A new approach to a deadly childhood cancer

Cancers of the blood, bone marrow and lymph nodes (also called hematologic malignancies) are the most common form of cancer in children and young adults. Current treatments can be effective but can also pose life-threatening health risks to the child. Now researchers at Stanford have developed a new approach and the Board of the California Institute for Regenerative Medicine (CIRM) voted to support that approach in a clinical trial.

The Board approved investing $11,996,634 in the study, which is the Stem Cell Agency’s 76th clinical trial.

The current standard of care for cancers such as acute leukemias and lymphomas is chemotherapy and a bone marrow (also called HSCT) transplant. However, without a perfectly matched donor the risk of the patient’s body rejecting the transplant is higher. Patients may also be at greater risk of graft vs host disease (GVHD), where the donor cells attack the patient’s body. In severe cases GVHD can be life-threatening.

Dr. Maria Grazia Roncarlo: Photo courtesy Stanford

Dr. Maria Grazia Roncarolo and her team at Stanford will test an immunotherapy cell approach using a therapy that is enriched with specialized immune cells called type 1 regulatory T (Tr1) cells. These cells will be infused into the patient following the bone marrow transplant. Both the Tr1 cells and the bone marrow will come from the same donor. The hope is this will help provide the patient’s immune system with these regulatory cells to combat life-threatening graft versus host disease and increase the success of treatment and bone marrow (HSCT) transplant.

“Every year around 500 children receive stem cell transplants in California, and while many children do well, too many experiences a rejection of the transplant or a relapse of the cancer,” says Dr. Maria T. Millan, President and CEO of CIRM. “Finding an improved therapy for these children means a shorter stay in the hospital, less risk of the need for a second transplant, and a greater quality of life for the child and the whole family.”

The CIRM Board has previously approved funding for 12 other clinical trials targeting cancers of the blood. You can read about them here.

CIRM funds clinical trials targeting heart disease, stroke and childhood brain tumors

Gary Steinberg (Jonathan Sprague)

Heart disease and stroke are two of the leading causes of death and disability and for people who have experienced either their treatment options are very limited. Current therapies focus on dealing with the immediate impact of the attack, but there is nothing to deal with the longer-term impact. The CIRM Board hopes to change that by funding promising work for both conditions.

Dr. Gary Steinberg and his team at Stanford were awarded almost $12 million to conduct a clinical trial to test a therapy for motor disabilities caused by chronic ischemic stroke.  While “clot busting” therapies can treat strokes in their acute phase, immediately after they occur, these treatments can only be given within a few hours of the initial injury.  There are no approved therapies to treat chronic stroke, the disabilities that remain in the months and years after the initial brain attack.

Dr. Steinberg will use embryonic stem cells that have been turned into neural stem cells (NSCs), a kind of stem cell that can form different cell types found in the brain.  In a surgical procedure, the team will inject the NSCs directly into the brains of chronic stroke patients.  While the ultimate goal of the therapy is to restore loss of movement in patients, this is just the first step in clinical trials for the therapy.  This first-in-human trial will evaluate the therapy for safety and feasibility and look for signs that it is helping patients.

Another Stanford researcher, Dr. Crystal Mackall, was also awarded almost $12 million to conduct a clinical trial to test a treatment for children and young adults with glioma, a devastating, aggressive brain tumor that occurs primarily in children and young adults and originates in the brain.  Such tumors are uniformly fatal and are the leading cause of childhood brain tumor-related death. Radiation therapy is a current treatment option, but it only extends survival by a few months.

Dr. Crystal Mackall and her team will modify a patient’s own T cells, an immune system cell that can destroy foreign or abnormal cells.  The T cells will be modified with a protein called chimeric antigen receptor (CAR), which will give the newly created CAR-T cells the ability to identify and destroy the brain tumor cells.  The CAR-T cells will be re-introduced back into patients and the therapy will be evaluated for safety and efficacy.

Joseph Wu Stanford

Stanford made it three in a row with the award of almost $7 million to Dr. Joe Wu to test a therapy for left-sided heart failure resulting from a heart attack.  The major issue with this disease is that after a large number of heart muscle cells are killed or damaged by a heart attack, the adult heart has little ability to repair or replace these cells.  Thus, rather than being able to replenish its supply of muscle cells, the heart forms a scar that can ultimately cause it to fail.  

