How CIRM support helped a promising approach to type 1 diabetes get vital financial backing

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The “Valley of Death” sounds like a scary place from “Lord of the Rings” or “Game of Thrones” that our heroes have to navigate to reach safety. The reality is not that different. It’s the space that young companies have to navigate from having a good idea to getting financial backing, so they can move their projects towards the clinic. At the other side of the Valley are deep-pocket investors, waiting to see what makes it through before deciding if they want to support them.

It’s a Catch 22 situation. Without financing companies can’t make it through the Valley; but they need to get through before the folks with money will considering investing. As a result many companies languish or even fail to make it through the Valley of Death. Without that financial support promising therapies are lost before they even get a chance to show their potential.

CIRM was created, in part, to help those great ideas get through the Valley. That’s why it is so gratifying to hear the news today from ViaCyte – that is developing a promising approach to treating type 1 diabetes – that they have secured $80 million in additional financing.

The money comes from Bain Capital Life Sciences, TPG and RA Capital Management and several other investors. It’s important because it is a kind of vote of confidence in ViaCyte, suggesting these deep-pocket investors believe the company’s approach has real potential.

In a news release Adam Koppel, a Managing Director at Bain, said:

“ViaCyte is the clear leader in beta cell replacement, and we are excited about the lasting impact that it’s stem cell-derived therapies can potentially have on improving treatment and quality of life for people living with insulin-requiring diabetes. We look forward to partnering with ViaCyte’s management team to accelerate the development of ViaCyte’s transformative cell therapies to help patients.”

CIRM has been a big supporter of ViaCyte for several years, investing more than $70 million to help them develop a cell therapy that can be implanted under the skin that is capable of delivering insulin to people with type 1 diabetes when needed. The fact that these investors are now stepping up to help it progress suggests we are not alone in thinking this project has tremendous promise.

But ViaCyte is far from the only company that has benefitted from CIRM’s early and consistent support. This year alone CIRM-funded companies have raised more than $1.0 billion in funding from outside investors; a clear sign of validation not just for the companies and their therapies, but also for CIRM and its judgement.

This includes:

  • Humacyte raising $225 million for its program to help people battling kidney failure
  • Forty Seven Inc. raising $113 million from an Initial Public Offering for its programs targeting different forms of cancer
  • Nohla Therapeutics raising $56 million for its program treating acute myeloid leukemia

We have shown there is a path through the Valley of Death. We are hoping to lead many more companies through that in the coming years, so they can bring their therapies to people who really need them, the patients.

 

 

 

Support cells have different roles in blood stem cell maintenance before and after stress

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Expression of pleiotrophin (green) in bone marrow blood vessels (red) and stromal cells (white) in normal mice (left), and in mice 24 hours after irradiation (right). UCLA Broad Stem Cell Research Center/Cell Stem Cell

A new study published in the journal Cell Stem Cell, reveals how different types of cells in the bone marrow are responsible for supporting blood stem cell maintenance before and after injury.

It was already well known in the field that two different cell types, namely endothelial cells (which line blood vessels) and stromal cells (which make up connective tissue, or tissue that provides structural support for any organ), are responsible for maintaining the population of blood stem cells in the bone marrow. However, how these cells and the molecules they secrete impact blood stem cell development and maintenance is not well understood.

Hematopoietic stem cells are responsible for generating the multiple different types of cells found in blood, from our oxygen carrying red blood cells to the many different types of white blood cells that make up our immune system.

Dr. John Chute’s group at UCLA had previously discovered that a molecule called pleiotrophin, or PTN, is important for promoting self-renewal of the blood stem cell population. They did not, however, understand which cells secrete this molecule and when.

To answer this question, the scientists developed mouse models that did not produce PTN in different types of bone marrow cells, such as endothelial cells and stromal cells. Surprisingly, they saw that the inability of stromal cells to produce PTN decreased the blood stem cell population, but deletion of PTN in endothelial cells did not affect the blood stem cell niche.

Even more interestingly, the researchers found that in animals that were subjected to an environmental stressor, in this case, radiation, the result was reversed: endothelial cell PTN was necessary for blood stem cell renewal, whereas stromal cell PTN was not. While an important part of the knowledge base for blood stem cell biology, the reason for this switch in PTN secretion at times of homeostasis and disease is still unknown.

As Dr. Chute states in a press release, this result could have important implications for cancer treatments such as radiation:

“It may be possible to administer modified, recombinant versions of pleiotrophin to patients to accelerate blood cell regeneration. This strategy also may apply to patients undergoing bone marrow transplants.”

