Stem Cell Agency invests in stem cell therapies targeting sickle cell disease and solid cancers

Today CIRM’s governing Board invested almost $10 million in stem cell research for sickle cell disease and patients with solid cancer tumors.

Clinical trial for sickle cell disease

City of Hope was awarded $5.74 million to launch a Phase 1 clinical trial testing a stem cell-based therapy for adult patients with severe sickle cell disease (SCD). SCD refers to a group of inherited blood disorders that cause red blood cells to take on an abnormal, sickle shape. Sickle cells clog blood vessels and block the normal flow of oxygen-carrying blood to the body’s tissues. Patients with SCD have a reduced life expectancy and experience various complications including anemia, stroke, organ damage, and bouts of excruciating pain.

A mutation in the globlin gene leads to sickled red blood cells that clog up blood vessels

CIRM’s President and CEO, Maria T. Millan, explained in the Agency’s news release:

Maria T. Millan

“The current standard of treatment for SCD is a bone marrow stem cell transplant from a genetically matched donor, usually a close family member. This treatment is typically reserved for children and requires high doses of toxic chemotherapy drugs to remove the patient’s diseased bone marrow. Unfortunately, most patients do not have a genetically matched donor and are unable to benefit from this treatment. The City of Hope trial aims to address this unmet medical need for adults with severe SCD.”

The proposed treatment involves transplanting blood-forming stem cells from a donor into a patient who has received a milder, less toxic chemotherapy treatment that removes some but not all of the patient’s diseased bone marrow stem cells. The donor stem cells are depleted of immune cells called T cells prior to transplantation. This approach allows the donor stem cells to engraft and create a healthy supply of non-diseased blood cells without causing an immune reaction in the patient.

Joseph Rosenthal, the Director of Pediatric Hematology and Oncology at the City of Hope and lead investigator on the trial, mentioned that CIRM funding made it possible for them to test this potential treatment in a clinical trial.

“The City of Hope transplant program in SCD is one of the largest in the nation. CIRM funding will allow us to conduct a Phase 1 trial in six adult patients with severe SCD. We believe this treatment will improve the quality of life of patients while also reducing the risk of graft-versus-host disease and transplant-related complications. Our hope is that this treatment can be eventually offered to SCD patients as a curative therapy.”

This is the second clinical trial for SCD that CIRM has funded – the first being a Phase 1 trial at UCLA treating SCD patients with their own genetically modified blood stem cells. CIRM is also currently funding research at Children’s Hospital of Oakland Research Institute and Stanford University involving the use of CRISPR gene editing technologies to develop novel stem cell therapies for SCD patients.

Advancing a cancer immunotherapy for solid tumors

The CIRM Board also awarded San Diego-based company Fate Therapeutics $4 million to further develop a stem cell-based therapy for patients with advanced solid tumors.

Fate is developing FT516, a Natural Killer (NK) cell cancer immunotherapy derived from an engineered human induced pluripotent stem cell (iPSC) line. NK cells are part of the immune system’s first-line response to infection and diseases like cancer. Fate is engineering human iPSCs to express a novel form of a protein receptor, called CD16, and is using these cells as a renewable source for generating NK cells. The company will use the engineered NK cells in combination with an anti-breast cancer drug called trastuzumab to augment the drug’s ability to kill breast cancer cells.

“CIRM sees the potential in Fate’s unique approach to developing cancer immunotherapies. Different cancers require different approaches that often involve a combination of treatments. Fate’s NK cell product is distinct from the T cell immunotherapies that CIRM also funds and will allow us to broaden the arsenal of immunotherapies for incurable and devastating cancers,” said Maria Millan.

Fate’s NK cell product will be manufactured in large batches made from a master human iPSC line. This strategy will allow them to treat a large patient population with a well characterized, uniform cell product.

The award Fate received is part of CIRM’s late stage preclinical funding program, which aims to fund the final stages of research required to file an Investigational New Drug (IND) application with the US Food and Drug Administration. If the company is granted an IND, it will be able to launch a clinical trial.

Scott Wolchko, President and CEO of Fate Therapeutics, shared his company’s goals for launching a clinical trial next year with the help of CIRM funding:

“Fate has more than a decade of experience in developing human iPSC-derived cell products. CIRM funding will enable us to complete our IND-enabling studies and the manufacturing of our clinical product. Our goal is to launch a clinical trial in 2019 using the City of Hope CIRM Alpha Stem Cell Clinic.”

