Stem Cells in Action
by Eve Jacobs
here’s an 11- bed hospital unit in downtown New Brunswick where life and death are played out every day, hour by hour, sometimes minute by minute — often against a backdrop of absolute boredom. In the world just beyond its walls, fungi invisible to the naked eye lurk, viruses scramble, and bacteria show their worst faces — hurling threats at the lives of those inside whose desiccated immune systems make them sitting ducks for any little infectious critter hovering in the wings. No one who works here can afford to allow even a faint crack to seep into the elaborate defense system of purified filtered air and supreme cleanliness: everyone is on alert for the littlest signs of encroaching illness that most of us have learned to ignore. This is the temporary “home” of the stem cell transplantees who are waiting — just waiting — to be sprung when their body’s new immune system raises its defenses and they can return to the everyday world of generally-friendly germs and dirt.
Doctors have gotten a lot better at this in the past few years, according to Arnold Rubin, MD, director of the stem cell transplantation program at The Cancer Institute of New Jersey (CINJ), and the head of this unit. In addition to the private rooms with ultra filtration and positive pressure airflow [airborne germs are pulled out], where patients live for up to four weeks, advanced anti-fungals, anti-virals, and antibiotics are now part of the routine to ward-off the threatening infections that once felled up to 25 percent of the defenseless.
“Stem cell transplant is still a very serious business. You need to treat it with respect,” says the expert, “but its effect can be absolutely miraculous.”
It’s the miraculous that Rubin strives for every time — about 50 times a year — in that little hospital unit in Central New Jersey. But there’s no fanfare here: the pivotal action takes less than an hour and seems much the same as any infusion that cancer patients get, and surely they get many. But this one is the pot of gold because it has a shot at curing them, or buying them years of good time.
So how did this most basic building block of animal life become such a hot commodity in the medical world? Suffice it to say that its very immaturity and lack of defined purpose make it replete with previously untapped potential (See sidebar). This cell is the most talented of superstars when given appropriate “guidance”— and that’s what scientists are learning how to do.
Ahead of the game are blood stem cell experts like Rubin who have been studying, manipulating and coaxing this cell for several decades. Until just a few years ago their results were sometimes very good, but oftentimes less than stellar. Now, armed with knowledge and experience, and new technology and drugs, these specialists are a force to be reckoned with. And patients with lymphomas, leukemia and multiple myeloma can stand up and cheer because they are the beneficiaries of these advances.
For those of us who have not closely followed this field’s evolution, there is much to learn. When asked to describe the difference between a stem cell transplant and a bone marrow transplant for this article, Rubin says, “Stem cell covers the whole thing. We used to use the term bone marrow transplant but we don’t go into the bone marrow for stem cells anymore. We’ve found the results are the same.”
All blood production starts in the bone marrow, he explains. The adult blood stem cells produced there are precursors to all of the body’s white and red blood cells and platelets.
“These stem cells know where to go,” he continues. “There are a number of niches, several of them in the bone marrow, that keep stem cells healthy and allow them to grow. Stem cells travel —going from the bone niche to the vascular niche, for instance — but you don’t generally find them circulating in the blood.” Luring them from their protective nooks and pumping up their numbers are chief among the challenges that face the doctors who use them for treatment.
There are specific blood cancers and blood disorders that are particularly responsive to what is termed a “stem cell transplant,” which is not really a transplant at all, according to Rubin, since it is usually the patient’s own stem cells that are rallied to do battle. After chemotherapy to beat back the disease, growth factors (such as GMCSF) or other drugs are used to pump up the marrow’s production of stem cells and also to “call out” the stem cells from their niches into the blood stream, where they can be captured for a limited number of days in a process called apheresis.
The next step employs very high-dose chemotherapy, sometimes coupled with radiation, to wipe out the cancerous cells and the immune system, leaving the patient effectively without defenses against disease for a period of time — usually two to three weeks.
The “harvested” stem cells are sometimes put through a process to purge them of residual cancer cells, and are then infused back into the patient through a drip to rebuild the shattered immune system. It takes a week or two for the infused stem cells to “rescue” the immune system — effectively recreating it, Rubin explains. While all of that is going on, the patient often feels weak and debilitated and is not able to do much.
The point of all this is to rid the body of cancer cells, and in the case of lymphomas and Hodgkin’s disease, the high dose chemotherapy coupled with an autologous (from self) stem cell transplant can actually cure the patient of his disease. “With diffuse large cell lymphoma, for instance, in 60 percent of cases, the disease will not come back with standard doses of chemo. We raise the ante to the high dose if the lower dose doesn’t work. You want to give enough drugs to wipe out the disease but you don’t want to wipe out the patient,” he says.
Cure is not a word used lightly in the cancer world. But Rubin says that half of those with recurring Hodgkin’s disease can be cured with high dose chemo and a stem cell rescue.
When leukemia is in its first remission, meaning no disease is left in the marrow, autologous stem cell transplant often does the trick for those under age 60, according to the doctor. “We also have a large degree of success with aggressive lymphomas.”
Multiple myeloma, a cancer of the bone marrow, can’t be cured with this process, but we can “turn back the clock anywhere from several months to 10 years,” explains the specialist, and “we can do a second stem cell transplant right after the first if the initial response isn’t good enough. Patients can be treated well into their 70s.” He says that male germ cell tumors that don’t respond to standard chemotherapy will also often respond to tandem transplants.