Another important consideration to take away from this work is that animal models developed in the laboratory should take into account the possibility that blood stem cell maintenance and regeneration is distinctly controlled under healthy and disease state. In other words, cellular function in one state is not always indicative of its role in another state.

This work was partially funded by a CIRM Leadership Award.

 

 

Has Regenerative Medicine Come of Age?

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For the past few years the Signals blog site –  which offers an insiders’ perspectives on the world of regenerative medicine and stem cell research – has hosted what it calls a “Blog Carnival”. This is an event where bloggers from across the stem cell field are invited to submit a piece based on a common theme. This year’s theme is “Has Regenerative Medicine Come of Age?” Here’s my take on that question:

Many cultures have different traditions to mark when a child comes of age. A bar mitzvah is a Jewish custom marking a boy reaching his 13th birthday when he is considered accountable for his own actions. Among Latinos in the US a quinceañera is the name given to the coming-of-age celebration on a girl’s 15th birthday.

Regenerative Medicine (RM) doesn’t have anything quite so simple or obvious, and yet the signs are strong that if RM hasn’t quite come of age, it’s not far off.

For example, look at our experience at the California Institute for Regenerative Medicine (CIRM). When we were created by the voters of California in 2004 the world of stem cell research was still at a relatively immature phase. In fact, CIRM was created just six years after scientists first discovered a way to derive stem cells from human embryos and develop those cells in the laboratory. No surprise then that in the first few years of our existence we devoted a lot of funding to building world class research facilities and investing in basic research, to gain a deeper understanding of stem cells, what they could do and how we could use them to develop therapies.

Fast forward 14 years and we now have funded 49 projects in clinical trials – everything from stroke and cancer to spinal cord injury and HIV/AIDS – and our early funding also helped another 11 projects get into clinical trials. Clearly the field has advanced dramatically.

In addition the FDA last year approved the first two CAR-T therapies – Kymriah and Yescarta – another indication that progress is being made at many levels.

But there is still a lot of work to do. Many of the trials we are funding at the Stem Cell Agency are either Phase 1 or 2 trials. We have only a few Phase 3 trials on our books, a pattern reflected in the wider RM field. For some projects the results are very encouraging – Dr. Gary Steinberg’s work at Stanford treating people recovering from a stroke is tremendously promising. For others, the results are disappointing. We have cancelled some projects because it was clear they were not going to meet their goals. That is to be expected. These clinical trials are experiments that are testing, often for the first time ever in people, a whole new way of treating disease. Failure comes with the territory.

As the number of projects moving out of the lab and into clinical trials increases so too are the other signs of progress in RM. We recently held a workshop bringing together researchers and regulators from all over the world to explore the biggest problems in manufacturing, including how you go from making a small batch of stem cells for a few patients in an early phase clinical trial to mass producing them for thousands, if not millions of patients. We are also working with the National Institutes of Health and other stakeholders in discussing the idea of reimbursement, figuring out who pays for these therapies so they are available to the patients who need them.

And as the field advances so too do the issues we have to deal with. The discovery of the gene-editing tool CRISPR has opened up all sorts of possible new ways of developing treatments for deadly diseases. But it has also opened up a Pandora’s box of ethical issues that the field as a whole is working hard to respond to.

These are clear signs of a maturing field. Five years ago, we dreamed of having these kinds of conversations. Now they are a regular feature of any RM conference.

The simple fact that we can pose a question asking if RM has come of age is a sign all by itself that we are on the way.

Like little kids sitting in the back of a car, anxious to get to their destination, we are asking “Are we there yet?” And as every parent in the front seat of their car responds, “Not yet. But soon.”

Stem Cell Roundup: Crafty Cancer, Fighting Viruses, and Brainstorm ALS Trial Expands to Canada

TGIF! Here is your weekly dose of stem cell news…

Shapeshifting cancer cells

This week’s awesome stem cell photo comes with a bizarre story and bonus video footage.

New research from Duke has found that some lung cancer cells with errors in transcription factors begin to resemble their nearest relatives – the cells of the stomach and gut. (Credit – Tata Lab, Duke University)

Researchers at Duke University were studying lung tumor samples and discovered something that didn’t quite belong. Inside the lung tumors were miniature parts of the digestive system including the stomach, duodenum and small intestine. It turns out that the lung cancer cells (and cancer cells in general) are super crafty and had turned off the expression of a gene called NKX2-1. This gene is a master switch that tells developing cells to turn into lung cells. Without this command, cells switch their identity and mature into gut tissue instead. By manipulating these master switches, cancer cells are able to develop resistance to chemotherapy and other cancer treatments.

