Genetically engineered immune cells melt away deadly brain tumors

MRI scan of patient with glioblastoma tumor. (wikicommons)

MRI scan of patient with glioblastoma. (wikicommons)

Cancers come in many different forms. Some are treatable if caught early and other aren’t. One of the most deadly types of cancers are glioblastomas – a particularly aggressive form of brain tumor.  Patients diagnosed with glioblastoma have an average life expectancy of 12-15 months and there is no cure or effective treatment that extends life.

While a glioblastoma diagnosis has pretty much been a death sentence, now there could be a silver lining to this deadly, fast-paced disease. Last week, scientists from the City of Hope in southern California reported in the New England Journal of Medicine, a new cell-based therapy that melted away brain tumors in a patient with an advanced stage of glioblastoma.

An Immunotherapy Approach to Glioblastoma

The patient is a 50-year-old man named Richard Grady who was participating in an investigational clinical trial run out of the City of Hope’s CIRM Alpha Stem Cell Clinic. A brain scan revealed a brightly lit tumor on the right side of Richard’s brain. Doctors surgically removed the tumor and treated him with radiation in an attempt to staunch further growth. But after six months, the tumors came back with a vengeance, spreading to other parts of his brain, lighting up his MRI scan like a Christmas tree.

With few treatment options and little time left, Richard was enrolled in the City of Hope trial that was testing a cell-based immunotherapy that recognizes and attacks cancer cells. It’s called CAR T-cell therapy – a term that you probably have heard in the news as a promising and cutting-edge treatment for cancer. Scientists extract immune cells, called T-cells, from a patient’s blood and reengineer them in the laboratory to recognize unique surface markers on cancer cells. These specialized CAR T-cells are then put back into the patient to attack and kill off cancer cells.

In Richard’s case, CAR-T cells were first infused into his brain through a tube in an area where a tumor was recently removed. No new tumors grew in that location of his brain, but tumors in other areas continued to grow and spread to his spinal cord. At this point, the scientists decided to place a second tube into a cavity of the brain called the ventricles, which contain a clear liquid called cerebrospinal fluid. Directly infusing into the spinal fluid allowed the cancer fighting cells to travel to different parts of the brain and spinal cord to attack the tumors.

Behnam Badie, senior author on the study and neurosurgery chief at the City of Hope, explained in a news release,

Benham Badie, City of Hope

Benham Badie, City of Hope

“By injecting the reengineered CAR-T cells directly into the tumor site and the ventricles, where the spinal fluid is made, the treatment could be delivered throughout the patient’s brain and also to the spinal cord, where this particular patient had a large metastatic tumor.”

 

Bye Bye Brain Tumors? Almost…

Three infusions of the CAR T-cell treatment shrunk Richard’s tumors noticeably, and a total of ten infusions was enough to melt away Richard’s tumors completely. Amazingly, Richard was able to reduce his medications and go back to work.

TESt

CAR T-cell therapy reduces brain tumors when infused into the spinal fluid. (NEJM)

The effects of the immunotherapy lasted for seven-and-a-half months. Unfortunately, his glioblastoma did come back, and he is now undergoing radiation treatment. Instead of being discouraged by these results, we should be encouraged. Patients with advanced cases of glioblastoma like Richard often have only weeks left to live, and the prospect of another seven months of life with family and friends is a gift.

Following these promising results in a single patient, the City of Hope team has now treated a total of nine patients in their clinical trial. Their initial results indicate that the immunotherapy is relatively safe. Further studies will be done to determine whether this therapy will be effective at treating other types of cancers.

CIRM Alpha Clinics Advance Stem Cell Treatments

The findings in this study are particularly exciting to CIRM, not only because they offer a new treatment option for a deadly brain cancer, but also because the clinical trial testing this treatment is housed at one of our own Alpha Clinics. In 2014, CIRM funded three stem cell-focused clinics at the City of Hope, UC San Diego, and a joint clinic between UC Los Angeles and UC Irvine. These clinics are specialized to support high quality trials focused on stem cell treatments for various diseases. The CIRM team will be bringing a new Alpha Clinics concept plan to its governing Board for approval in February.

Geoff Lomax, Senior Officer of Strategic Infrastructure at CIRM who oversees the CIRM Alpha Clinics, commented on the importance of City of Hope’s glioblastoma trial,

“Treating this form of brain cancer is one of the most vexing challenges in medicine. With the support and expertise of the CIRM Alpha Stem Cell Clinic, City of Hope is harnessing the power of patients’ immune cells to treat this deadly disease.”

