Big time validation for early support

It’s not every day that a company and a concept that you helped support from the very beginning gets snapped up for $4.9 billion. But that’s what is happening with Forty Seven Inc. and their anti-cancer therapies. Gilead, another California company by the way, has announced it is buying Forty Seven Inc. for almost $5 billion.

The deal gives Gilead access to Forty Seven’s lead antibody therapy, magrolimab, which switches off CD47, a kind of “do not eat me” signal that cancer cells use to evade the immune system.

CIRM has supported this program from its very earliest stages, back in 2013, when it was a promising idea in need of funding. Last year we blogged about the progress it has made from a hopeful concept to an exciting therapy.

When Forty Seven Inc. went public in 2018, Dr. Irv Weissman, one of the founders of the company, attributed a lot of their success to CIRM’s support.

Dr. Irv Weissman

“The story of the funding of this work all of the way to its commercialization and the clinical trials reported in the New England Journal of Medicine is simply this: CIRM funding of a competitive grant took a mouse discovery of the CD47 ‘don’t eat me’ signal through all preclinical work to and through a phase 1 IND with the FDA. Our National Institutes of Health (NIH) did not fund any part of the clinical trial or preclinical run up to the trial, so it is fortunate for those patients and those that will follow, if the treatment continues its success in larger trials, that California voters took the state’s right action to fund research not funded by the federal government.”

Dr. Maria Millan, CIRM’s President & CEO, says the deal is a perfect example of CIRM’s value to the field of regenerative medicine and our ability to work with our grantees to make them as successful as possible.

“To say this is incredible would be an understatement! Words cannot describe how excited we are that this novel approach to battling currently untreatable malignancies has the prospect of making it to patients in need and this is a major step. Speaking on behalf of CIRM, we are very honored to have been a partner with Forty Seven Inc. from the very beginning.

CIRM Senior Science Officer, Dr. Ingrid Caras, was part of the team that helped a group of academic scientists take their work out of the lab and into the real world.

“I had the pleasure of working with and helping the Stanford team since CIRM provided the initial funding to translate the idea of developing CD47 blockade as a therapeutic approach. This was a team of superb scientists who we were fortunate to work closely with them to navigate the Regulatory environment and develop a therapeutic product. We were able to provide guidance as well as funding and assist in the ultimate success of this project.”

Forty Seven Inc. is far from the only example of this kind of support and collaboration. We have always seen ourselves as far more than just a funding agency. Money is important, absolutely. But so too is bringing the experience and expertise of our team to help academic scientists take a promising idea and turn it into a successful therapy.

After all that’s what our mission is, doing all we can to accelerate stem cell therapies to patients with unmet medical needs. And after a deal like this, Forty Seven Inc. is definitely accelerating its work.

Two CIRM supported studies highlighted in Nature as promising approaches for blood disorders

Blood stem cells (blue) are cleared from the bone marrow (purple) before new stem cells can be transplanted.Credit: Dennis Kunkel Microscopy/SPL

Problems with blood stem cells, a type of stem cell in your bone marrow that gives rise to various kinds of blood cells, can sometimes result in blood cancer as well as genetic and autoimmune diseases.

It is because of this that researchers have looked towards blood stem cell transplants, which involves replacing a person’s defective blood stem cells with healthy ones take from either a donor or the patient themselves.

However, before this can be done, the existing population of defective stem cells must be eradicated in order to allow the transplanted blood stem cells to properly anchor themselves into the bone marrow. Current options for this include full-body radiation or chemotherapy, but these approaches are extremely toxic.

But what if there was a way to selectively target these blood stem cells in order to make the transplants much safer?

An article published in Nature highlights the advancements made in the field of blood stem cell transplantation, some of which is work that is funded by yours truly.

One of the approaches highlighted involves the work that we funded related to Forty Seven and an antibody created that inhibits a protein called CD47.

The article discusses how Forty Seven tested two antibodies in monkeys. One antibody blocks the activity of a molecule called c-Kit, which is found on blood stem cells. The other is the antibody that blocks CD47, which is found on some immune cells. Inhibiting CD47 allows those immune cells to sweep up the stem cells that were targeted by the c-Kit antibody, thereby boosting its effectiveness. In early tests, the two antibodies used together reduced the number of blood stem cells in bone marrow. The next step for this team is to demonstrate that the treatment clears out the old supply of stem cells well enough to allow transplanted cells to flourish.