So, what does this bizarre finding mean for cancer research? Purushothama Rao Tata, first author on the Developmental Cell study, provided an answer in a news release:

“Cancer biologists have long suspected that cancer cells could shape shift in order to evade chemotherapy and acquire resistance, but they didn’t know the mechanisms behind such plasticity. Now that we know what we are dealing with in these tumors – we can think ahead to the possible paths these cells might take and design therapies to block them.”

For more cool photos and insights into this study, watch the Duke Univeristy video below.


Secrets to the viral-fighting ability of stem cells uncovered (Todd Dubnicoff)

I’ve been writing about stem cells for many years and thought I knew most of the basic info about these amazing cells. But up until this week, I had no idea that stem cells are known to fight off viral infections much better than other cells. It does makes sense though. Stem cells give rise to and help maintain all the organs and tissues of the body. So, it would be bad news if, let’s say, a muscle stem cell multiplied to repair damaged tissue while carrying a dangerous virus.

How exactly stem cells fend off attacking viruses is a question that has eluded researchers for decades. But this week, results published in Cell by Rockefeller University scientists may provide an answer.

Stem cells lacking their protective genes are susceptible to infection by the dengue virus, in red. (Rockefeller University)

The researchers found that liver cells and stem cells defend themselves against viruses differently. In the presence of a virus, liver cells and most other cells react by releasing large amounts of interferon, a protein that acts as a distress signal to other cells in the vicinity. That signal activates hundreds of genes responsible for attracting protective immune cells to the site of infection.

Stem cells, however, are always in this state of emergency. Even in the absence of interferon, the antiviral genes were activated in stem cells. And when the stem cells were genetically engineering to lack some of the antiviral genes, the cells no longer could stop viral infection.

In a press release, senior author Charles Rice explained the importance of this work:

“By understanding more about this biology in stem cells, we may learn more about antiviral mechanisms in general.”


CIRM-funded clinical trial for ALS now available next door – in Canada (Kevin McCormack)

In kindergarten we are taught that it’s good to share. So, we are delighted that a Phase 3 clinical trial for ALS – also known as Lou Gehrig’s disease – that CIRM is helping fund is now expanding its reach across the border from the U.S. into Canada.

Brainstorm Cell Therapeutics, the company behind the therapy, says it is going to open a clinical trial site in Canada because so many Canadians have asked for it.

The therapy, as we described in a recent blog post, takes mesenchymal stem cells from the patient’s own bone marrow. Those cells are then modified in the lab to be able to churn out specific proteins that can help protect the brain cells attacked by ALS. The cells are then transplanted back into the patient and the hope is they will slow down, maybe even stop the progression of the disease.

Earlier studies showed the therapy was safe and seemed to benefit some patients. Now people with ALS across our northern border will get a chance to see if it really works.

Chaim Lebovits, the president and chief executive officer of BrainStorm, said in a press release:

“Although there are thousands of patients worldwide with ALS, we initially designed the Phase 3 trial to enroll U.S.-based patients only, primarily to make it easier for patient follow-up visits at the six U.S. clinical sites. However, due to an outpouring of inquiry and support from Canadian patients wanting to enroll in the trial, we filed an amendment with the FDA [the U.S. Food and Drug Administration] to allow Canada-based ALS patients to participate.”

We are happy to share.

Stem Cell Agency Heads to Inland Empire for Free Patient Advocate Event

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I am embarrassed to admit that I have never been to the Inland Empire in California, the area that extends from San Bernardino to Riverside counties.  That’s about to change. On Monday, April 16th CIRM is taking a road trip to UC Riverside, and we’re inviting you to join us.

We are holding a special, free, public event at UC Riverside to talk about the work that CIRM does and to highlight the progress being made in stem cell research. We have funded 45 clinical trials in a wide range of conditions from stroke and cancer, leukemia, lymphoma, vision loss, diabetes and sickle cell disease to name just a few. And will talk about how we plan on funding many more clinical trials in the years to come.

We’ll be joined by colleagues from both UC Riverside, and City of Hope, talking about the research they are doing from developing new imaging techniques to see what is happening inside the brain with diseases like Alzheimer’s, to using a patient’s own cells and immune system to attack deadly brain cancers.

It promises to be a fascinating event and of course we want to hear from you, our supporters, friends and patient advocates. We are leaving plenty of time for questions, so we can hear what’s on your mind.

So, join us at UC Riverside on Monday, April 16th from 12.30pm to 2pm. The doors open at 11am so you can enjoy a poster session (highlighting some of the research at UCR) and a light lunch before the event. Parking will be available on site.

Visit the Eventbrite page we have created for all the information you’ll need about the event, including a chance to RSVP and book your place.

