A Fishy Tale: A gene that blocks regeneration in fish blocks cancer in humans

Evolution is a fascinating thing. Over time, the human race has evolved from cavemen to a bustling civilization fueled by technology, science, and economics. While we’ve gained many abilities that separate us from other mammals and our closest ancestors, the apes, we’ve also lost a number of skills along the way.

One of them is the ability to regenerate. Some animals such as lizards, fish, and frogs, have a robust capacity to regenerate entire limbs and organs while humans can only partially regenerate some tissues and organs on a much smaller scale. Why did we lose this advantageous trait?

A human gene that stops cancer also blocks regeneration

Image courtesy of Flickr.

Zebrafish. (Image courtesy of Flickr)

Scientists from UCSF have found a new piece to this evolutionary puzzle in a paper published today in eLife. They found that a gene responsible for preventing cells from growing uncontrollably into deadly cancers in humans is also able to block tissue regeneration in zebrafish.

Detailed in a UCSF news release, professor and senior author on the study, Jason Pomerantz, was always intrigued by why humans can’t regenerate limbs like salamanders. To answer these questions, he turned to model organisms like fish and amphibians:

Jason Pomerantz, UCSF

Jason Pomerantz, UCSF

In the last 10 to 15 years, as regenerative organisms like zebrafish have become genetically tractable to study in the lab, I became convinced that these animals might be able to teach us what is possible for human regeneration. Why can these vertebrates regenerate highly complex structures, while we can’t?


Like other scientists, Pomerantz was curious to know if humans “grew out of” their regenerative abilities in order to acquire systems that block cancer growth. Humans and other mammals have genes called tumor-suppressors that are important for regulating tissue differentiation during development and for preventing excessive cell growth and tumor formation after birth and beyond. Many of these tumor suppressor genes are conserved across a wide range of species, but Pomerantz knew of one that wasn’t shared between humans and regenerative animals, a gene called ARF.

Pomerantz and his team decided to see what happened when they added the human Arf gene into the genome of a highly regenerative animal, the zebrafish. While the addition of ARF did not affect zebrafish development, it did almost fully block their ability to regrow their tail fins after the tips were removed.

Normal zebrafish can regrow their tail fins after they are clipped, but fish that have the ARF gene cannot. (eLife)

Normal zebrafish can regrow their tail fins after they are clipped (top) , but fish that have the human ARF gene cannot (bottom). (Image from eLife)

Pomerantz explained ARF’s anti-regenerative role in the fish:

“It’s like the gene is mistaking the regenerating fin cells for aspiring cancer cells. And so it [ARF] springs into action to block it.”

Is Wolverine our future?

Wolverine. (Courtesy of wired.com)

Marvel’s Wolverine has regenerative powers. (Courtesy of wired.com)

Knowing that ARF suppresses tissue regeneration in fish, the obvious question that arises from this study is whether blocking the Arf gene in humans would promote tissue regeneration. Would doing this mean we could all be regenerative super heroes like Wolverine one day?

Pomerantz explained further in the UCSF new release that boosting regeneration in humans that need new organs or limbs could be possible but would require a careful balance to avoid setting off rampant tumor growth:

Future efforts to promote regeneration in humans will likely require carefully balanced suppression of this anti-tumor system. The same pathway in humans theoretically could be blocked to enhance researchers’ ability to grow model organs from stem cells in a laboratory dish, to enhance patients’ recovery from injury. Since tumor suppressors are thought to play a role in aging by limiting the rejuvenating potential of stem cells, blocking this pathway could even be a part of future anti-aging therapies.

Scientists will likely have to weigh the risks and benefits for human tissue regeneration on a case by case basis. Pomerantz concluded with this admission:

The ratio of risk and benefit has to be appropriate. For instance, there are certain congenital diseases that cause craniofacial deformities so severe that the risks of such a treatment might be clinically reasonable.


Stem cell stories that caught our eye: cancer fighting virus, lab-grown guts work in dogs, stem cell trial to cure HIV

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.

Cancer fighting virus approved for melanoma

(Disclaimer: While this isn’t a story about stem cells, it’s pretty cool so I had to include it.)

The term “virus” generally carries a negative connotation, but in some cases, viruses can be the good guys. This was the case on Tuesday when our drug approval agency, the US Food and Drug Administration (FDA), approved the use of a cancer fighting virus for the treatment of advanced stage melanoma (skin cancer).

