If you’re into stem cell manufacturing, this is the conference for you!

GMP cells

Manufacturing stem cells: Photo courtesy of Pluristem

Fulfilling CIRM’s mission doesn’t just mean accelerating promising stem cell treatments to patients. It also involves accelerating the whole field of regenerative medicine, which involves not just research, but developing candidate treatments, manufacturing cell therapies, and testing these therapies in clinical trials.

Manufacturing and the pre-clinical safety evaluation of cell therapies are topics that don’t always receive a lot of attention, but they are essential and crucial steps in bringing cell therapies to market. Manufacturing cells that meet the strict standards for use in human trials is often a bottleneck where different methods of making pluripotent stem cells (PSCs) are used and standardization is not readily possible.

Abla-8Abla Creasey, Vice President of Therapeutics and Strategic Infrastructure at CIRM, notes:

“The field of stem cell research and regenerative medicine has matured to the point where there are over 900 clinical trials worldwide. It is critical to develop a system of effective regulation of how these stem cell treatments are developed and manufactured so patients can benefit from future treatments.”

To address this challenge, CIRM has teamed up the International Alliance for Biological Standardization to host the 4th Cell Therapy Conference on Manufacturing and Testing of Pluripotent Stem Cells on June 5-6th in Los Angeles, California.

WHAT

The aim of this conference is twofold. Speakers will discuss how product development programs can be moved forward in a way that will meet regulatory requirements, so treatments can be approved.

The conference will also focus on key unresolved issues that need to be addressed for the manufacturing and safety testing of pluripotent stem cell-based therapies and then make recommendations to inform the future national and international policies. The overall aim is to provide participants with a road map so new treatments can achieve the highest regulatory standards and be made available to patients around the world.

The agenda of the conference will cover four main topics:

  1. Learning from the current pluripotent space and the development of international standards
  2. Bioanalytics and comparability of therapeutic stem cells
  3. Tumorigenicity testing for therapeutic safety
  4. Pluripotent stem cell manufacturing, storage, and shipment Issues

Using this “big tent” approach, speakers will exchange knowledge, experience and expertise to develop consensus recommendations around stem cell manufacturing and testing.  New data in this area will be introduced at the conference for the first time, such as a multi-center study to identify and optimize manufacturing-compatible methods for cell therapy safety.

WHO

The conference will bring together leading experts from industry, academia, health services and therapeutic regulatory bodies around the world, including the US Food and Drug Administration, European Medicines Agency, Japan Pharmaceuticals and Medical Devices Agency, and World Health Organization.

CIRM and IABS encourage individuals and organizations actively pursuing the development of stem cell therapies to attend.

WHY

robert deansIf you’re interested, but not quite sold on this conference, take the word of these experts:
Robert Deans, Chief Technology Officer at BlueRock Therapeutics:

“I believe standardization will be an increasingly crucial element in securing commercial success for regenerative cell therapies.  This applies to all facets of development, from cell characterization and patent protection through safety testing of final product.  Most important is the adherence of players in this sector to harmonized standards and creation of a scientifically credible market to the capital community.”

martin-pera-profileProfessor Martin Pera of the Jackson Laboratory, who directs the International  Stem Cell Initiative Genetics and Epigenetics Study Group:

“Participants at this meeting will survey and discuss the state of the art in the development of definitive assays for assessing the safety of pluripotent stem cell based therapies, a critical issue for the future of the field.  Anyone active in cell therapy should attend this meeting to contribute to a dialogue that will impact on research directions and ultimately help to define best practice in this sector.”

When and Where

The conference will be held in Los Angeles Airport Marriott on June 5-6th, 2018. Registration is now open on the IABS website and you can take advantage of discounted early bird registration before April 24th.

Researchers, beware: humanized mice not human enough to study stem cell transplants

A researcher’s data is only as good as the experimental techniques used to obtain those results. And a Stanford University study published yesterday in Cell Reports, calls into question the accuracy of a widely used method in mice that helps scientists gauge the human immune system’s response to stem cell-based therapies. The findings, funded in part by CIRM, urge a healthy dose of caution before using promising results from these mouse experiments as a green light to move on to human clinical trials.

Humanized mice aren’t quite human. Illustration: Pascal Gerard

Immune rejection of stem cell-based products is a major obstacle to translating these therapies from cutting-edge research into everyday treatments for the general population for people. If the genetic composition between the transplanted cells and the patient are mismatched, the patient’s immune system will see that cell therapy as foreign and will attack it. Unlike therapies derived from embryonic stem cells or from another person, induced pluripotent stem cells (iPSC) are exciting because scientists can potentially develop stem cell-based therapies from a patient’s own cells which relieves most of the immune rejection fears.

But manufacturing iPSC-derived therapies for each patient can take months, not to mention a lot of money, to complete. Some patients with life-threatening conditions like a heart attack or stroke don’t have the luxury of waiting that long. So even with these therapies, many researchers are working towards developing non-matched cell products which would be available “off-the-shelf. In all of these cases, immune-suppressing drugs would be needed which have their own set of concerns due to dangerous side effects, like serious infection or cancer. So, before testing in humans begins, it’s important to be able to test various immune-suppressing drugs and doses in animals to understand how well a stem cell-based therapy will survive once transplanted.

But how do you test a human immune response to a human cell product in an animal? Believe it or not, researchers – some of whom are authors in this Cell Reports publication – developed “humanized mice” back in the 1980’s. These mice were engineered to lack their own immune system to allow the engraftment of a human immune system. Over the years, advances in this mouse experimental system has gotten it closer and closer to imitating a human immune system response to transplantation of mismatched cell product.

Close but no cigar, it seems.

The team in the current study performed a detailed analysis of the immune response in two different strains of humanized mice. Both groups of animals did not mount a normal, healthy immune response and so they could not completely reject transplants of various human stem cells or stem cell-based products. Now, if you didn’t know about the abnormally weak immune response in these humanized mice, you might conclude that very little immunosuppression would be needed for a given cell therapy to keep a patient’s immune system in check. But conclusively making that interpretation is not possible, according to team lead Dr. Joseph Wu, director of Stanford’s Cardiovascular Institute:

Joseph Wu. Photo: Steve Fisch/Stanford University

“In an ideal situation, these humanized mice would reject foreign stem cells just as a human patient would”, he said in a press release. “We could then test a variety of immunosuppressive drugs to learn which might work best in patients, or to screen for new drugs that could inhibit this rejection. We can’t do that with these animals.”

To uncover what was happening, the team took a step back and, rather than engrafting a human immune system into the mice, they engrafted immune cells from an unrelated mouse strain. Think of it as a mouse-ified mouse, if you will. When mouse iPSCs or human embryonic stem cells were transplanted into these mouse, the engrafted mouse immune system effectively rejected the stem cells. So, compared to these mice, some elements of the immune system in the humanized mouse strains are not quite capturing the necessary complexity to truly reproduce a human immune response.

More work will be needed to understand the underlying mechanisms of this difference. Other experiments in this study suggest that signals that inhibit the immune response may be elevated in the humanized mouse models. Dr. Leonard Shultz, a pioneer in the development of humanized mice at Jackson Laboratory and an author of this study, is optimistic about building a better model:

“The immune system is highly complex and there still remains much we need to learn. Each roadblock we identify will only serve as a landmark as we navigate the future. Already, we’ve seen recent improvements in humanized mouse models that foster enhancement of human immune function.”

Until then, the team urges other scientists to tread carefully when drawing conclusions from the humanized mice in use today.