The event is free so feel free to share this with anyone and everyone you think might be interested in joining us.

 

 

Stem Cell Roundup: Lab-grown meat, stem cell vaccines for cancer and a free kidney atlas for all

Here are the stem cell stories that caught our eye this week.

Cool Stem Cell Photo: Kidneys in the spotlight

At an early stage, a nephron forming in the human kidney generates an S-shaped structure. Green cells will generate the kidneys’ filtering device, and blue and red cells are responsible for distinct nephron activities. (Image/Stacy Moroz and Tracy Tran, Andrew McMahon Lab, USC Stem Cell)

I had to take a second look at this picture when I first saw it. I honestly thought it was someone’s scientific interpretation of Vincent van Gogh’s Starry Night. What this picture actually represents is a nephron. Your kidney has over a million nephrons packed inside it. These tiny structures filter our blood and remove waste products by producing urine.

Scientists at USC Stem Cell are studying kidney development in animals and humans in hopes of gaining new insights that could lead to improved stem cell-based technologies that more accurately model human kidneys (by coincidence, we blogged about another human kidney study on Tuesday). Yesterday, these scientists published a series of articles in the Journal of American Society of Nephrology that outlines a new, open-source kidney atlas they created. The atlas contains a catalog of high resolution images of different structures representing the developing human kidney.

CIRM-funded researcher Andrew McMahon summed it up nicely in a USC news release:

“Our research bridges a critical gap between animal models and human applications. The data we collected and analyzed creates a knowledge-base that will accelerate stem cell-based technologies to produce mini-kidneys that accurately represent human kidneys for biomedical screening and replacement therapies.”

And here’s a cool video of a developing kidney kindly provided by the authors of this study.

Video Caption: Kidney development begins with a population of “progenitor cells” (green), which are similar to stem cells. Some progenitor cells (red) stream out and aggregate into a ball, the renal vesicle (gold). As each renal vesicle grows, it radically morphs into a series of shapes — can you spot the two S-shaped bodies (green-orange-pink structures)? – and finally forms a nephron. Each human kidney contains one million mature nephrons, which form an expansive tubular network (white) that filters the blood, ensuring a constant environment for all of our body’s functions. (Video courtesy of Nils Lindstorm, Andy McMahon, Seth Ruffins and the Microscopy Core Facility at the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at the Keck School of Medicine of USC)


Lab-grown hamburgers coming to a McDonald’s near you…

“Lab-grown meat is coming, whether you like it or not” sure makes a splashy headline! This week, Wired magazine featured two Bay Area startup companies, Just For All and Finless Foods, dedicated to making meat-in-a-dish in hopes of one day reducing our dependence on livestock. The methods behind their products aren’t exactly known. Just For All is engineering “clean meat” from cells. On the menu currently are cultured chorizo, nuggets, and foie gras. I bet you already guessed what Finless Foods specialty is. The company is isolating stem-like muscle progenitor cells from fish meat in hopes of identifying a cell that will robustly create the cell types found in fish meat.

Just’s tacos made with lab-grown chorizo. (Wired)

I find the Wired article particularly interesting because of the questions and issues Wired author Matt Simon raises. Are clean meat companies really more environmentally sustainable than raising livestock? Currently, there isn’t enough data to prove this is the case, he argues. And what about the feasibility of convincing populations that depend on raising livestock for a living to go “clean”? And what about flavor and texture? Will people be willing to eat a hamburger that doesn’t taste and ooze in just the right way?

As clean meat technologies continue to advance and become more affordable, I’ll be interested to see what impact they will have on our eating habits in the future.


Induced pluripotent stem cells could be the next cancer vaccine

Our last story is about a new Cell Stem Cell study that suggests induced pluripotent stem cells (iPSCs) could be developed into a vaccine against cancer. CIRM-funded scientist Joseph Wu and his team at Stanford University School of Medicine found that injecting iPSCs into mice that were transplanted with breast cancer cells reduced the formation of tumors.

The team dug deeper and discovered that iPSCs shared similarities with cancer cells with respect to the panel of genes they express and the types of proteins they carry on their cell surface. This wasn’t surprising to them as both cells represent an immature development stage. Because of these similarities, injecting iPSCs primed the mouse’s immune system to recognize and reject similar cells like cancer cells.

The team will next test their approach on human cancer cells in the lab. Joseph Wu commented on the potential future of iPSC-based vaccines for cancer in a Stanford news release:

“Although much research remains to be done, the concept itself is pretty simple. We would take your blood, make iPS cells and then inject the cells to prevent future cancers. I’m very excited about the future possibilities.”

