging barrier was able to hold up with advancing age. They observed that this barrier actually weakens with age and allows aging factors to go with the stem cell progeny. This happens because an important cell structure called the nuclear lamina, which regulates cell division, doesn’t function properly in the old stem cells. When they disrupted the lamina structure in young brain stem cells, as expected, the anti-aging barrier couldn’t properly block the transfer of aging-factors into the new daughter stem cells.
Young brain stem cells on the left divide asymmetrically and have a barrier that keeps age-related damage in the non-stem daughter cell (red). This barrier weakens in older brain stem cells and aging factors are transferred to the stem cell progeny. (Moore et al., 2015)
Thus it seems that brain stem cells maintain their youth by generating diffusible barriers that block the transfer of damaged proteins and aging factors into their stem cell progeny during cell division. The strength of this barrier weakens with age, and when this happens, aging factors are more evenly divided between the non-stem and stem cell progeny, potentially causing stem cell damage and reducing their regenerative function.
Anti-aging implications
The authors note at the end of their report that further studies should be done to determine whether this anti-aging mechanism is unique to brain stem cells or if it occurs in other adult stem cells or cancer cells which display stem cell like properties. If similar anti-aging barriers exist, then targeting the age-related breakdown of this barrier could be a potential strategy to keep adult stem cells forever young and humans feeling and acting younger for a little longer.
Caladrius Biosciences has been funded by CIRM to conduct a Phase 3 clinical trial to treat the most severe form of skin cancer: metastatic melanoma. Metastatic melanoma is a disease with no effective treatment, only around 15 percent of people with it survive five years, and every year it claims an estimated 10,000 lives in the U.S.
The CIRM/Caladrius Clinical Advisory Panel meets to chart future of clinical trial
The Caladrius team has developed an innovative cancer treatment that is designed to target the cells responsible for tumor growth and spread. These are called cancer stem cells or tumor-initiating cells. Cancer stem cells can spread in the body because they have the ability to evade the body’s immune defense and survive standard anti-cancer treatments such as chemotherapy. The aim of the Caladrius treatment is to train the body’s immune system to recognize the cancer stem cells and attack them.
Attacking the cancer
The treatment process involves taking a sample of a patient’s own tumor and, in a laboratory, isolating specific cells responsible for tumor growth . Cells from the patient’s blood, called “peripheral blood monocytes,” are also collected. The mononucleocytes are responsible for helping the body’s immune system fight disease. The tumor and blood cells (after maturation into dendritic cells) are then combined and incubated so that the patient’s immune cells become trained to recognize the cancer cells.
After the incubation period, the patient’s immune cells are injected back into their body where they generate an immune response to the cancer cells. The treatment is like a vaccine because it trains the body’s immune system to recognize and rapidly attack the source of disease.
Recruiting the patients
Caladrius has already dosed the first patient in the trial (which is double blinded so no one knows if the patient got the therapy or a placebo) and hopes to recruit 250 patients altogether.
This is the first Phase 3 trial that CIRM has funded so we’re obviously excited about its potential to help people battling this deadly disease. In a recent news release David J. Mazzo, the CEO of Caladrius echoed this excitement, with a sense of cautious optimism:
“The dosing of the first patient in this Phase 3 trial is an important milestone for our Company and the timing underscores our focus on this program and our commitment to impeccable trial execution. We are delighted by the enthusiasm and productivity of the team at Jefferson University (where the patient was dosed) and other trial sites around the country and look forward to translating that into optimized patient enrollment and a rapid completion of the Phase 3 trial.”
And that’s the key now. They have the science. They have the funding. Now they need the patients. That’s why we are all working together to help Caladrius recruit patients as quickly as possible. Because their work perfectly reflects our mission of accelerating the development of stem cell therapies for patients with unmet medical needs.
You can learn more about what the study involves and who is eligible by clicking here.
An end run around sickle cell disease with CRISPR The CRISPR-based gene editing technique has got to be the hottest topic in biomedical research right now. And I sense we’re only at the tip of the iceberg with more applications of the technology popping up almost every week. Just two days ago, researchers at the Dana Farber Cancer Institute in Boston reported in Nature that they had identified a novel approach to correcting sickle cell disease (SCD) with CRISPR.