Neil Littman, CIRM Director of Business Development and Strategic Infrastructure added,

“This study provides important proof-of-concept that CAR-T cells can be used to target hard-to-treat solid tumors and is precisely the type of trial the CIRM Alpha Stem Cell Clinic Network is designed to support.”

For more details on this study, watch the video below from City of Hope:

Key Steps Along the Way To Finding Treatments for HIV on World AIDS Day

Today, December 1st,  is World AIDS Day. It’s a day to acknowledge the progress that is being made in HIV prevention and treatment around the world but also to renew our commitment to a future free of HIV. This year’s theme is Leadership. Commitment. Impact.  At CIRM we are funding a number of projects focused on HIV/AIDS, so we asked Jeff Sheehy, the patient advocate for HIV/AIDS on the CIRM Board to offer his perspective on the fight against the virus.

jeff-sheehy

At CIRM we talk about and hope for cures, but our actual mission is “accelerating stem cell treatments to patients with unmet medical needs.”

For those of us in the HIV/AIDS community, we are tremendously excited about finding a cure for HIV.  We have the example of Timothy Brown, aka the “Berlin Patient”, the only person cured of HIV.

Multiple Shots on Goal

Different approaches to a cure are under investigation with multiple clinical trials.  CIRM is funding three clinical trials using cell/gene therapy in attempts to genetically modify blood forming stem cells to resist infection with HIV.  While we hope this leads to a cure, community activists have come together to urge a look at something short of a “home run.”

A subset of HIV patients go on treatment, control the virus in their blood to the point where it can’t be detected by common diagnostic tests, but never see their crucial immune fighting CD4 T cells return to normal levels after decimation by HIV.

For instance, I have been on antiretroviral therapy since 1997.  My CD4 T cells had dropped precipitously, dangerous close to the level of 200.  At that level, I would have had an AIDS diagnosis and would have been extremely vulnerable to a whole host of opportunistic infections.  Fortunately, my virus was controlled within a few weeks and within a year, my CD T cells had returned to normal levels.

For the immunological non-responders I described above, that doesn’t happen.  So while the virus is under control, their T cell counts remain low and they are very susceptible to opportunistic infections and are at much greater risk of dying.

Immunological non-responders (INRs) are usually patients who had AIDS when they were diagnosed, meaning they presented with very low CD4 T cell counts.  Many are also older.  We had hoped that with frequent testing, treatment upon diagnosis and robust healthcare systems, this population would be less of a factor.  Yet in San Francisco with its very comprehensive and sophisticated testing and treatment protocols, 16% of newly diagnosed patients in 2015 had full blown AIDS.

Until we make greater progress in testing and treating people with HIV, we can expect to see immunological non-responders who will experience sub-optimal health outcomes and who will be more difficult to treat and keep alive.

Boosting the Immune System

A major cell/gene trial for HIV targeted this population.  Their obvious unmet medical need and their greater morbidity/mortality balanced the risks of first in man gene therapy.  Sangamo, a CIRM grantee, used zinc finger nucleases to snip out a receptor, CCR5, on the surface of CD4 T cells taken from INR patients.  That receptor is a door that HIV uses to enter cells.  Some people naturally lack the receptor and usually are unable to be infected with HIV.  The Berlin Patient had his entire immune system replaced with cells from someone lacking CCR5.

Most of the patients in that first trial saw their CD4 T cells rise sharply.  The amount of HIV circulating in their gut decreased.  They experienced a high degree of modification and persistence in T stem cells, which replenish the T cell population.  And most importantly, some who regularly experienced opportunistic infections such as my friend and study participant Matt Sharp who came down with pneumonia every winter, had several healthy seasons.

Missed Opportunities

Unfortunately, the drive for a cure pushed development of the product in a different direction.  This is in large part to regulatory challenges.  A prior trial started in the late 90’s by Chiron tested a cytokine, IL 2, to see if administering it could increase T cells.  It did, but proving that these new T cells did anything was illusive and development ceased.  Another cytokine, IL 7, was moving down the development pathway when the company developing it, Cytheris, ceased business.  The pivotal trial would have required enrolling 4,000 participants, a daunting and expensive prospect.  This was due to the need to demonstrate clinical impact of the new cells in a diverse group of patients.

Given the unmet need, HIV activists have looked at the Sangamo trial, amongst others, and have initiated a dialogue with the FDA.  Activists are exploring seeking orphan drug status since the population of INRs is relatively small.