The virus, called T-VEC, is a modified version of the herpesvirus, which causes a number of diseases and symptoms including painful blisters and sores in the mouth. Scientists engineered this virus to specifically infect cancer cells and not healthy cells. Once inside cancer cells, T-VEC does what a virus normally does and wreaks havoc by attacking and killing the tumor.

The beauty of this T-VEC is that in the process of killing cancer cells, it causes the release of a factor called GM-CSF from the cancer cells. This factor signals the human immune system that other cancer cells are nearby and they should be attacked and killed by the soldiers of the immune system known as T-cells. The reason why cancers are so deadly is because they can trick the immune system into not recognizing them as bad guys. T-VEC rips off their usual disguise and makes them vulnerable again to attack.

T-VEC recruits immune cells (orange) to attack cancer cells (pink) credit Dr. Andrejs Liepins/SPL

T-VEC recruits immune cells (orange) to attack cancer cells (pink). Photo credit Dr. Andrejs Liepins/SPL.

This is exciting news for cancer patients and was covered in many news outlets. Nature News wrote a great article, which included the history of how we came to use viruses as tools to attack cancer. The piece also discussed options for improving current T-VEC therapy. Currently, the virus is injected directly into the cancer tumor, but scientists hope that one day, it could be delivered intravenously, or through the bloodstream, so that it can kill hard to reach tumors or ones that have spread to other parts of the body. The article suggested combining T-VEC with other cancer immunotherapies (therapies that help the immune system recognize cancer cells) or delivering a personalized “menu” of cancer-killing viruses to treat patients with different types of cancers.

As a side note, CIRM is also interested in fighting advanced stage melanoma and recently awarded $17.7 million to Caladrius Biosciences to conduct a Phase 3 clinical trial with their melanoma killing vaccine. For more, check out our recent blog.

Lab-grown guts work in mice and dogs

If you ask what’s trending right now in stem cell research, one of the topics that surely would pop up is 3D organoids. Also known as “mini-organs”, organoids are tiny models of human organs generated from human stem cells in a dish. To make them, scientists have developed detailed protocols that sometimes involve the use of biological scaffolds (structures on which cells can attach and grow).

A study published in Regenerative Medicine and picked up by Science described the generation of “lab-grown gut” organoids using intestine-shaped scaffolds. Scientists from Johns Hopkins figured out how to grow intestinal lining that had the correct anatomy and functioned properly when transplanted into mice and dogs. Previous studies in this area used flat scaffolds or dishes to grow gut organoids, which weren’t able to form proper functional gut lining.

Lab-grown guts could help humans with gut disorders. (Shaffiey et al., 2015)

Lab-grown guts could help humans with gut disorders. (Shaffiey et al., 2015)

What was their secret recipe? The scientists took stem cells from the intestines of human infants or mice and poured a sticky solution of them onto a scaffold made of suture-like material. The stem cells then grew into healthy gut tissue over the next few weeks and formed tube structures that were similar to real intestines.

They tested whether their mini-guts worked by transplanting them into mice and dogs. To their excitement, the human and mouse lab-grown guts were well tolerated and worked properly in mice, and in dogs that had a portion of their intestine removed. Even more exciting was an observation made by senior author David Hackham:

“The scaffold was well tolerated and promoted healing by recruiting stem cells. [The dogs] had a perfectly normal lining after 8 weeks.”

The obvious question about this study is whether these lab-grown guts will one day help humans with debilitating intestinal diseases like Crohn’s and IBS (inflammatory bowel disorder). Hackam said that while they are still a long way from taking their technology to the clinic, “in the future, scaffolds could be custom-designed for individual human patients to replace a portion of an intestine or the entire organ.”

Clinical trial using umbilical cord stem cells to treat HIV

This week, the first clinical trial using human umbilical cord stem cells to treat HIV patients was announced in Spain. The motivation of this trial is the previous success of the Berlin Patient, Timothy Brown.

The Berlin patient can be described as the holy grail of HIV research. He is an American man who suffered from leukemia, a type of blood cancer, but was also HIV-positive. When his doctor in Berlin treated his leukemia with a stem cell transplant from a bone-marrow donor, he chose a special donor whose stem cells had an inherited mutation in their DNA that made them resistant to infection by the HIV virus. Surprisingly, after the procedure, Timothy was cured of both his cancer AND his HIV infection.