CIRM-Funded Scientist is Developing a Stem Cell Therapy that Could Cure HIV

Photo Illustration by the Daily Beast

This week, UCLA scientist Scott Kitchen made the news for his efforts to develop a CIRM-funded stem cell gene therapy that could potentially cure patients infected with HIV. Kitchen’s work was profiled in the Daily Beast, which argued that his “research could significantly up survival rates from the virus.”

Scott Kitchen, UCLA Medicine

Kitchen and a team of scientists at the UCLA David Geffen School of Medicine are genetically modifying blood-forming, hematopoietic stem cells (HSCs) to express chimeric antigen receptors (CARs) that target HIV-infected cells. CARs are protein complexes on the surface of cells that are designed to recognize specific types of cells and are being developed as powerful immunotherapies to fight cancer and HIV infection.

These CAR-expressing HSCs can be transplanted into patients where they develop into immune cells called T cells and natural killer (NK) cells that will destroy cells harboring HIV. This strategy also aims to make patients resistant to HIV because the engineered immune cells will stick around to prevent further HIV infection.

By engineering a patient’s own blood-forming stem cells to produce an unlimited supply of HIV-resistant immune cells that can also eradicate HIV in other cells, Kitchen and his team are creating the possibility for a life-long, functional cure.

Dr. Kelly Shepard, Senior Science Officer of Discovery and Translation Research at CIRM, reflected on significance of Kitchen’s research in an interview:

Kelly Shepard

“This unique approach represents a two-pronged strategy whereby a patient’s own stem cells are engineered not only to be protected from new HIV infection, but also to produce HIV-specific CAR T cells that will seek out and destroy existing and new pools of HIV infection in that patient, ideally leading to a lifelong cure.”

Kitchen and his team are currently testing this stem cell-based CAR-T therapy against HIV in a large-animal model. Their latest findings, which were published recently in the journal PLOS Pathogens, showed that stem cell-derived human CAR T cells were effective at reducing the amount of HIV virus (called the viral load) in their animal-model. They also saw that the CAR T cells survived for more than two years without causing any toxic side effects. This work was funded by an earlier CIRM award led by another CIRM grantee, Dr. Jerome Zack, who is research collaborator of Kitchen’s.

In December 2017, Kitchen received a $1.7 million CIRM Discovery Stage Quest award so that the team can continue to optimize their stem cell CAR T therapy in animal models. Ultimately, they hope to gain insights into how this treatment could be further developed to treat patients with HIV.

Currently, there is no widely available cure for HIV and standard antiretroviral therapies are expensive, difficult for patients to manage and have serious side effects that reduce life expectancy. CIRM has awarded almost $75 million in funding to California scientists focused on developing novel stem cell-based therapies for HIV to address this unmet medical need. Three of these awards support early stage clinical trials, while the rest support earlier stage research projects like Kitchen’s.

CIRM Communications Director, Kevin McCormack, was quoted at the end Daily Beast article explaining CIRM’s strategy for tackling HIV:

“There are a lot of researchers working on developing stem cell therapies for HIV. We fund different approaches because at this stage we don’t know which approach will be most effective, and it may turn out that it’s ultimately a combination of these approaches, or others, that works.”

Harnessing the body’s immune system to tackle cancer

Often on the Stem Cellar we write about work that is in a clinical trial. But getting research to that stage takes years and years of dedicated work. Over the next few months, we are profiling some of the scientists we fund who are doing Discovery (early stage) and Translational (pre-clinical) research, to highlight the importance of this work in developing the treatments that could ultimately save lives. 

This second profile in the series is by Ross Okamura, Ph.D., a science officer in CIRM’s Discovery & Translation Program.

Your immune system is your body’s main protection against disease; harnessing this powerful defense system to target a given disorder is known as immunotherapy.  There are different types of immunotherapies that have been developed over the years. These include vaccines to help generate antibodies against viruses, drugs to direct immune cell function and most recently, the engineering of immune cells to fight cancer.

Understanding How Immunotherapies Work

One of the more recent immunotherapy approaches to fight cancer that has seen rapid development is equipping a subset of immune cells (T cells) with a chimeric antigen receptor (CAR). In brief, CAR T ceIls are first removed from the patient and then engineered to recognize a specific feature of the targeted cancer cells.  This direct targeting of T cells to the cancer allows for an effective anti-cancer therapy made from your own immune system.

Simplified explanation of how CAR T cell therapies fight cancer. (Memorial Sloan Kettering)

For the first time this fall, two therapeutics employing CAR T cells targeting different types of blood cancers were approved for use by the US Food and Drug Administration (FDA) based on remarkable results found during the clinical trials. Specifically, Kymriah (developed by Novartis) was approved for treatment of acute lymphoblastic leukemia and Yescarta (developed by Kite Pharma) was approved for treatment of non-Hodgkin lymphoma.