Charting a New Course

They have also discussed trial designs looking at markers of immune activity and discussed potentially identifying a segment of INRs where clinical efficacy could be shown with far, far fewer participants.

Activists are calling for companies to join them in developing products for INRs.  I’ve included the press release issued yesterday by community advocates below.

With the collaboration of the HIV activist community, this could be a unique opportunity for cell/gene companies to actually get a therapy through the FDA. On this World AIDS Day, let’s consider the value of a solid single that serves patients in need while work continues on the home run.

NEWS RELEASE: HIV Activists Seek to Accelerate Development of Immune Enhancing Therapies for Immunologic Non-Responders.

Dialogues with FDA, scientists and industry encourage consideration of orphan drug designations for therapies to help the immunologic non-responder population and exploration of novel endpoints to reduce the size of efficacy trials.

November 30, 2016 – A coalition of HIV/AIDS activists are calling for renewed attention to HIV-positive people termed immunologic non-responders (INRs), who experience sub-optimal immune system reconstitution despite years of viral load suppression by antiretroviral therapy. Studies have shown that INR patients remain at increased risk of illness and death compared to HIV-positive people who have better restoration of immune function on current drug therapies. Risk factors for becoming an INR include older age and a low CD4 count at the time of treatment initiation. To date, efforts to develop immune enhancing interventions for this population have proven challenging, despite some candidates from small companies showing signs of promise.

“We believe there is an urgent need to find ways to encourage and accelerate development of therapies to reduce the health risks faced by INR patients,” stated Nelson Vergel of the Program for Wellness Restoration (PoWeR), who initiated the activist coalition. “For example, Orphan Drug designations[i] could be granted to encourage faster-track approval of promising therapies.  These interventions may eventually help not only INRs but also people with other immune deficiency conditions”.

Along with funding, a major challenge for approval of any potential therapy is proving its efficacy. While INRs face significantly increased risk of serious morbidities and mortality compared to HIV-positive individuals with more robust immune reconstitution, demonstrating a reduction in the incidence of these outcomes would likely require expensive and lengthy clinical trials involving thousands of individuals. Activists are therefore encouraging the US Food & Drug Administration (FDA), industry and researchers to evaluate potential surrogate markers of efficacy such as relative improvements in clinical problems that may be more frequent in INR patients, such as upper respiratory infections, gastrointestinal disease, and other health issues.

“Given the risks faced by INR patients, every effort should be made to assess whether less burdensome pathways toward approval are feasible, without compromising the regulatory requirement for compelling evidence of safety and efficacy”, said Richard Jefferys of the Treatment Action Group.

The coalition is advocating that scientists, biotech and pharmaceutical companies pursue therapeutic candidates for INRs. For example, while gene and anti-inflammatory therapies for HIV are being assessed in the context of cure research, there is also evidence that they may have potential to promote immune reconstitution and reduce markers associated with risk of morbidity and mortality in INR patients. Therapeutic research should also be accompanied by robust study of the etiology and mechanisms of sub-optimal immune responses.

“While there is, appropriately, a major research focus on curing HIV, we must be alert to evidence that candidate therapies could have benefits for INR patients, and be willing to study them in this context”, argued Matt Sharp, a coalition member and INR who experienced enhanced immune reconstitution and improved health and quality of life after receiving an experimental gene therapy.

The coalition has held an initial conference call with FDA to discuss the issue. Minutes are available online.

The coalition is now aiming to convene a broader dialogue with various drug companies on the development of therapies for INR patients. Stakeholders who are interested in becoming involved are encouraged to contact coalition representatives.

[i] The Orphan Drug Act incentivizes the development of treatments for rare conditions. For more information, see:  http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/ucm2005525.htm

For more information:

Richard Jefferys

Michael Palm Basic Science, Vaccines & Cure Project Director
Treatment Action Group richard.jefferys@treatmentactiongroup.org

Nelson Vergel, Program for Wellness Restoration programforwellness@gmail.com

 

 

Stem cell stories that caught our eye: fashionable stem cells, eliminating HIV, cellular Trojan horse fights cancer

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.

Stem cell fashion for a cause. Science and art are not mutually exclusive subjects. I know plenty of scientists who are talented painters or designers. But you don’t often see science being displayed in an artistic way or art being used to help explain complex scientific topics. I think that in the future, this will change as both subjects have a lot to offer one another.

Stem cell ties are in fashion!