 

Recap of the 2018 Alliance for Regenerative Medicine Cell and Gene Therapy State of the Industry

What happened in the Cell and Gene Therapy sector in 2017, and what should we be looking out for in 2018? Over 500 executives, investors, scientists and patient advocates gathered together yesterday to find out at the Alliance for Regenerative Medicine (ARM) State of the Industry Briefing in San Francisco, California.

ARM Chairman, Robert Preti, and ARM CEO, Janet Lynch Lambert, kicked off the session by discussing how 2017 marked an inflection point for the sector. They underscored the approval of three cell/gene therapies (see slide below) by the U.S. Food and Drug Administration (FDA), a “bright and robust” future pipeline that should yield over 40 approved therapies in the next five years, and an improving regulatory environment that’s accelerating approvals of regenerative medicine therapies. This year alone, the FDA has granted 12 Regenerative Medicine Advanced Therapy (RMAT) designations through the 21st Century Cures Act (see slide below for companies/products that received RMAT in 2017).

In 2017, a total of four cell/gene therapies were approved and the US FDA awarded 12 RMAT designations. This slide is from the 2018 ARM Cell and Gene Therapy State of the Industry Briefing presentation.

Next up was a snapshot of the clinical landscape highlighting a total of 946 ongoing clinical trials at the end of 2017, and their breakdown by disease (see chart below). Oncology (cancer) is the clear winner comprising over 50% of the trials while Cardiovascular (heart) took second with 8.6% and diseases of the central nervous system (brain and spinal cord) took third with 6.5%.

Lambert also gave a brief overview of finances in 2017 and listed some impressive numbers. $7.5 Billion in capital was raised in 2017 compared to $4.2 Billion in 2016. She also mentioned major acquisitions, mergers, partnerships and public financings that paved the way for this year’s successes in cell and gene therapy.

Lambert concluded that while there was significant progress with product approvals, growing public awareness of successes in the sector, regulatory advances and financial maturity, there is a need for further commercial support and a focus on policy making, industrialization and manufacturing.

The Industry Update was followed by two panel sessions.

The first panel focused on cell-based cancer immunotherapies and featured company leaders from Juno Therapeutics, Mustang Bio, Adaptimmune, Novartis, and Fate Therapeutics.

In the cancer field, companies are aggressively pursuing the development of cell-based immunotherapies including Chimeric Antigen Receptor T (CAR-T) cells, modified T-cells and Natural Killer (NK) cells, to name a few. These therapies all involve engineering or modifying human immune cells to identify and target cancer cells that resist first-line cancer treatments like radiation or chemotherapy.

The panelists spoke of a future that involved the development of combination therapies that partner cell-based immunotherapies with other drugs and treatments to better target specific types of cancer. They also spent a significant portion of the panel discussing the issues of manufacturing and reimbursement. On manufacturing, the panel argued that a centralized cell manufacturing approach will be needed to deliver safe products to patients. On reimbursement, they addressed the difficulty of finding a balance between pricing life-saving therapies and navigating reimbursements from insurance companies.

The second panel focused on the state of gene therapy and the outlook for 2018. This panel featured company and academic leaders from CRISPR Therapeutics, Sangamo Therapeutics, BioMarin Pharmaceutical, Adverum Biotechnologies, and the Gladstone Institutes.

ARM Gene Therapy Panel: Martha Rook (MilliporeSigma), Deepak Srivastava (Gladstone Institutes), Amber Salzman (Adverum Biotechnologies), Bill Lundberg (CRISPR Therapeutics), Geoff Nichol (BioMarin Pharmaceutical), Sandy Macrae (Sangamo Therapeutics)

The panel spoke about the difference between gene editing (fixing an existing gene within a cell) and gene therapy (adding a new gene into a cell) technologies and how the delivery of these therapies into tissues and cells is the biggest challenge in the area right now.

Sandy Macrae, President and CEO of Sangamo Therapeutics, made an interesting point when he said that for gene therapy to be successful, companies need to plan two to three years in advance for a phase III trial (the final stage before a product is approved) because manufacturing gene therapies takes a long time. He said the key for success is about having medicines that are ready to launch, not just reporting good results.

Overall, ARM’s State of the Industry provided an exciting overview of the progress made in the Cell and Gene Therapy Sector in 2017 and shared outlooks for 2018 and beyond.

You can access the Live Webcast of ARM’s State of the Industry Briefing including both panel sessions on the ARM website. Be sure to check out our blog featuring our 2018 Stem Cell Conference Guide for more ARM events and other relevant stem cell research meetings in the coming year.

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.”