Berlin patient Timothy Brown. Photo credit: Griffin Boyce/Flickr.

Berlin patient Timothy Brown. Photo credit: Griffin Boyce/Flickr.

The National Organization of Transplants (ONT) in Spain references this discovery as its impetus to conduct a stem cell clinical trial to treat patients with HIV and hopefully cure them of this deadly virus. The trial will use umbilical cord blood stem cells instead of bone-marrow stem cells from 157 blood donors that have the special HIV-resistance genetic mutation.

In coverage from Tech Times, the president of the Spanish Society of Hematology and Hemotherapy, Jose Moraleda, was quoted saying:

“This project can put us at the cutting edge of this field within the world of science. It will allow us to gain more knowledge about HIV and parallel offer us a potential option for curing a poorly diagnosed malignant hematological disease.”

The announcement for the clinical trial was made at the Haematology conference in Valencia, and ONT hopes to treat its first patient in December or January.

Stem cells and prostate cancer are more similar than we thought

Prostate cancer is a scary word for men, no matter how macho or healthy they are. These days however, prostate cancer is no longer a death sentence for them. In fact, many men survive this disease if diagnosed early. However, for those unlucky ones who have more advanced stages of prostate cancer (where the tumor has metastasized and spread to other organs), the typical treatments used to fight the tumors don’t work effectively because advanced tumors become resistant to these therapies.

To help those afflicted with late stage prostate cancer, scientists are trying to understand the nature of prostate cancer cells and what makes them so “deadly”. By understanding the biology behind these tumor cells, they hope to develop better therapies to treat the late-stage forms of this disease.

UCLA scientists Bryan Smith and Owen Witte. (Image credit: UCLA Broad Stem Cell Research Center)

UCLA scientists Bryan Smith and Owen Witte. (Image credit: UCLA Broad Stem Cell Research Center)

But don’t worry, help is already on its way. Two groups from the University of California, Los Angeles and the University of California, Santa Cruz published a breakthrough discovery yesterday on the similarity between prostate cancer cells and prostate stem cells. The study was published in the journal PNAS and was led by senior author and director of the UCLA Broad Stem Cell Research Center, Dr. Owen Witte.

Using bioinformatics, Witte and his team compared the gene expression profiles of late-stage, metastatic prostate cancer cells sourced from tumor biopsies of living patients to healthy cell types in the male prostate. Epithelial cells are one of the main cell types in the prostate (they form the prostate glands) and they come in two forms: basal and luminal. When they compared the gene expression profiles of the prostate cancer cells to healthy prostate epithelial cells, they found that the cancer cells had a similar profile to normal prostate epithelial basal stem cells.

Image of a prostate cancer tumor. Green and red represent different stem cell traits and the yellow areas show where two stem cell traits are expressed together. (Image credit: UCLA Broad Stem Cell Research Center)

Image of a prostate cancer tumor. Green and red represent different stem cell traits and the yellow areas show where two stem cell traits are expressed together. (Image credit: UCLA Broad Stem Cell Research Center)

In fact, they discovered a 91-gene signature specific to the basal stem cells in the prostate. This profile included genes important for stem cell signaling and invasiveness. That meant that the metastatic prostate cancer cells also expressed “stem-like” genes.

First author Bryan Smith explained how their results support similar findings for other types of cancers. “Evidence from cancer research suggests that aggressive cancers have stem–cell-like traits. We now know this to be true for the most aggressive form of prostate cancer.”

So what does this study mean for prostate cancer patients? I’ll let Dr. Witte answer this one…

Treatments for early stage prostate cancer are often successful, but therapies that target the more aggressive and late-stage forms of the disease are urgently needed. I believe this research gives us important insight into the cellular nature of aggressive prostate cancer. Pinpointing the cellular traits of cancer — what makes those cells grow and spread — is crucial because then we can possibly target those traits to reverse or stop cancer’s progression. Our findings will inform our work as we strive to find treatments for aggressive prostate cancer.

Related links:


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.

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.

Helping patient’s fight back against deadliest form of skin cancer

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 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.