You can read more about the CD47 antibody in a previous blog post.

Another notable segment of this article is the CIRM funded trial that is being conducted by Dr. Judith Shizuru at Stanford University. This clinical trial also uses an antibody that targets c-Kit found on blood stem cells.

The purpose of this trial is to wipe out the problematic blood stem cells in infants with X-linked Severe combined immunodeficiency (SCID), a rare fatal genetic disorder that leaves infants without a functional immune system, in order to introduce properly functioning blood stem cells. Dr. Shizuru and her team found that transplanted blood stem cells, in this case from donors who did not have the disease, successfully took hold in the bone marrow of four out of six of the babies.

You can read more about Dr. Shizuru’s work in a previous blog post as well.

Newly discovered “don’t eat me” signal shows potential for ovarian and triple-negative breast cancer treatment

Stanford researchers have found that cancer cells have a protein called CD24 on their surface that enables them to protect themselves against the body’s immune cells.
Courtesy of Shutterstock

Getting a breast cancer diagnosis is devastating news in and of itself. Currently, there are treatment options that target three different types of receptors, which are named hormone epidermal growth factor receptor 2 (HER-2), estrogen receptors (ER), and progesterone receptors (PR), commonly found in breast cancer cells, . Unfortunately, in triple-negative breast cancer, which occurs in 10-20% of breast cancer cases, all three receptors are absent, making this form of breast cancer very aggressive and difficult to treat.

In recent years, researchers have discovered that proteins on the cell surface can tell macrophages, an immune cell designed to detect and engulf foreign or abnormal cells, not to eat and destroy them. This can be useful to help normal cells keep the immune system from attacking them, but cancer cells can also use these “don’t eat me” signals to hide from the immune system. 

An illustration of a macrophage, a vital part of the immune system, engulfing and destroying a cancer cell. Antibody 5F9 blocks a “don’t eat me” signal emitted from cancer cells. Courtesy of Forty Seven, Inc.

In fact, because of this concept, a CIRM-funded clinical trial is being conducted that uses an antibody called 5F9 to block a “don’t eat me” signal known as CD47 that is found in cancer cells. The results of this trial, which have been announced in a previous blog post, are very promising.

Further building on this concept, a CIRM-funded study has now discovered a potential new target for triple-negative breast cancer as well as ovarian cancer. Dr. Irv Weissman and a team of researchers at Stanford University have discovered an additional “don’t eat me” signal called CD24 that cancers seem to use to evade detection and destruction by the immune system.

In a press release, Dr. Weissman talks about his work with CD47 and states that,

“Finding that not all patients responded to anti-CD47 antibodies helped fuel our research at Stanford to test whether non-responder cells and patients might have alternative ‘don’t eat me’ signals.” 

The scientists began by looking for signals that were produced more highly in cancers than in the tissues from which the cancers arose. It is here that they discovered CD24 and then proceeded to implant human breast cancer cells in mice for testing. When the CD24 signaling was blocked, the mice’s immune system attacked the cancer cells.

An important discovery was that ovarian and triple-negative breast cancer were highly affected by blocking of CD24 signaling. The other interesting discovery was that the effectiveness of CD24 blockage seems to be complementary to CD47 blockage. In other words, some cancers, like blood cancers, seem to be highly susceptible to blocking CD47, but not to CD24 blockage. For other cancers, like ovarian cancer, the opposite is true. This could suggest that most cancers will be susceptible to the immune system by blocking the CD24 or CD47 signal, and that cancers may be even more vulnerable when more than one “don’t eat me” signal is blocked.

Dr. Weissman and his team are now hopeful that potential therapies to block CD24 signaling will follow in the footsteps of the clinical trials related to CD47.

The full results to the study were published in Nature.

CIRM funded clinical trial shows promising results for patients with blood cancers

An illustration of a macrophage, a vital part of the immune system, engulfing and destroying a cancer cell. Antibody 5F9 blocks a “don’t eat me” signal emitted from cancer cells.
Courtesy of Forty Seven, Inc.

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are both types of blood cancers that can be difficult to treat. CIRM is funding Forty Seven, Inc. to conduct a clinical trial to treat patients with these blood cancers with an antibody called 5F9. CIRM has also given multiple awards prior to the clinical trial to help in developing the antibody.

