06/17/2016

Unlocking Blood-Forming Stem Cells for Personalized Therapies

12:09 minutes

Researchers at Stanford are reviving a technique that can use uncontaminated, blood-forming stem cells to treat a patient with cancer, autoimmune deficiency and other diseases.

Beginning in the 1960s, hematopoietic, or blood-forming, stem cells became the basis for bone marrow transplants used to treat cancer patients. Then, in the 1980s and 1990s, scientists found a way to stimulate these stem cells to move from the bone marrow into the bloodstream for collection — a process called mobilization — which gradually lessened the need for bone marrow transplants.

According to a 1996 study, the use of mobilized blood cells in cancer patients had multiple benefits: It led to “lower morbidity, and greater cost-effectiveness compared with conventional bone marrow transplant …and the relative ease of obtaining large amounts of stem cells made multi-cycle transplantation a viable option in the treatment of malignancies, allowing further escalation of chemotherapy dose intensity.”

In 1988, Irv Weissman, a longtime stem cell researcher, developed a process that could create “purified” blood-forming stem cells from mobilized blood — that is, they could extract pure, uncomtaminated stem cells from all the other cells in the mobilized blood.

This discovery became important, Weissman says, because of results found in a 1990 trial that treated women with metasticized breast cancer — cancer that has moved beyond the breast and the lymph nodes to the bones, the lung and the liver. These patients had no hope of any localized therapy to save them, but “you could give high-dose chemotherapy, and the more chemotherapy you gave the more cancer cells in the body you killed,” Weissman explains.

“[But] when we looked at the mobilized blood from those women, we saw that over half of the samples [still] had breast cancer cells in them,” he continues. “When we purified the blood-forming stem cell from the [full] mobilized blood, for the first time in medical history we could give back to those women cancer-free stem cells to regenerate their blood-forming system at doses of chemotherapy that, without return of cells, would kill them.”

The company Weissman formed after these clinical trials was bought by a larger company, which shut down the studies on purified blood cells. It is a complicated story, Weissman says, but the long and the short of it is: “They didn’t want to go into this research. There’s no money to be made in this sort of thing … They told me it was a business decision.”

Five years ago, Weissman and two other colleagues, retrieved the old data and found that one-third of the women who had received the cancer-free stem cells in the 1996 trial were alive, apparently without disease. Only 7 percent of the women who were treated with full mobilized blood — that is, cancer-contaminated blood — were alive.

Weissman had to give away any financial profit arising from his old company, but now all the materials are back at Stanford, where Weissman is the director of the Institute of Stem Cell Biology in Regenerative Medicine. Thanks to California’s Proposition 71, which created the California Institute of Regenerative Medicine in 2004 and granted power to the state to fund stem cell research independent of any profit-making enterprise, Weissman will have sufficient funds to begin this summer a trial of transplants using purified stem cells.

The first transplants won’t be for breast cancer patients right away, he says. He and his colleagues will focus first on patients with blood disorders — diseases like sickle cell anemia, Thalassemia or juvenile diabetes, in which the blood-forming system has genetically gone wrong. In these cases, Weissman says, they can give back purified blood-forming stem cells from a related donor who doesn’t have the disease, effectively replacing the defective blood system with one that isn’t defective.

Weissman also plans to approach children with SCID (Sever Combined Immunodeficiency) — a disease in which no adult immune system develops — and transplant these patients with pure, blood-forming stem cells, either from their mother or from a sibling.

“With pure stem cells, we show in animal model after animal model, that we could have a platform for regenerative medicine,” Weissman says. “If you need a lung, you would get a blood-forming stem cell from the lung donor, along with the lung itself, and eventually a lung stem cell. This is the basis for regenerative medicine.”

Two other recent discoveries could advance the field even more, Weissman says.

The discovery of the Crispr enzyme, which can actually edit genetic code, could lead to an even better way to treat a child with SCID. Doctors could use the Crispr enzyme to remove the defective gene and replace it with a healthy gene, so patients get back their own blood-forming stem cells.

Pluripotent stem cell lines, “master” cells that can potentially produce any cell or tissue the body needs to repair itself, also show great promise. “We are working right now on the project, as are many other labs, to get every tissue-specific stem cell from these pluripotent stem cell lines,” Weissman says.

—Adam Wernick (originally published on PRI.org)

Segment Guests

Irving Weissman

Irving Weissman is the director of the Institute of Stem Cell Biology and Regenerative Medicine and of the Ludwig Center for Cancer Stem Cell Research at the Stanford University School of Medicine in Stanford, California.

Segment Transcript

IRA FLATOW: This is Science Friday. I’m Ira Flatow. A bit later in the hour, we’re going to be talking about our summer reading list. And not just any books, we’re going to be talking science fiction. So you want to get ready for that.

But first, stem cells, those raw building blocks of our body that can form any type of cell. They have opened up an exciting area for personalized medicine. You’ve probably heard of all sorts of potential treatments, from quick fixes for athletes to repairment of ligaments or cartilage, to growing new teeth or corneas. And one of the first treatments was to use stem cells formed into the blood to treat cancer.

And that therapy started in the 1960s. It has become common practice since then. So how have these blood forming stem cell therapies progressed in 50 years? And what might we see in the next half century?

Irv Weissman is the Director of the Institute of Stem Cell Biology and Regenerative Medicine, also the Ludwig Center for Cancer Stem Cell Research at Stanford University, a longtime researcher in stem cell research. Irv, welcome to Science Friday.

IRV WEISSMAN: Thank you.

IRA FLATOW: You’ve researched blood forming stem cells in cancer therapy since the 1970s. How far have we come? Are we still talking about bone marrow transplants or a lot of different stuff?

IRV WEISSMAN: Well, we are talking about what was then bone marrow transplants. But the scientists in the ’80s and ’90s found a way to tease out those earlier cells that make blood from the bone marrow into the blood. That’s called mobilization.

And I formed a company called SyStemix in 1988, where we found that we could purify from mobilized blood pure blood forming stem cells with no other cells that contaminate it. That became important because one of the trials that was going on in the ’90s was to treat women with widespread breast cancer. So it had gone beyond the breast, beyond the lymph node to the bones, the lungs, the liver, and so on.

So they had no hope of any local therapy to save them. But you could give high dose chemotherapy. And the more chemotherapy you gave, the more cancer cells in the body you killed.

When we looked at the mobilized blood from those women, we saw that over half of the samples had breast cancer cells in it. And it was true the same whether was lymphoma patients and lymphoma mobilized blood, myeloma patients, myeloma cancer cells in the blood. But when we purified the blood forming stem cell from the mobilized blood for the first time on Earth, we could give back to those women cancer free stem cells to regenerate their blood forming system at doses of chemotherapy that without return of cells would kill them.

That was done at a trial at Stanford University. And my company was bought by a large company later, for many reasons. And we can discuss that in a minute.

But they shut it all down in 2000. So five years ago, Judith Shizuru, one of the therapeutic bone marrow transplanters at Stanford and [? Antonio ?] [? Muller ?] and I went back. And we found out that 1/3 of the women who got our cancer free stem cells were alive apparently without disease. But at that time point, only 7% of the women who were rescued with full mobilized blood, cancer-contaminated blood, we’re alive.

So that was 1/3 versus 7%. And I, of course, immediately notified that large company. But they remained silent.

IRA FLATOW: They didn’t want to go into this research or there’s no money to be made in this sort of thing?

IRV WEISSMAN: It’s always a speculation of why they decided not. But they told me it was a business decision. So I was able to get back all of the materials and antibodies, eventually. I had to give away any financial gain I had to other people so I couldn’t make a profit. And we have it Stanford.

And beginning this summer, we are opening up pure stem cell transplants. Now, the first transplants, in fact, won’t be for the breast cancer patients. We have to work that up. But the blood forming system is sometimes genetically gone wrong, like in sickle cell anemia or thalassemia or juvenile diabetes. And we wanted to be able to give back purified blood forming stem cells from a donor, a related donor, who didn’t have that disease so that we could replace the defective blood system with one that’s not defective.

Now, we are actually going to approach children that have the bubble boy disease. They have no adult immune system. And we will transplant them with pure blood forming stem cells, either from their mother or from a sibling.

Normally when you do a donor to host transplant with full mobilized blood, there are cells in the blood called T cells, whose normal job is to kill cancer cells, to kill invading cells, to kill cancer cells, and so on. And when they are given from a donor to a host, the ones that would have rejected the recipient skin will go to the skin and reject it.

The ones that would have rejected the lung will go to the lungs and reject it. In a word, they have a multisystem immune reaction of the donor or the graft against the host. That happens in every patient now who gets a donor transplant. So our field hasn’t an advance that much. They’ve advanced to try to ameliorate that with immunosuppressive drugs that you often take for life.

But with cancer free and T cell free stem cells, we found not only would they in graft in all the model systems but there was no graft-versus-host-disease. And because the blood forming system, let’s say from me put into you, could regenerate my blood forming system in you, we found that you could receive from me a skin graft or a heart graft or an insulin-producing allograft without any more immunosuppression. The key is to get my blood forming system to grow up in you.

So with pure stem cells, we showed in animal model after animal model that we could have a platform for regenerative medicine. If you needed a lung, you would get a stem cell from the lung donor, a blood forming stem cell, and the lung itself, and eventually, a lung stem cell. So this is the basis for regenerative medicine.

And our clinical trial to start at Stanford this summer for those children with the bubble boy disease will have instead of chemotherapy to prepare them– because it is dangerous, high-dose chemotherapy– we have substituted antibodies that will remove their own defective stem cells so the new ones can come in.

IRA FLATOW: Let me move on because I only have a few more minutes. I want to ask you about CRISPR. You know what CRISPR is. that it’s been in the news lately.

And it’s been said that to be a big game changer for the field of gene editing, you know that, do stem cells need a CRISPR, some kind of technology that will advance the field?

IRV WEISSMAN: Sure. So one way to treat this child with severe combined immunodeficiency would be use the CRISPR enzymes to remove the defective gene and also to replace it with a healthy gene so they could get their own blood forming stem cells. Now, we don’t care whether it’s a donor T cell free stem cell or their own stem cell genetically modified. We just want to see the kids get cured.

IRA FLATOW: I’m sorry. I want to move on.

IRV WEISSMAN: Go ahead.

IRA FLATOW: There’s another promising use for stem cells possibly in diabetes. Is it possible to use it to cure diabetes?

IRV WEISSMAN: That’s what I was going to say. So Judith Shizuru and I showed years ago in the animals that have the same genetic Type 1 diabetes that blood forming stem cells from a donor that is not going to get diabetes prevents the immune system from killing the insulin-producing cells in the pancreas. If they already had lost their insulin-producing cells, we have to co-transplant blood forming stem cells and insulin-producing cells or the stem cells that give rise to insulin-producing cells, all of which we would get from either embryonic stem cells, eventually, or that induced pluripotent cells, where you reprogram an adult cell back to that young form. And, of course, it would be the same whether we were doing diabetes or if we wanted to treat multiple sclerosis with blood forming stem cells and brain forming stem cells. Or even spinal cord injury, blood forming stem cells from the donor and brain forming stem cells from the same donor.

IRA FLATOW: So it seems like these blood forming stem cells hold the key, potentially, to a lot of different diseases or maladies.

IRV WEISSMAN: I think it’s the platform. It’s the one big leap we need. And so we need to be able to do that now from adult donors.

But 5 years from now, 10 years from now, we want to have those what’s called pluripotent or embryonic [INAUDIBLE], embryonic stem cells to turn them into blood forming stem cells, turn them into the other cell type we want, and then co-transplant them from the same donor.

IRA FLATOW: And how far away do you think we are from that day?

IRV WEISSMAN: We’re starting the first part right now. And thanks to the California Institute of Regenerative Medicine, Prop 71, we are able to carry out this next trial with purified stem cells. And we are working right now on the project, many labs are, to get every tissue specific stem cell from these pluripotent stem cell lines.

IRA FLATOW: And the stem cells are able to actually knock out the autoimmune disease that might bring back, let’s say, diabetes?

IRV WEISSMAN: Yes. The way they do it is that you use antibodies to clear out the autoimmune cells. So we’ll use anti-T cell antibodies and anti-stem cell antibodies. And then when the new stem cells come in, they make new T cells in your body. And they eliminate all of the autoimmune T cells against yourself and against me as the donor.

IRA FLATOW: Wow. Because I know people who have been working on this to sort of relieve the symptoms. But they always said that the disease, the autoimmunity, is just going to come back and start it again. But you found something new here.

IRV WEISSMAN: Right. This, in animal models, works for Type 1 diabetes, lupus, and a whole set of others that we’ve explored. So we have high hopes that we’ll be able to overcome the current barriers, which are mainly financial and company-type barriers, to take a discovery from the laboratory in an academic institution, do the first proof of principle in a clinical trial at that same institution with the same investigators, and then be able to release it to the public for some commercial entity.

IRA FLATOW: Good luck to you, Irv. Irv Weissman, Director of the Institute of Stem Cell Biology and Regenerative Medicine. He’s out there at Stanford.

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