A mutation in the globlin gene leads to sickled red blood cells that clog up blood vessels (image: CIRM video)
Sickle cell anemia is a devastating blood disorder caused by a single, inherited DNA mutation in the adult form of the hemoglobin gene (which is responsible for making blood). A CIRM-funded team at UCLA is getting ready to start testing a therapy in clinical trials that uses a similar but different gene editing tool to correct this mutation. Rather than directly fixing the SCD mutation as the UCLA team is doing, the Dana Farber team focused on a protein called BCL11A. Acting like a molecular switch during development, BCL11A shifts hemoglobin production from a fetal to an adult form. The important point here is that the fetal form of hemoglobin can substitute for the adult form and is unaffected by the SCD mutation.
So using CRISPR gene editing, they deleted a section of DNA from a patient’s blood stem cells that reduced BCL11A and increased production of the fetal hemoglobin. This result suggests the technique can, to pardon the football expression, do an end run around the disease.
But if there’s already a recipe for directly fixing the SCD mutation, why bother with this alternate CRISPR DNA deletion method? In a press release Daniel Bauer, one of the project leaders, explains the rationale:
“It turns out that blood stem cells, the ultimate targets for this kind of therapy, are much more resistant to genetic repair than to genetic disruption.”
Whatever the case, we’re big believers in the need to have several shots on goal to help ensure a victory for patients.
Clinical trial asks: does sparing salivary stem cells protect against severe dry mouth? I bet you rarely think about or appreciate your saliva. But many head and neck cancer patients who undergo radiation therapy develop severe dry mouth caused by damage to their salivary glands. It doesn’t sound like a big deal, but in reality, the effects of dry mouth are life-changing. A frequent need to drink water disrupts sleep and leads to chronic fatigue. And because saliva is crucial for preventing tooth decay, these patients often lose their teeth. Eating and speaking are also very difficult without saliva, which cause sufferers to retreat from society.
Help may now be on the way. On Wednesday, researchers from University of Groningen in the Netherlands reported in Science Translational Medicine the identification of stem cells in a specific region within the large salivary glands found near each ear. In animal experiments, the team showed that specifically irradiating the area where the salivary stem cells lie shuts down saliva production. And in humans, the amount of radiation to this area is linked to the severity of dry mouth symptoms.
Doctors have confirmed that focusing the radiation therapy beams can minimize exposure to the stem cell-rich regions in the salivary glands. And the research team has begun a double-blind clinical trial to see if this modified radiation treatment helps reduce the number of dry mouth sufferers. They’re looking to complete the trial in two to three years.
Keeping a Lid on Jumping Genes Believe it or not, you have jumping genes in your cells. The scientific name for them is retrotransposons. They are segments of DNA that can literally change their location within your chromosomes.
While retrotransposons have some important benefits such as creating genetic diversity, the insertion or deletion of DNA sequences can be bad news for a cell. Such events can cause genetic mutations and chromosome instability, which can lead to an increased risk of cancer growth or cell death.
To make its jump, the DNA sequence of a retrotransposon is copied with the help of an intermediary RNA (the green object in the picture below). A special enzyme converts the RNA back into DNA and this new copy of the retrotransposon then gets inserted at a new spot in the cell’s chromosomes.
The duplication and insertion of transposons into our chromosomes can be bad news for a cell
Most of our cells keep this gene jumping activity in check by adding inhibitory chemical tags to the retrotransposon DNA sequence. Still, researchers have observed that in unspecialized cells, like induced pluripotent stem (iPS) cells, these inhibitory chemical tags are reduced significantly.
So you’d think that iPS cells would be prone to the negative consequences of retrotransposon reactivation and unleashed jumping genes. But in a CIRM-funded paper published on Monday in Nature Structural and Molecular Biology, UC Irvine researchers show that despite the absence of those inhibitory chemical tags, the retrotransposon activity is reduced due to the presence of microRNA (miRNA), in this case miRNA-128. This molecule binds and blocks the retrotransposon’s RNA intermediary so no duplicate jumping gene is made.
The team’s hope is that by using miRNA-128 to curb the frequency of gene jumping, they can reduce the potential for mutations and tumor growth in iPS cells, a key safety step for future iPS-based clinical trials.
Great hope for lung stem cells Chronic lung disease is the third leading cause of death in the U.S. but sadly doctors don’t have many treatment options except for a full lung transplant, which is a very risky procedure with very limited sources of donated organs. For these reasons, there is great interest in better understanding the location and function of lung stem cells. Harnessing the regenerative abilities of these cells may lead to more alternatives for people with end stage lung disease.
In a BioMedicine Development commentary that’s geared for our scientist readers, UCSF researchers summarize the evidence for stem cell population in the lung. We’re proud to say that one of the lead authors, Matt Donne, is a former CIRM Scholar.
The Stem Cellar 