Cancer cells express a signal known as CD47, which sends a “don’t eat me” message to macrophages, which are white blood cells that are part of the immune system designed to “eat” and destroy unhealthy cells. The antibody works by blocking the signal, enabling the body’s own immune system to detect and destroy the cancer cells.

In a press release, Forty Seven, Inc. announced early clinical results from their CIRM funded trial using the antibody to treat patients with AML and MDS. Some patients received just the antibody while others received the antibody in combination with azacitidine, a chemotherapy drug used to treat these cancers.

Here is a synopsis of the trial:

  • 35 patients treated in a Phase 1 clinical trial have been evaluated for a response assessment to-date.
  • 10 of these have MDS or AML and only received the 5F9 antibody.
  • 11 of these have higher-risk MDS and received the 5F9 antibody along with the chemotherapy drug azacitidine.
  • 14 of these have untreated AML and received the 5F9 antibody along with the chemotherapy drug azacitidine.

For the 11 patients with higher-risk MDS treated with the antibody and chemotherapy, they found that:

  • All 11 patients achieved an objective response rate (ORR), meaning that there was a reduction in tumor burden of a predefined amount.
  • Six of these patients achieved a complete response (CR), indicating a disappearance of all signs of cancer in response to treatment.

For the 14 patients with untreated AML treated with the antibody and chemotherapy, they found that:

  • Nine of these patients achieved an ORR.
  • Five of these nine patients achieved a CR.
  • Two of these nine patients achieved a morphologic leukemia-free state (MLFS), indicating the disappearance of all cells with formal and structural characteristics of leukemia, accompanied by bone marrow recovery, in response to treatment. 
  • The remaining five patients achieved stable disease (SD), meaning that the tumor is neither growing nor shrinking.

The results also showed that:

  • There was no evidence of increased toxicities when the antibody was used alongside the chemotherapy drugs, demonstrating tolerance and safety of the treatment.
  • No responding MDS or AML patient has relapsed or progressed on the antibody in combination with chemotherapy, with a median follow-up of 3.8 months.
  • The median time to response was rapid at 1.9 months.
  • Several patients have experienced deepening responses over time resulting in complete remissions. 

Based on the favorable results observed in this clinical trial to-date, expansion cohorts have been initiated, meaning that additional patients will be enrolled in a phase I trial. This will include patients with both higher-risk MDS and untreated AML as well as using the antibody in combination with chemotherapy.

In the press release, Dr. David Sallman, an investigator in the clinical trial, is quoted as saying,

“These new data for 5F9 show encouraging clinical activity in a broad population of patients with MDS and AML, who may be unfit for existing therapeutic options or at higher-risk for developing rapidly-advancing disease. Despite an evolving treatment landscape, physicians continue to seek new therapies for MDS and AML that can be used safely in combination with standard-of-care to help patients more rapidly achieve durable responses. To that end, I am excited to see meaningful clinical activity in a majority of patients treated with 5F9 in combination with azacitidine, with a median time to response of under two months and no relapses or progressions among responding patients.”

Saying goodbye to a good friend and a stem cell pioneer: Karl Trede

FrankTrede_B_0110_20161204120959_2016_12_04_CIRM_AnnualReport_KarlTrede_SanJose_Portraits_SeesTheDay

Sometimes even courage and determination are not enough. Karl Trede had courage and determination in droves as he fought a 12 year battle against cancer. He recently lost that battle. But he remains an inspiration for all who knew him.

I got to know Karl for our 2016 Annual Report. Karl had been diagnosed with throat cancer in 2006. He underwent surgery to remove his vocal cords and the cancer seemed to be in remission. But then it returned, this time having spread to his lungs. His doctors said they had pretty much run out of options but would Karl consider trying something new, something no one else had tried before; stem cells.

Karl told me he didn’t hesitate.

“I said “sure”. I don’t believe I knew at the time that I was going to be the first one but I thought I’d give it a whirl. It was an experience for me. It was eye opening. I wasn’t real concerned about being the first, I figured I was going to have to go someday so I guess if I was the first person and something really went wrong then they’d definitely learn something. So, to me, that was kind of worth my time.”

Happily nothing went wrong and the team behind the therapy (Forty Seven Inc.) definitely learned something, they learned a lot about the correct dosage for patients; invaluable information in treating future patients.

Karl’s cancer was held at bay and he was able to do the one thing that brought him more pleasure than anything else; spend time with his family, his wife Vita, their four sons and their families. He doted on his grand kids and got to see them grow, and they got to know him.