There are drawbacks to the CAR T approach, however. Revving up the immune system to attack tumors can cause dangerous side effects. When CAR T cells enter the body, they trigger the release of proteins called cytokines, which join in the attack on the tumors. But this can also create what’s referred to as a cytokine storm or cytokine release syndrome (CRS), which can lead to a range of responses, from a mild fever to multi-organ failure and death. Balancing treatments to resolve CRS after it’s detected while still maintaining the treatment’s cancer-killing abilities is a significant challenge that remains to be overcome.  A second issue is that cancer cells can evade the immune system by no longer producing the target that the CAR-T therapy was designed to recognize. When this happens, the patient subsequently experiences a cancer relapse that is no longer treatable by the same cell therapy.

Natural Killer (NK) T cells represent another type of anti-cancer immunotherapy that is also being tested in clinical trials. NK cells are part of the innate immune system responsible for defending your body against both infection and tumor formation.  NK cells target stressed cells by releasing cell-penetrating proteins that poke holes in the cells leading to induced cell death.  As an immunotherapy, NK cells have the potential to avoid both the issues of CRS and cancer cell immune evasion as they release a more limited array of cytokines and do not rely on a specific single target to recognize tumors.  NK cells instead selectively target tumor cells due to the presence of stress-induced proteins on the cancer cells. In addition, the cancer cells lack other proteins that would normally send out a “I’m a healthy cell you can ignore me” message to NK cells. Without that message, NK cells target and kill those cancer cells.

Developing new immunotherapies against cancer

Dan Kaufman, UCSD

Dr. Dan Kaufman of the University of California at San Diego is a physician-scientist whose research group developed a method to produce functional NK cells from human pluripotent stem cells (PSC).  In order to overcome a major hurdle in the use of NK cells as an anti-cancer therapeutic, Dr. Kaufman is exploring using stem cells as a limitless source to produce a scalable, standardized, off-the-shelf product that could treat thousands of patients.  CIRM is currently funding Dr. Kaufman’s work under both a Discovery Quest award and a just recently funded Translational research award in order to try to advance this candidate approach.

In the CIRM Translational award, Dr. Kaufman is looking to cure acute myelogenous leukemia (AML) which in the US has a 5-year survival rate of 27% (National Cancer Institute, 2017) and is estimated to kill over 10,000 individuals this year (American Cancer Society, 2017).  He has previously shown that his stem cell-derived NK cells can kill human cancer cells in a dish and in mouse models, and his goals are to perform preliminary safety studies and to develop a process to scale his production of NK cells to support a clinical trial in people.  Since NK cells don’t require the patient and the donor to be a genetic match to be effective, a bank of PSC-derived NK cells derived from a single donor could potentially treat thousands of patients.

Looking forward, CIRM is also providing Discovery funding to Dr. Kaufman to explore ways to improve his existing approach against leukemia as well as expand the potential of his stem cell-derived NK cell therapeutic by engineering his cells to directly target solid tumors like ovarian cancer.

The field of pluripotent stem cell-based immunotherapies is full of game-changing potential and important innovations like Dr. Kaufman’s are still in the early stages.  CIRM recognizes the importance of supporting early stage research and is currently investing $27.9 million to fund 8 active Discovery and Translation awards in the cancer immunotherapy area.

Scientists find switch that targets immunotherapies to solid tumors

Cancer immunotherapies harness the power of the patient’s own immune system to fight cancer. One type of immunotherapy, called adoptive T cell therapy, uses immune cells called CD8+ Killer T cells to target and destroy tumors. These T cells are made in the spleen and lymph nodes and they can migrate to different locations in the body through a part of our circulatory system known as the lymphatic system.

CD8+ T cells can also leave the circulation and travel into the body’s tissues to fight infection and cancer. Scientists from the Scripps Research Institute and UC San Diego are interested in learning how these killer T cells do just that in hopes of developing better immunotherapies that can specifically target solid tumors.

In a study published last week in the journal Nature, the teams discovered that a gene called Runx3 acts as a switch that programs CD8+ T cells to set up shop within tissues outside of the circulatory system, giving them access to solid tumors.

“Runx3 works on chromosomes inside killer T cells to program genes in a way that enables the T cells to accumulate in a solid tumor,” said Matthew Pipkin, co-senior author and Associate Professor at The Scripps Research Institute.

Study authors Adam Getzler, Dapeng Wang and Matthew Pipkin of The Scripps Research Institute collaborated with scientists at the University of California, San Diego.