Dr. Wu will use human embryonic stem cells (hESCs) to generate cardiomyocytes (CM), a type of cell that makes up the heart muscle.  The newly created hESC-CMs will then be administered to patients at the site of the heart muscle damage in a first-in-human trial.  This initial trial will evaluate the safety and feasibility of the therapy, and the effect upon heart function will also be examined.  The ultimate aim of this approach is to improve heart function for patients suffering from heart failure.

“We are pleased to add these clinical trials to CIRM’s portfolio,” says Maria T. Millan, M.D., President and CEO of CIRM.  “Because of the reauthorization of CIRM under Proposition 14, we have now directly funded 75 clinical trials.  The three grants approved bring forward regenerative medicine clinical trials for brain tumors, stroke, and heart failure, debilitating and fatal conditions where there are currently no definitive therapies or cures.”

Saying thanks and farewell to a friend

Tom Howing

In this job you get to meet a lot of remarkable people, none more so than the patients who volunteer to take part in what are giant experiments. They are courageous pioneers, willing to be among the first people to ever try a new therapy, knowing that it may not help them and, potentially, might even harm them.

Tom Howing was one such person. I got to know Tom when we were putting together our 2017 Annual Report. Back in 2015 Tom was diagnosed with Stage 4 cancer that had spread throughout his body. He underwent surgery and chemotherapy. That worked for a while, but then the cancer returned. So, Tom had more surgery and chemotherapy. Again, it worked for a while but when the cancer returned again Tom was running out of options.

That’s when he learned about a clinical trial with a company called Forty Seven Inc. that was testing a new anti-cancer therapy that CIRM was supporting. Tom says he didn’t hesitate.

“When I was diagnosed with cancer I knew I had battle ahead of me. After the cancer came back again they recommended I try this CD47 clinical trial. I said absolutely, let’s give it a spin. I guess one is always a bit concerned whenever you put the adjective “experimental” in front of anything. But I’ve always been a very optimistic and positive person and have great trust and faith in my caregivers.”

Optimistic and positive are great ways to describe Tom. Happily, his optimism was rewarded. The therapy worked.

“Scans and blood tests came back showing that the cancer appears to be held in check. My energy level is fantastic. The treatment that I had is so much less aggressive than chemo, my quality of life is just outstanding.”

But after a year or so Tom had to drop out of the trial. He tried other therapies and they kept the cancer at bay. For a while. But it kept coming back. And eventually Tom ran out of options. And last week, he ran out of time.

Tom was a truly fine man. He was kind, caring, funny, gracious and always grateful for what he had. He talked often about his family and how the stem cell therapy helped him spend not just more time with them, but quality time.

He knew when he signed up for the therapy that there were no guarantees, but he wanted to try, saying that even if it didn’t help him that the researchers might learn something to help others down the line.

“The most important thing I would say is, I want people to know there is always hope and to stay positive.”

Tom ultimately lost his battle with cancer. But he never lost his spirit, his delight in his family and his desire to keep going as long as he could. In typical Tom fashion he preferred to put his concerns aside and cheer others along.

“To all those people who are putting in all the hours at the bench and microscope, it’s important for them to know that they are making a huge impact on the lives of real people and they should celebrate it and revel in it and take great pride in it.”

We consider ourselves fortunate to have known Tom and to have been with him on part of his journey. He touched our lives, as he touched the lives of so many others. Our thoughts and wishes go out to his family and friends. He will be remembered, because we never forget our friends.

A few years ago Tom came and talked to the CIRM Board. Here is the video of that event.

How early CIRM support helped an anti-cancer therapy overcome obstacles and help patients

Dr. Catriona Jamieson, UC San Diego

When you read about a new drug or therapy being approved to help patients it always seems so simple. Researchers come up with a brilliant idea, test it to make sure it is safe and works, and then get approval from the US Food and Drug Administration (FDA) to sell it to people who need it.

But it’s not always that simple, or straight forward. Sometimes it can take years, with several detours along the way, before the therapy finds its way to patients.

That’s the case with a blood cancer drug called fedratinib (we blogged about it here) and the relentless efforts by U.C. San Diego researcher Dr. Catriona Jamieson to help make it available to patients. CIRM funded the critical early stage research to help show this approach could help save lives. But it took many more years, and several setbacks, before Dr. Jamieson finally succeeded in getting approval from the FDA.

The story behind that therapy, and Dr. Jamieson’s fight, is told in the San Diego Union Tribune. Reporter Brad Fikes has been following the therapy for years and in the story he explains why he found it so fascinating, and why this was a therapy that almost didn’t make it.

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.