Recently the cancer returned and this time there was no holding it at bay. To the end Karl remained cheerful and positive.

KARL poster

In our office is a huge poster of Karl with the words “Every Moment Counts” at the bottom. It’s a reminder to us why we come to work every day, why the people at Forty Seven Inc. and all the other researchers we support work so hard for years and years; to try and give people like Karl a few extra moments with his family.

At the top of the poster the word “Courage” is emblazoned across it. Karl has a huge smile on his face. Karl was certainly courageous, a stem cell pioneer willing to try something no one else ever had. He was also very modest.

Here is Karl speaking to our governing Board in December 2016

When I spoke to him in 2016, despite all he had gone through in his fight against cancer, he said he had no regrets:

“I consider myself very fortunate. I’m a lucky guy.”

Those of us who got to spend just a little time with Karl know that we were the lucky ones.

Our hearts go out to his family and friends for their loss.

 

 

Early CIRM support helps stem cell pioneer develop promising new therapy for cancer

Irv Weissman

Irv Weissman, Ph.D., Photo: courtesy Stanford University

When you get praise from someone who has been elected to the National Academy of Sciences and has been named California Scientist of the Year you know you must be doing something right.

That’s how we felt the other day when Irv Weissman, Director of the Stanford Institute of Stem Cell Biology and Regenerative Medicine, issued a statement about how important the support of CIRM was in advancing his research.

The context was the recent initial public offering (IPO) of Forty Seven Inc.. a company co-founded by Dr. Weissman. That IPO followed news that two Phase 2 clinical trials being run by Forty Seven Inc. were demonstrating promising results against hard-to-treat cancers.

Dr. Weissman says the therapies used a combination of two monoclonal antibodies, 5F9 from Forty Seven Inc. and Rituximab (an already FDA-approved treatment for cancer and rheumatoid arthritis) which:

“Led to about a 50% overall remission rate when used on patients who had relapsed, multi-site disease refractory to rituximab-plus-chemotherapy. Most of those patients have shown a complete remission, although it’s too early to tell if this is complete for life.”

5F9 attacks a molecule called CD47 that appears on the surface of cancer cells. Dr. Weissman calls CD47 a “don’t eat me signal” that protects the cancer against the body’s own immune system. By blocking the action of CD47, 5F9 strips away that “don’t eat me signal” leaving the cancer vulnerable to the patient’s immune system. We have blogged about this work here and here.

The news from these trials is encouraging. But what was gratifying about Dr. Weissman’s statement is his generosity in sharing credit for the work with CIRM.

Here is what he wrote:

“What is unusual about Forty Seven is that not only the discovery, but its entire preclinical development and testing of toxicity, etc. as well as filing two Investigational New Drug [IND] applications to the Food and Drug Administration (FDA) in the US and to the MHRA in the UK, as well as much of the Phase 1 trials were carried out by a Stanford team led by two of the discoverers, Ravi Majeti and Irving Weissman at Stanford, and not at a company.

The major support came from the California Institute of Regenerative Medicine [CIRM], funded by Proposition 71, as well as the Ludwig Cancer Research Foundation at the Ludwig Center for Cancer Stem Cell Research at Stanford. CIRM will share in downstream royalties coming to Stanford as part of the agreement for funding this development.

This part of the state initiative, Proposition 71, is highly innovative and allows the discoverers of a field to guide its early phases rather than licensing it to a biotech or a pharmaceutical company before the value and safety of the discovery are sufficiently mature to be known. Most therapies at early-stage biotechs are lost in what is called the ‘valley of death’, wherein funding is very difficult to raise; many times the failure can be attributed to losing the expertise of the discoverers of the field.”

Dr. Weissman also had praise for CIRM’s funding model which requires companies that produce successful, profitable therapies – thanks to CIRM support – to return a portion of those profits to California. Most other funding agencies don’t have those requirements.

“US federal funds, from agencies such as the National Institutes of Health (NIH) similarly support discovery but cannot fund more than a few projects to, and through, early phase clinical trials. And, under the Bayh-Dole Act, the universities keep all of the equity and royalties derived from licensing discoveries. In that model no money flows back to the agency (or the public), and nearly a decade of level or less than level funding (at the national level) has severely reduced academic research. So this experiment of funding (the NIH or the CIRM model) is now entering into the phase that the public will find out which model is best for bringing new discoveries and new companies to the US and its research and clinical trials community.”