They discovered Runx3 by comparing what genes were expressed in CD8+ T cells found in the lymphatic system to CD8+ T cells that were found in tissues outside of the circulation. They then screened thousands of potential factors for their ability to influence CD8+ T cells to infiltrate solid tumors.

“We found a distinct pattern,” Pipkin said. “The screens showed that Runx3 is one at the top of a list of regulators essential for T cells to reside in non-lymphoid tissues.”

The team then set out to prove that Runx3 was a key factor in getting CD8+ T cells to localize at the site of solid tumors. To do this, they took T cells that either overexpressed Runx3 or did not express Runx3 in these cells. The T cells were then transplanted into mice with melanoma through a process known as adoptive cell transfer. Overexpression of Runx3 in T cells not only reduced tumor size but also extended lifespan in the mice. On the other hand, removing Runx3 expression had a negative impact on their survival rate.

This research, which was supported in part by CIRM funding, offers a new strategy for developing better cancer immunotherapies for solid tumors.

Pipkin concluded in a Scripps Research Institutes News Release,

“Knowing that modulating Runx3 activity in T cells influences their ability to reside in solid tumors opens new opportunities for improving cancer immunotherapy. We could probably use Runx3 to reprogram adoptively transferred cells to help drive them to amass in solid tumors.”

CIRM-Funded Research Makes Multiple Headlines this Week

When it rains it pours.

This week, multiple CIRM-funded studies appeared in the news, highlighting the exciting progress our Agency is making towards funding innovative stem cell research and promoting the development of promising stem cell therapies for patients.

Below are highlights.


Fate Therapeutics Partners with UC San Diego to Develop Cancer Immunotherapy

Last week, Dr. Dan Kaufman and his team at UC San Diego, received a $5.15 million therapeutic translational research award from CIRM to advance the clinical development of a stem cell-derived immunotherapy for acute myelogenous leukemia (AML), a rare form of blood cancer.

Today, it was announced that the UCSD team is entering into a research collaboration with a San Diego biopharmaceutical company Fate Therapeutics to develop a related immunotherapy for blood cancers. The therapy consists of immune cells called chimeric antigen receptor-targeted natural killer (CAR NK) cells that can target tumor cells and stop their growth. Fate Therapeutics has developed an induced pluripotent stem cell (iPSC) platform to develop and optimize CAR NK cell therapies targeting various cancers.

According to an article by GenBio, this new partnership is already bearing fruit.

“In preclinical studies using an ovarian cancer xenograft model, Dr. Kaufman and Fate Therapeutics had shown that a single dose of CAR-targeted NK cells derived from iPSCs engineered with the CAR construct significantly inhibited tumor growth and increased survival compared to NK cells containing a CAR construct commonly used for T-cell immunotherapy.”

 


City of Hope Brain Cancer Trial Featured as a Key Trial to Watch in 2018

Xconomy posted a series this week forecasting Key Clinical Data to look out for next year. Today’s part two of the series mentioned a recent CIRM-funded trial for glioblastoma, an aggressive, deadly brain cancer.

Christine Brown and her team at the City of Hope are developing a CAR-T cell therapy that programs a patient’s own immune cells to specifically target and kill cancer cells, including cancer stem cells, in the brain. You can read more about this therapy and the Phase 1 trial on our website.

Alex Lash, Xconomy’s National Biotech Editor, argued that good results for this trial would be a “huge step forward for CAR-T”.

Alex Lash

“While CAR-T has proven its mettle in certain blood cancers, one of the biggest medical questions in biotech is whether the killer cells can also eat up solid tumors, which make up the majority of cancer cases. Glioblastoma—an aggressive and usually incurable brain cancer—is a doozy of a solid tumor.”


ViaCyte Receives Innovative New Product Award for Type 1 Diabetes

Last week, San Diego-based ViaCyte was awarded the “Most Innovative New Product Award” by CONNECT, a start-up accelerator focused on innovation, for its PEC-Direct product candidate. The product is a cell-based therapy that’s currently being tested in a CIRM-funded clinical trial for patients with high-risk type 1 diabetes.

In a company news release published today, ViaCyte’s CEO Paul Laikind commented on what the award signifies,

Paul Laikind

“This award acknowledges how ViaCyte has continually broken new ground in stem cell research, medical device engineering, and cell therapy scaling and manufacturing. With breakthrough technology, clinical stage product candidates, an extensive intellectual property estate, and a strong and dedicated team, ViaCyte has all the pieces to advance a transformative new life-saving approach that could help hundreds of thousands of people with high-risk type 1 diabetes around the world.”

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: