Regina Kelder

The Stem Cell Frontier: Translating Breakthrough Therapies (Video)

A novel collaboration forged by the California Institute of Regeneration Medicine is helping stem cell scientists translate their therapies from the bench to the clinic 

In 2004, California voters approved a landmark proposition that made conducting stem cell research a state constitutional right. The passage of the legislation, known as Proposition 71, also authorized the sale of general obligation bonds to allocate $3 billion dollars over a period of ten years to stem cell research and research facilities. The California Institute for Regenerative Medicine (CIRM) was born.

The impetus behind Proposition 71 was the executive order in 2001 by President George W. Bush barring federal funding for human embryonic stem cell research. California hoped by boosting state funding for stem cell research—which was largely being done then using embryonic stem cells—it would pave the way for treatments for some of the most intractable diseases.

But it turned out that the people with the groundbreaking ideas did not necessarily have the expertise to bring stem cell products to the clinic. They needed a partner. Enter the Stem Cell Translating Center—a project funded by CIRM in 2016 to provide support services for California-based academic entrepreneurs and small biotechs working in this space.

The collaborators in the Translating Center—IQVIA, Charles River Laboratories, the City of Hope National Medical Center and most recently WuXi AppTec all have distinct roles. IQVIA, based in San Diego, provides grantees with a roadmap and a development plan on how they can get their product to market. City of Hope, a cancer hospital about 30 minutes from Los Angeles that specializes in regenerative medicine, supports the scale-up and production of stem cell therapies. WuXi, a contract research organization (CRO) that specializes in stem cell manufacturing, was added to the Translating Center last year to help meet the increasing demand for services from CIRM grantees. Lastly, Charles River, a CRO that partners with companies to develop their stem cell and cellular Four entities join together to form a Stem Cell Translating Center in California.therapies, helps researchers design in vitro and in vivo studies that meet regulatory expectations.

“Many of the IQVIA clients are quite inexperienced in all aspects of the drug discovery and development process,” says Thorsten Gorba, PhD, Translating Center Director of IQVIA’s Stem Cell Center and manager of the US15 million grant CIRM Translating Center. “We can take them by the hand and guide them from early drug discovery all the way to market. In this sense the Translating Center is really a unique source.”

Shawna Jackman, PhD, Principal Scientist with the Photobiology and Cellular Therapy Safety Group at Charles River, said the Translating Center is there so that stem cell researchers don’t need to worry about the “nooks and crannies” of the regulatory process. “The researchers developing these are experts in their actual cells,” said Jackman. “I’m more than happy to provide services to them so they can have confidence in the direction they are taking in assessing the safety of their product.”

Engineered Cellular Killers

One client who has used all aspects of the Translating Center is Fate Therapeutics, a small biotech of about 100 employees based in La Jolla that is working on stem cell therapy products that target blood cancers and solid tumors. In 2017, it was awarded a $4 million grant from CIRM to advance a product that is using engineered natural killer (NK) cells as an immunotherapy. Fate already has one NK product in clinical trials, FATE-NK100, which is being tested in patients with refractory or relapsed acute myeloid leukemia. The immunotherapy is comprised of adaptive memory NK cells (shown below, at left), a highly specialized and functionally distinct subset of NK cells.

The CIRM-funded project, FT-516, involves an off-the-shelf NK product derived from an induced pluripotent cell line engineered to uniformly express a novel receptor found on the surface of NK cells. The receptor enables the NK cell to bind to the neck of the Y-shaped antibodies—referred to as the FC receptor—and activate the antibody. The antibodies then form a bridge between the NK cells and the cancerous cell so that the NK cells can kill the cancerous cell. 

Induced pluripotent (iPS) cells are cells that have been reprogrammed to an embryonic stem cell-like state by introducing genes important for maintaining the essential properties of embryonic stem cells. Fourteen years ago, Japanese scientists identified conditions in 2004 that allowed these specialized cells to be genetically "reprogrammed" to assume a stem cell-like state, greatly enhancing the possibilities for therapies. But they are maverick products with virtually no blueprint.

“We are, in a petri dish, changing the state of the cell to go from a stem cell to a hemopoetic stem cell progenitor to a natural killer cell. We figured this out but it has taken us 10 years to figure it out,” says Bob Valamehr, PhD, Chief Development Officer at Fate. “Now we are going outside the petri dish into these large vessels to be able to create thousands of doses so then we can make it off-the-shelf. As we try to scale up we need to overcome all the challenges.

Fate sought help from IQVIA to develop and submit a grant proposal and turned to City of Hope to obtain the viral vector needed to deliver one of their therapeutic approaches. Charles River conducted the preclinical animal testing for the grant and helped with some of the studies required by regulators for human trials.

Fate has already submitted an IND application for another off-the-shelf NK candidate and is hoping to file an IND for its CIRM-funded product soon as well.   

No room for error

Consistency is one of the biggest challenges for developers of stem cell and cellular products.

Since the cells are living things, they are not easy to manufacture to a consistent standard like small-molecule drugs and might do unpredictable things in the body. Like blood products and transplanted organs, they can also carry infections or be rejected by the recipient’s immune system.

Joseph Gold, PhD, Senior Director of Manufacturing at City of Hope’s Center for Biomedicine and Genetics, said that when you are manufacturing any kind of cell or gene therapy the big thing you have to watch out for is variability. “We have to have very, very precise manufacturing protocols to make sure everything is done exactly the same way every time and then we have to characterize them to make sure all these cell therapy products come out within a really very stem cell translating center, project of the California Institute of Regenerative Medicinenarrow range of tolerance [because you need to know] what cells you are making, and how and effective they are.”

Gold said over time the field has gotten better and better at controlling the processes used to create certain types of cells. Researchers are also learning more about how to get rid of the cells that they don’t want there.

Shawna Jackman, PhD, Senior Research Scientist with the Photobiology and Cellular Therapy Safety Group at Charles River said the animal studies needed to validate the cell therapy add another layer of complexity.  “In order to show that a stem cell therapy is actually going to work, and give us the desired treatment effect, we have to emulate that disease in an animal model to determine proof of concept,” says Jackman. “Often that’s a challenge because no one animal model can perfectly emulate any a human disease. In addition to that we really have to understand where the cells go once they are in the patients, we need to understand their biodistribution and any other potential safety risk such as tumorigenicity.”

Jackman said this the CIRM initiative is uniquely positioned to help researchers sort out these problems. “The Translating Center is there so that stem cell researchers don’t need to worry about the “nooks and crannies” of the regulatory process. “The researchers developing these are experts in their actual cells,” said Jackman. “I’m more than happy to provide services to them so they can have confidence in the direction they are taking in assessing the safety of their product.”

Translating Center services are humming 

The stem cell manufacturing support provided by City of Hope has been in such high demand that the Translating Center opted to add the manufacturing capabilities of WuXi last year. Clients can come to WuXi’s facility, located in Philadelphia, with either a process they are ready to tech transfer or one that that they need developed from scratch, says Hillary Youngberg, the company’s Business Development Manager. “We certainly are seeing a lot of requests and a lot of people who need materials right away,” she said. “If you ask people what your time line is they say yesterday.”

George Smith, the Integrated Program Lead for IQVIA, says the ultimate goal is to get safe and effective products to patients as soon as possible. This was, in fact, why IQVIA was recruited to lead the CRIM Accelerating Center in 2015, and later the Translating Center. “A couple of years ago, the new CEO at CIRM wanted to refocus more on the clinical trials, which they called CIRM 2.0,” says Smith. “We were brought in to re-work the budget and help them convert to this new [system].”

Smith said a year later, CIRM realized that a lot of grantees were struggling because there wasn’t enough infrastructure, so they released a series of grants to California Institute of Regenerative Medicine forms a Stem Cell Translating Center.establish preclinical and clinical infrastructure to help these trailblazing scientists. “Typically with drug discovery and development you already know what you need to do and how to get there,” says Smith. “With stem cell and cellular therapies the clinical design is unprecedented and the endpoints are really focused on therapies that help the underlying disease mechanisms rather than standard drugs that alleviate symptoms.”

Gorba says about 50 CIRM-funded projects have reached clinical trials. The hope is that some of the products being supported by the Translating Center will also reach the clinic soon. 

Jackman acknowledged that these therapies would be life-changing, but she urged caution. “Providing these therapies to the clinicians as soon as possible so they can be administered to patients that are in desperate need of them is paramount,” says Jackman. “But we also have to do it in a way where we thoroughly ensure the safety of the products themselves. We need to provide the clinicians using these therapies with the appropriate information for them to perform their risk assessment and we also want to make sure the therapies, while they are going to be treating a specific need, do not do any additional harm.”