We have been funding Dr. Weissman’s work since 2006. In fact, he was one of the first recipients of CIRM funding.  It’s starting to look like a very good investment indeed.

 

Seeing is believing. Proof a CIRM-funded therapy is making a difference

ThelmaScreenShotFB

Thelma, participant in the CAMELLIA clinical trial

You have almost certainly never heard of Thelma, or met her, or know anything about her. She’s a lady living in England who, if it wasn’t for a CIRM-funded therapy, might not be living at all. She’s proof that what we do, is helping people.

Thelma is featured in a video about a treatment for acute myeloid leukemia, one of the most severe forms of blood cancer. Thelma took part in a clinical trial, called CAMELLIA, at Oxford Cancer Centre in Oxford, UK. The clinical trial uses a therapy that blocks a protein called CD47 that is found on the surface of cancer cells, including cancer stem cells which can evade traditional therapies. The video was shot to thank the charity Bloodwise for raising the funds to pay for the trial.

Prof. Paresh Vyas of Oxford University, who was part of the clinical trial team that treated Thelma, says patients with this condition face long odds.

“Patients with acute myeloid leukemia have the most aggressive blood cancer. We really haven’t had good treatments for this condition for the last 40 years.”

While this video was shot in England, featuring English nurses and doctors and patients, the therapy itself was developed here in California, first at Stanford University under the guidance of Irv Weissman and, more recently, at Forty Seven Inc. That company is now about to test their approach in a CIRM-funded clinical trial here in the US.

This is an example of how CIRM doesn’t just fund research, we invest in it. We help support it at every stage, from the earliest research through to clinical trials. Without our early support this work may not have made it this far.

The Forty Seven Inc. therapy uses the patient’s own immune system to help fight back against cancer stem cells. It’s looking very promising. But you don’t have to take our word for it. Take Thelma’s.

How Tom Howing turned to stem cells to battle back against a deadly cancer

As we enter the new year, CIRM’s 2017 Annual Report will be posted in less than two weeks!  Here’s one of the people we are profiling in the report, a patient who took part in a CIRM-funded clinical trial.

Tom Howing

In March of 2015, Tom Howing was diagnosed with stage 4 cancer. Over the next 18 months, he underwent two rounds of surgery and chemotherapy. Each time the treatments held the cancer at bay for a while. But each time the cancer returned. Tom was running out of options and hope when he heard about a CIRM-funded clinical trial using a new approach.

The clinical trial uses a therapy that blocks a protein called CD47 that is found on the surface of cancer cells, including cancer stem cells which can evade traditional therapies. CD47 acts as a ‘don’t eat me’ signal that tells immune cells not to kill off the cancer cells. When this ‘don’t eat me’ signal is blocked by the antibody, the patient’s immune system is able to identify, target and kill the cancer stem cells.

“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.

“Whenever you are dealing with a Phase 1 clinical trial (the earliest stage where the goal is first to make sure it is safe), there are lots of unknowns.  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.”

Tom says he feels fortunate to be part of the clinical trial because it is helping advance research, and could ultimately help many others like him.

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

He says he feels grateful to the people of California who created CIRM and the funding behind this project: “I say a very heartfelt thank you, that this was a good investment and a good use of public funds.”

He also wants the researchers, who spent many years developing this approach, to know that they are making a difference.

“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.”

Second “Don’t Eat Me” Signal Identified in Cancer Cells, Points to New Immunotherapies

When the immune system comes up as a topic in everyday conversation, it’s usually related to fighting off a cold or flu. While our immune cells certainly do detect and neutralize invading bacteria and viruses, they also play a critical role in killing abnormal, cancerous cells from within our bodies.

“Don’t Eat Me” Signal 101
A white blood cell called a macrophage (macro = “big”; phage = “eater”) is part of the so-called innate immune system and acts as a first line of defense by patrolling our organs and gobbling up infected as well as cancerous cells (see macrophages in action in the cool video below).

Unfortunately, cancer cells possess the ability to cloak themselves and escape a macrophage’s engulfing grasp. Nearly all cancer cells carry a protein called CD47 on their surface. When CD47 binds to a protein called SIRPalpha on the surface of macrophages, a “don’t eat me” signal is triggered and the macrophage ignores the cancer cell.