Stem cell ties are in fashion!

Take this story from the University of Michigan for instance. Designer Dominic Pangborn has joined forces with the Heinz C. Prechter Bipolar Research Fund at the University of Michigan (UOM) to design fashionable scarves and ties featuring beautiful pictures of stem cells. The goal of the Prechter Fund scarf and tie project is to raise awareness for mental health research.

The scarves and ties feature pictures of brain stem cells taken by UOM scientists who are studying them to understand the mechanisms behind bipolar disorder. These stem cells were generated from induced pluripotent stem cells or iPS cells that were derived from donated skin biopsies of patients with bipolar disease. Studying these diseased brain cells in a dish revealed that the nerve cells from bipolar patients were misbehaving, sending out electrical signals more frequently compared to healthy nerve cells.

Dr. Melvin McInnis, the Prechter Fund research director, explained:

“By understanding the causes of bipolar disorder, we will be able to develop new treatments for the illness and most importantly, we’ll be able to prevent destructive mood episodes. Our ultimate goal is to allow people to live happy, normal lives.”

Pangborn is passionate about using art to reflect an important cause.

“I decided to add butterflies to the design because they signify metamorphosis. Our society is finally at a point where mental illness is openly talked about and research is taking a turn for the better.”

He plans to release his collection in time for National Mental Health Awareness month in May. All proceeds will go to the Prechter bipolar research projects at UOM.

Dr. Melvin McInnis, left, and Dominic Pangborn in the Pangborn Design Store in Ann Arbor. (UOM)

Dr. Melvin McInnis, left, and Dominic Pangborn in the Pangborn Design Store in Ann Arbor. (UOM)

New stem cell therapy could eliminate HIV for good

The stem cells therapies being developed to cure HIV are looking more promising every day. A few are already being tested in clinical trials, and CIRM is funding two of them (you can read more about them here). News came out this week about a new trial conducted at the City of Hope’s CIRM Alpha Stem Cell Clinic. They reported in a news release that they’ve treated their first patient. His name is Aaron Kim, and he’s had HIV since he was born. In 1983, he and his twin sister were born prematurely and due to a complication, Aaron had to get a blood transfusion that unfortunately gave him HIV.

Aaron Kim with nurse. (City of Hope)

Aaron Kim with nurse. (City of Hope)

Aaron thought he would live with this disease the rest of his life, but now he has a chance at being cured. In March, Aaron received a transplant of his own bone marrow stem cells that were genetically engineered to have a modified version of the CCR5 gene that makes his cells resistant to HIV infection. CCR5 is a is a protein receptor on the surface of blood cells that acts as a gateway for HIV entry. The hope is that his reengineered stem cells will populate his immune system with HIV-resistant cells that can eliminate the virus completely.

Dr. John Zaia who is the director the the City of Hope Alpha Clinic explained,

“The stem cell therapy Aaron received is one of more than 20 cure strategies for HIV. It may not cure him, but our goal is to reduce or even halt Aaron’s reliance on HIV drugs, potentially eliminating the virus completely.”

My favorite part of this story was that it acknowledged how importance it is for patients to participate in clinical trials testing promising new stem cell therapies where the outcomes aren’t always known. Brave patients such as Aaron make it possible for scientists to make progress and develop better and safer treatments for patients in the future.

Dr. Zaia commented, “It’s a wonderful and generous humanitarian gesture on Aaron’s part to participate in this trial.”

Stem cell Trojan horse fights cancer

Chemotherapy is great at killing cancer cells, but unfortunately, it’s also great at killing healthy cells too. To combat this issue, scientists are developing new delivery methods that can bring high doses of chemotherapy drugs to the cancer tumors and minimize exposure of healthy tissues.

Mesenchymal stem cells loaded with drug-containing microparticles. Credit: Jeff Karp and Oren Levy, Brigham and Women's Hospital

Mesenchymal stem cells loaded with drug-containing microparticles.
Credit: Jeff Karp and Oren Levy, Brigham and Women’s Hospital

A study published this week in Biomaterials, describes a new drug delivery method that has the potential to be an effective treatment for prostate cancer. Researchers from the Brigham and Women’s Hospital and Johns Hopkins University developed a drug delivery platform using mesenchymal stem cells. They packaged a non-active, prodrug version of a potent prostate cancer chemotherapy drug into microparticles that they loaded into MSCs. When the MSCs and prostate cancer cells were cultured together in a dish, the MSCs released their prodrug cargo, which was then internalized by the prostate cancer cells. The prodrug was then metabolized into its active, cancer-killing form and was very effective at killing the cancer cells.