Stanford researcher Irv Weissman and his team discovered this “don’t eat me” signal several years ago and showed that adding an antibody protein that binds tightly to CD47 interferes with the CD47/SIRPalpha signal. As a result, the anti-CD47 antibody deactivates the cancer cell’s “don’t eat me” signal and restores the macrophage’s ability to detect and kill the cancer cells.

cd47-gene3

CD47 protein on surface of cancer cells triggers “don’t eat me signal” which can be blocked with anti-CD47 antibody. Image: Acrobiosystems

Because CD47 is found on the surface of most cancer cells, this anti-CD47 antibody represents an exciting new strategy for targeting cancer stem cells – the cells thought to maintain cancer growth and cause tumor relapse – in a wide variety of cancers. In fact, CIRM has provided funding for three clinical trials, one sponsored by Stanford University and two by Forty-Seven Inc. (a company that was spun out of Stanford), that are testing anti-CD47 therapy for the treatment of the blood cancer acute myeloid leukemia (AML), as well as colon cancer and other solid tumors.

“Reaching Clinical Trials” does not equal “The Research is Done”
Although these clinical trials are underway, the Weissman team continues to seek new insights related to blocking the CD47 “don’t eat me” signal. They observed that although anti-CD47 led to increased macrophage-induced killing of most cancer cell samples tested, some were resistant to anti-CD47 and remained cloaked from macrophages. And even the cancer cells that did respond to the antibody varied widely in the amount of increased killing by macrophages.

These results suggested that alternate processes may exist that allow some cancers to evade macrophages even when the CD47 “don’t eat me” signal is blocked. In a report published this week in Nature Immunology, the researchers report the identification of a second, independent “don’t eat me” signal, which may lead to more precise methods to disarm a cancer’s evasiveness.

To track down this alternate “don’t eat me” signal, they looked for, but didn’t find, correlations between specific types of cancer cells and the cancer’s resistance to anti-CD47 treatment.  So instead they analyzed surface proteins found on the various cancer cell samples and found that cancer cells that had high levels of MHC (Major Histocompatibility Complex) class I proteins were more likely to be resistant to anti-CD47 antibodies.

A Second “Don’t Eat Me” Signal
MHC class I proteins help another arm of the immune system, the adaptive immune response, detect what’s going inside a cell. They are found on nearly all cells and display, at the cell surface, bits of proteins sampled from inside the cell. If cells of the adaptive immune response, such as T or B cells, recognize one of those protein bits as abnormal or foreign, efficient killing mechanisms are kicked into high gear to destroy those cells.

But in the case of cancers cells, the MHC class I protein are harnessed as a “don’t eat me” signal by binding to a protein called LILRB1 on macrophages. When either the MHC class I proteins or LILRB1 were blocked, the “don’t eat me” signal was lifted and restored the macrophages’ ability to kill the cancer cells both in petri dish samples as well as in mice that carried human cancers.

Graduate student and co-lead author Amira Barkal described in a press release the impact of blocking both “don’t eat me” signals at the same time:

barkalSm

Amira Barkal

“Simultaneously blocking both these pathways in mice resulted in the infiltration of the tumor with many types of immune cells and significantly promoted tumor clearance, resulting in smaller tumors overall. We are excited about the possibility of a double- or perhaps even triple-pronged therapy in humans in which we combine multiple blockades to cancer growth.”

The Big Picture for Cancer Immunotherapies
Because MHC protein class I proteins play an important role in stimulating immune cells called T cells to kill cancer cells as part of the adaptive immune response, the level of MHC protein on an individual patient’s cancer cells could serve as an indicator, or “biomarker”, for what type of cancer therapy to pursue.  The big picture implications of this idea are captured in the press release:

“Understanding the balance between adaptive and innate immunity is important in cancer immunotherapy. For example, it’s not uncommon for human cancer cells to reduce the levels of MHC class 1 on their surfaces to escape destruction by T cells. People with these types of tumors may be poor candidates for cancer immunotherapies meant to stimulate T cell activity against the cancer. But these cells may then be particularly vulnerable to anti-CD47 treatment, the researchers believe. Conversely, cancer cells with robust MHC class 1 on their surfaces may be less susceptible to anti-CD47.”

Curing the Incurable through Definitive Medicine

“Curing the Incurable”. That was the theme for the first annual Center for Definitive and Curative Medicine (CDCM) Symposium held last week at Stanford University, in Palo Alto, California.