In a news release picked up by Science Daily, one of the lead scientists on the study, Dr. Oren Levy, further explained the stem cell Trojan horse concept:

“Mesenchymal stem cells represent a potential vehicle that can be engineered to seek out tumors. Loading those cells with a potent chemotherapeutic drug is a promising cell-based Trojan horse approach to deliver drugs to sites of cancer.”

If all goes well, the teams plan to develop different versions of their stem cell-based drug delivery method that target different cancers and other diseases.

Patients are the Heroes at the CIRM Alpha Stem Cell Clinics Symposium

Alpha Cat and Sandra.jpg

UCSD’s Catriona Jamieson and patient advocate Sandra Dillon at the CIRM Alpha Clinic Network Symposium

Sometimes, when you take a moment to stand back and look at what you have accomplished, you can surprise yourself at how far you have come, and how much you have done in a short space of time.

Take the CIRM Alpha Stem Cell Clinics Network for example. In the 18 months since our Board invested $24 million to kick start the first three Alpha Clinics the Network has signed up 21 clinical trials. That’s no small achievement. But as far as the Alpha Clinics Network team is concerned, that’s just a start.

Alpha clinic table

Last week UC San Diego hosted the Second Annual CIRM Alpha Stem Cell Clinics Network Symposium. The gathering of scientists, medical staff and patient advocates spent a little time talking about the past, about what has been achieved so far, but most of the time was devoted to looking to the future, planning where they want to go and how they are going to get there.

The Network’s goal is to now dramatically increase the number of high quality stem cell clinical trials it is running, to make it even easier for companies and researchers looking for a site to carry out their trial, and to make it even easier for patients looking to sign up for one.

Alpha clinic panel

Panel at symposium: L to R: David Higgins, CIRM Board; David Parry, GSK; Catriona Jamieson, UCSD: John Zaia, City of Hope; John Adams, UCLA

For companies, the lure of having three Alpha Clinics (UC San Diego, City of Hope and the combined team of UCLA/UC Irvine) packed with skilled, experienced staff that specialize in delivering stem cell therapies is a big draw. (By the way, if you know anyone looking for funding for a clinical trial send them here).

The Alpha Clinic teams not only know how to deliver the therapies, they also know how to deliver patients. They spend a lot of time working with patients and patient advocates on the best ways to recruit people for trials, and the best way to design those trials so that they are as easy as possible for patients to take part in.

This attention to making it as good an experience for patients as possible starts from the very first time that a patient calls the clinics to find out if they are eligible for a trial. If there is no trial that is appropriate for that particular patient, the staff try to find an alternative trial at another location that might work.

Making sure it’s a good fit

If the Network does have a trial that meets the needs of the patient, then they begin the conversation to find out if the patient is eligible to apply. The goal of this part of the process is not simply to try and fill up available slots but to make sure that the patient is both a good match for the proposed therapy and that they also completely understand what’s involved in getting that therapy. For example, they need to understand if the trial involves staying overnight or several nights in the hospital, or if there are things they need to do ahead of time to prepare.

For the clinics themselves, one of the biggest challenges is insurance coverage. While the trial itself may be free, the patient may need to have some tests ahead of the treatment, to make sure they don’t have any underlying problems that could put their health at risk. The clinics need to know if the patient’s insurance will cover the cost of those tests and if they don’t what their options are. For a rare disease, where it’s challenging to find enough patients to produce meaningful results, these kinds of problems can jeopardize the whole trial.

The Alpha Clinics Network is working hard to develop answers to all of those problems, to create systems that make it as easy as possible to get a clinical trial up and running, and to recruit and keep patients in that trial.

Challenges to overcome

Part of the challenge is that many of these trials are for first-in-human therapies, meaning no one has ever tried this in a person before. That means the doctors, nurses and all the support staff in these clinics need to be specially trained in dealing with an entirely new way of treating people, with an entirely new class of therapies. And this isn’t just about technical skills. They also need to be good at communication, helping the patients understand everything that is happening or about to happen.

In a state like California, one of the most diverse places on earth, that’s no easy challenge. According to a UCLA study there are more than 220 languages spoken in LA County alone. Coping with that level of linguistic, cultural, and religious diversity is a challenge that the Alpha Clinics are working hard to meet.

Listening to patients

IMG_0822 (1)

Patient advocates were also an important voice at the symposium, talking about their experiences in clinical trials and how they have helped change their lives, and how they have, in some cases, saved their lives. But they also had some thoughts on how the researchers can do an even better job. That is the subject for a future blog.

While everyone acknowledged the challenges the CIRM Alpha Clinics face, they also celebrated what they have accomplished so far, and looked forward to the future. And the symposium was a chance to remind all of us that the reason we are in this is to help patients battling deadly diseases and disorders. So it was fitting that Thomas Kipps, the Deputy Director of Research at the UCSD Moore’s Cancer Center, took the opportunity to thank those who are not just the focus of this work, but also the heroes.

Kipps

Thomas Kipps: Photo courtesy Patient Power

“Clinical trials involve a very important skill set. You have to first and foremost put the patient first in any clinical trial. I think we cannot ignore the fact that these are human beings that are brave souls that have gone forward. These are the heroes who are going out and forging new territory.”

Calling for a cure for HIV/AIDS

Larry Kramer - Photo by David Shankbone

Larry Kramer – Photo by David Shankbone

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

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

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

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

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

Timothy Brown; photo courtesy CureAIDSreport.org

Timothy Brown; photo courtesy CureAIDSreport.org

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

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

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

Creativity sparks a bright future for science

When some people want to see the future they use a crystal ball. Others use tarot cards or runes. But when anyone at CIRM wants to see the future all we have to do is look into the faces of the students in our Creativity program.

Creativity students 2015 with program director Dr. Mani Vessal (front & center with tie)

Creativity students 2015 with program director Dr. Mani Vessal (front & center with tie)

Over the past three years the Creativity program has given some 220 California high school students a chance to spend the summer working in a world-class stem cell research facility. And when I say work, I mean work. They are required to attend lectures, grow their own stem cells, and do experiments. In short, they are expected to do what all the other scientists in the lab do. In return they get a great experience, and a modest stipend for their effort. At the end they produce papers on their work with titles like:

  • Notch Signaling as a Possible Regulator of Mesenchymal Stromal Cell Differentiation in the Hematopoietic Stem Cell Niche
  • RNA Splicing Factor ZRSR2 in Human Erythroleukemia and Stem Cells

We also ask the students to either write a blog or create a video about their experiences over the summer. Many do both. We’ll come back to the video portion later this week. The blogs make for a great read because they chart the students as they progress from knowing little if anything about stem cells, to being quite proficient at working with them. And all in just 8 weeks. One of the hardest parts of our job is choosing the best blog. For example Alice Lin, part of the City of Hope program, got an honorable mention for her blog that was a “diary” written by an embryonic stem cell. Here’s a small sample of her approach:

‘Also, this is NOT YOUR TYPICAL LAB JOURNAL ENTRY. It’s an autobiography chronicling my life. That way, when the stem cell controversy cools down, the general public can get a FIRST HAND ACCOUNT of what we do. This blog is going to rack up some serious views someday. Until then, I’m attached to my colony and the plate.’

Ryan Hale, part of the Scripps team, wrote about how the experience taught him to think like a scientist:

‘One day, after performing an experiment, our mentor asked us the reason behind our experiment. He wasn’t asking us about the experimental procedure or quizzing us on the pre-reading packet, he wanted us to understand the thought process a researcher would go through to actually think up such an experiment… Our mentor stressed how important it is to be creative, inquisitive, and critical if one wants to become a successful researcher.’

Selena Zhang

Selena Zhang

The winner was Selena Zhang, also part of the City of Hope team. She writes about her experiences in the lab, learning the ropes, getting to understand the technology and language of science. But it’s her closing paragraph that sealed the deal for us. In a few short sentences she manages to capture the romance, the mystery and the magic of science. And we’re also happy to say that this program is coming back next year, and the year after that, for five more years. Our Board has just approved renewed funding. The name of the program is changing, it will be called SPARK, but the essence will remain the same. Giving young students a glimpse at a future in science. You don’t need a crystal ball to know that with these students the future is bright. Here’s Selena’s winning blog:

My very own lab coat. It was a lot to live up to, my freshly laundered lab coat with the City of Hope logo. Looking around the lab, I was nervous and excited to start my very first day. There were papers to read and meetings with my mentor to hear about my project. I was starstruck, as I learned that I would be working with induced pluripotent stem cells, Alzheimer’s disease, and CRISPR. Terms that seemed to only exist in textbooks and science magazines that I lovingly read at the library were suddenly alive to me. Although, embarrassingly enough, the only thing that came to mind when my mentor mentioned CRISPR was a salad crisper. Fairly certain that she was a) speaking about something else and b) that I needed to eat more for breakfast, I asked her what that was. It turned out that CRISPR was a new genome editing tool we could use to create isogenic lines to study the independent effects of each allele of the APOE gene that is the most significant risk factor for Alzheimer’s. We would do this by converting a patient and wild-type fibroblast into induced pluripotent stem cells. From this, we would edit a normal allele into the patient’s cell for rescue and the mutated allele in the wild-type cell for insertion, respectively. We would eventually differentiate these cells into neurons and astrocytes to study how the change of this allele can impact neural interaction. This was real science in progress, not enshrined in a textbook, but free, fluid, and vibrant. I slowly grew into my own independence around the lab. I found myself more confident and emotionally invested with each experiment, every immunostaining and PCR. Science, for all of its realism, had always seemed like the unimaginable fantasy to me. Through this opportunity, science has become more tangible, grounded in unglamorous details: hard work and deadlines, mistakes and mishaps, long lab meetings and missed lunches. Yet, that has only made me more confident that I want to pursue science. Now, I’m embracing a reality, one that gives me something worth striving for. In fact, I am very fortunate that my project has encountered numerous obstacles. My initial response to these problems was and still is a lot less Zen and a lot more panic-driven. But I’ve slowly come to realize the beauty of the troubleshooting process for progress. My project has been an emotional rollercoaster, as our rescue cell line met success, but couldn’t advance to the next stage. Our insertion cell line appeared to have incorporated the mutation, but it turned out it only incorporated one allele. It’s been a process of finding the balance between defending our ideas and accepting new ones, the border between defending and defensiveness. My curiosity and drive to improve, to understand, to conquer the unknown is learning to coexist with the need for patience and flexibility No matter how solid our theory should have been, reality is fickle and all the more interesting for it. I thought science was all about doubt and skepticism, questioning everything. Through this internship, I’ve learned that there’s also a surprising amount of faith, the faith to accept any setbacks as part of the discovery process. I thought I loved science before because I loved how enough facts could help me make sense of things. But through this internship in the lab, I’m learning to love a larger part of science, which is not only loving knowledge, but also loving not knowing, loving discovery for all of its uncertainty and perfect imperfections. I’m learning to grow into my lab coat, and hopefully, to find my place in the field of science.

The search for a cure: how stem cells could eradicate the AIDS virus

It’s hard to overstate just how devastating the AIDS crisis was at its peak in the U.S. – and still is today in many parts of the world. In 1995 almost 51,000 Americans died from the disease, the numbers of new cases were at almost record highs, and there were few effective therapies against the virus.

HIV/AIDS medications

HIV/AIDS medications

Today that picture is very different. New medications and combination therapies have helped reduce the death rate, in some cases turning HIV into a chronic rather than fatal condition. But even now there is no cure.

That’s why the news that the Food and Drug Administration (FDA) has approved a clinical trial, that we are funding, aimed at eradicating HIV in the body, was so welcome. This could be an important step towards the Holy Grail of AIDS therapies, curing the disease.

The project is headed by Dr. John Zaia at City of Hope near Los Angeles. The team, with researchers from Keck Medicine of the University of Southern California (USC) and Sangamo BioSciences, plans on using an individual’s own stem cells to beat the virus.  They will remove some blood stem cells from HIV-infected individuals, then treat them with zinc finger nucleases (ZFNs), a kind of molecular scissors, snipping off a protein the AIDS virus needs to infect those cells.

It’s hoped the re-engineered stem cells, when returned to the body, will help create a new blood and immune system that is resistant to the virus. And if the virus can’t infect any new immune cells it could, theoretically, die off. Check out the video we produced a few years back about the project:

Studies in the lab show this approach holds a lot of promise. In a news release announcing the start of the clinical trial, Dr. Zaia said now it’s time to see if it will work in people:

“While we have a number of drugs that are effective in holding HIV at bay, we have nothing that cures it. In addition, for many patients, these medications come with significant long-term problems so there is a real need for a therapy that can help eradicate the virus from a patient completely. That is where our work is focused.”

Like all Phase 1 trials this one is focused on making sure this approach is safe for people, and identifying what, if any, side-effects there are from the treatment. The first group of patients to be treated consists of people with HIV/AIDS who have not responded well to the existing medications.