The CDCM is a joint initiative amongst Stanford Healthcare, Stanford Children’s Health and the Stanford School of Medicine. Its mission is to foster an environment that accelerates the development and translation of cell and gene therapies into clinical trials.

The research symposium focused on “the exciting first-in-human cell and gene therapies currently under development at Stanford in bone marrow, skin, cardiac, neural, pancreatic and neoplastic diseases.” These talks were organized into four different sessions: cell therapies for neurological disorders, stem cell-derived tissue replacement therapies, genome-edited cell therapies and anti-cancer cell-based therapies.

A few of the symposium speakers are CIRM-funded grantees, and we’ll briefly touch on their talks below.

Targeting cancer

The keynote speaker was Irv Weissman, who talked about hematopoietic or blood-forming stem cells and their value as a cell therapy for patients with blood disorders and cancer. One of the projects he discussed is a molecule called CD47 that is found on the surface of cancer cells. He explained that CD47 appears on all types of cancer cells more abundantly than on normal cells and is a promising therapeutic target for cancer.

Irv Weissman

Irv Weissman

“CD47 is the first gene whose overexpression is common to all cancer. We know it’s molecular mechanism from which we can develop targeted therapies. This would be impossible without collaborations between clinicians and scientists.”

 

At the end of his talk, Weissman acknowledged the importance of CIRM’s funding for advancing an antibody therapeutic targeting CD47 into a clinical trial for solid cancer tumors. He said CIRM’s existence is essential because it “funds [stem cell-based] research through the [financial] valley of death.” He further explained that CIRM is the only funding entity that takes basic stem cell research all the way through the clinical pipeline into a therapy.

Improving bone marrow transplants

judith shizuru

Judith Shizuru

Next, we heard a talk from Judith Shizuru on ways to improve current bone-marrow transplantation techniques. She explained how this form of stem cell transplant is “the most powerful form of cell therapy out there, for cancers or deficiencies in blood formation.” Inducing immune system tolerance, improving organ transplant outcomes in patients, and treating autoimmune diseases are all applications of bone marrow transplants. But this technique also carries with it toxic and potentially deadly side effects, including weakening of the immune system and graft vs host disease.

Shizuru talked about her team’s goal of improving the engraftment, or survival and integration, of bone marrow stem cells after transplantation. They are using an antibody against a molecule called CD117 which sits on the surface of blood stem cells and acts as an elimination signal. By blocking CD117 with an antibody, they improved the engraftment of bone marrow stem cells in mice and also removed the need for chemotherapy treatment, which is used to kill off bone marrow stem cells in the host. Shizuru is now testing her antibody therapy in a CIRM-funded clinical trial in humans and mentioned that this therapy has the potential to treat a wide variety of diseases such as sickle cell anemia, leukemias, and multiple sclerosis.

Tackling stroke and heart disease

img_1327We also heard from two CIRM-funded professors working on cell-based therapies for stroke and heart disease. Gary Steinberg’s team is using human neural progenitor cells, which develop into cells of the brain and spinal cord, to treat patients who’ve suffered from stroke. A stroke cuts off the blood supply to the brain, causing the death of brain cells and consequently the loss of function of different parts of the body.  He showed emotional videos of stroke patients whose function and speech dramatically improved following the stem cell transplant. One of these patients was Sonia Olea, a young woman in her 30’s who lost the ability to use most of her right side following her stroke. You can read about her inspiring recover post stem cell transplant in our Stories of Hope.

Dr. Joe Wu. (Image Source: Sean Culligan/OZY)

Dr. Joe Wu. (Image Source: Sean Culligan/OZY)

Joe Wu followed with a talk on adult stem cell therapies for heart disease. His work, which is funded by a CIRM disease team grant, involves making heart cells called cardiomyocytes from human embryonic stem cells and transplanting these cells into patient with end stage heart failure to improve heart function. His team’s work has advanced to the point where Wu said they are planning to file for an investigational new drug (IND) application with the US Food and Drug Administration (FDA) in six months. This is the crucial next step before a treatment can be tested in clinical trials. Joe ended his talk by making an important statement about expectations on how long it will take before stem cell treatments are available to patients.

He said, “Time changes everything. It [stem cell research] takes time. There is a lot of promise for the future of stem cell therapy.”