This is the second trial that CIRM is funding focused on curing HIV/AIDS. Our first, involving the company Calimmune, began its human clinical trial in July 2013. You can read more about that work here.

We know that the road to a cure will not be simple or straightforward. There have been too many false claims of cures or miracle therapies over the years for any of us to want to fall victim to hope and hype. It may even be that the most realistic goal for these approaches is what is called a “functional cure”, one that doesn’t eliminate the virus completely but does eliminate the need to take antiretroviral pills every day.

But when compared to the dark days of 1995, a functional cure is a world away from certain death.

Taking stock: ten years of the stem cell agency, progress and promise for the future

Under some circumstances ten years can seem like a lifetime. But when lives are at stake, ten years can fly by in a flash.

Ten years ago the people of California created the stem cell agency when they overwhelmingly approved Proposition 71, giving us $3 billion to fund and support stem cell research in the state.

In 2004 stem cell science held enormous potential but the field was still quite young. Back then the biology of the cells was not well understood, and our ability to convert stem cells into other cell types for potential therapies was limited. Today, less than 8 years after we actually started funding research, we have ten projects that are expected to be approved for clinical trials by the end of the year, including work in heart disease and cancer, HIV/AIDS and diabetes. So clearly great progress has been made.

Dean Carmen Puliafito and the panel at the Tenth Anniversary event at USC

Dean Carmen Puliafito and the panel at the Tenth Anniversary event at USC

Yesterday we held an event at the University of Southern California (USC) to mark those ten years, to chart where we have come from, and to look to where we are going. It was a gathering of all those who have, as they say, skin in the game: researchers, patients and patient advocates.

The event was held at the Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research. As Dr. Carmen Puliafito, Dean of USC’s Keck School of Medicine noted, without CIRM the building would not even exist.

“With this funding, our researchers, and researchers in 11 other facilities throughout the state, gained a dedicated space to hunt for cures for some of the most pernicious diseases in the world, including heart disease, stroke, cancer, diabetes, Alzheimer’s and Parkinson’s disease.”

Dr. Dhruv Sareen from Cedars-Sinai praised CIRM for creating a whole new industry in the state:

“What Silicon Valley has done for technology, CIRM is doing for stem cell research in California.”

One of the beneficiaries of that new industry has been ViaCyte, a San Diego-based company that is now in clinical trials with a small implantable device containing stem cell-derived cells to treat type 1 diabetes. ViaCyte’s Dr. Eugene Brandon said without CIRM none of that would have been possible.

“In 2008 it was extremely hard for a small biotech company to get funding for the kind of work we were doing. Without that support, without that funding from CIRM, I don’t know where this work would be today.”

As with everything we do, at the heart of it are the patients. Fred Lesikar says when he had a massive heart attack and woke up in the hospital his nurse told him about a measure they use to determine the scale of the attack. When he asked how big his attack had been, she replied, “I’ve never seen numbers that large before. Ever.”

Fred told of leaving the hospital a diminished person, unable to do most basic things because his heart had been so badly damaged. But after getting a stem cell-based therapy using his own heart cells he is now as active as ever, something he says doesn’t just affect him.

“It’s not just patients who benefit from these treatments, families do too. It changes the life of the patient, and the lives of all those around them. I feel like I’m back to normal and I’m so grateful for CIRM and Cedars-Sinai for helping me get here.”

The team behind that approach, based at Cedars-Sinai, is now in a much larger clinical trial and we are funding it.

The last word in the event was left to Bob Klein, who led the drive to get Proposition 71 passed and who was the agency’s first Chair. He said looking at what has happened in the last ten years: “it is beyond what I could have imagined.”

Bob noted that the field has not been without its challenges and problems to overcome, and that more challenges and problems almost certainly lie in the future:

“But the genius of the people of this state is reflected in their commitment to this cause, and we should all be eternally grateful for their vision in supporting research that will save and transform people’s lives.”

Creativity Program Students Reach New Heights with Stem Cell-Themed Rendition of “Let it Go”

This summer we’re sponsoring high school interns in stem cell labs throughout California as part of our annual Creativity Program. We asked those students to share their experiences through blog posts, photos and videos.

Today, we bring you an outstanding group video from CIRM Interns at City of Hope in Los Angeles, with their own special version of the popular song, “Let it Go” from the movie Frozen.

These students have without a doubt showcased their extensive scientific knowledge in one of the most creative ways we at CIRM have ever seen!

Without further ado, we present “Let it Grow.”