Introducing stem cells from a matched donor — after destroying the recipient’s immune system with very high levels of chemotherapy — is considered when autologous rescue doesn’t look promising. For instance, a donor might be needed if the bone marrow itself was contaminated with many cancer cells. Of course, infusing cells from a “foreign” body greatly complicates the stem cell transplant process.
If the donor is a twin, problems will be unlikely, and if a sibling, chances are higher for success than having to rely on an unrelated donor. The key is to find a donor whose cell surface proteins—called HLAs or human leukocyte antigens—will match those of the recipient as closely as possible.
The goal here is to replace the recipient’s impaired immune system with the donor’s healthy one, and for the new immune system to recognize and attack the cancer but not damage the recipient’s other tissues. Some patients with lymphoma or leukemia have very dramatic responses to an allogeneic (not self) transplant, such as a young man Rubin successfully treated who had malignant “masses under his arms like softballs” in addition to multiple abdominal tumors. The tumors disappeared.
The downside is when the foreign immune system not only destroys tumors, but also recognizes everything else as foreign, attacking the skin, intestinal tract and liver. Rubin says that “graft versus host disease” can be daunting, but that doctors have recently found a way around it. “Mini transplants,” which use lower doses of toxic drugs that suppress the immune system rather than completely destroying it, are proving quite effective without triggering life-threatening complications.
Since the chance of matching a sibling is only one in four, and, of course, many have no sibling-donor, there is a National Marrow Registry for those in need. Rubin says that individuals with European ancestry generally have no problem matching, but African Americans, American Indians, Pacific Islanders and those with mixed ancestry may encounter problems in finding a match. The Internet has made the process faster and easier, but not foolproof.
And this is where umbilical cord blood comes into the picture. “It’s not as fussy,” says Rubin, meaning a perfect match between donor and recipient is not necessary.
“The cells engraft and fight disease well, and the cord blood is banked,” says Rubin, who is also a professor of medicine at UMDNJ-Robert Wood Johnson Medical School (RWJMS). “You don’t have to harvest it first as you do for allogeneic transplants.”
For those who might consider donating stem cells but find the notion a little scary, Rubin — who was one of the state’s pioneers in harvesting bone marrow and stem cells — says that he has never heard a complaint from a donor. “People get a lot of satisfaction out of doing this,” he says. It takes three hours over two days to donate peripheral stem cells.
In New Jersey, obstetricians offer mothers the opportunity to donate the umbilical cord blood to the blood bank. The problem is that a lot of cells are required for a transplant, but each umbilical cord has only a small number. Scientists, including Joseph Bertino, MD, interim director of CINJ, are trying to grow cord blood stem cells in the lab, and Roger K. Strair, MD, PhD, professor of medicine at RWJMS and director of CINJ's Hematologic Malignancies Program, is investigating the use of half-matches in situations where there is no stem cell match.
The science of stem cell transplant is exploding and is now being applied to diseases such as sickle cell anemia and thallasemia, lupus and multiple sclerosis — although not at the New Brunswick site. “We’re not trying to build up huge numbers,” says Rubin, “we’re just trying to do what we do well.”
This hematologic malignancy program is so successful that it’s running out of openings. Each year its services are in greater demand, but there aren’t enough beds in the highly specialized unit to answer the need. In the meantime, experts like Rubin who are busy “rescuing” their patients from near-certain death must also target the larger arena of insurance and public awareness, where many (including myself) still think of stem cell transplantation as experimental, when, in fact, it is a proven winner in the relentless fight against cancer.
Stem Cells 101
So what’s all the hoopla about stem cells? Have the stem cell advocates gone loopy or are stem cells the next best thing since antibiotics in the lifesaving business?
First — the basics: Embryonic stems cells are controversial and right now they’re used purely for research. Adult stem cells are used in research and treatment, and they are not controversial. Cord blood cells arrived on the medical scene more recently and look promising without controversy — at least so far. Embryonic stem cells are “undifferentiated”— that’s their claim to fame — which means they’re not specialized but have the potential to differentiate, or specialize, into any of the more than 200 different cell types in the human body, and may help repair nerves, muscles, organs and other parts in dire need of fixing. Adult blood stem cells are the ones with a proven track record of medical “magic.”
A short review of their history reveals why there was no stem cell controversy 10 years ago. It isn’t that scientists didn’t know about them or work with them — they did — but it wasn’t until 1998 that first University of Wisconsin, then Johns Hopkins, researchers isolated human embryonic stem cells and so developed the first stem cell line in the lab. It’s the source of the cells — aborted fetuses and “extra” embryos from in vitro fertilizations — that ignited the firestorm.
The early history of adult stem cell experiments was also fraught with bumps and bruises. The first medical attempts to transplant bone marrow from one human to another — by mouth—failed miserably about 100 years ago. However,
experiments indicated that a bone marrow infusion from a healthy mouse into the bloodstream of an ailing mouse helped restore the sick critter’s health. But successfully translating that discovery to humans didn’t start to happen until years later, when, in 1958, the first human leukocyte antigen (HLA) was discovered. It is these proteins, says Arnold Rubin, MD, director of stem cell transplantation at RWJMS and CINJ, found on the surface of almost all human cells, which allow the body to distinguish self from non-self, and alert the immune system to foreign substances so it can go on the attack. These HLAs hugely complicate the transplant picture, according to Rubin. While identical twins are assured of success in a stem cell transplant, the first successful transplant between siblings who were not identical twins didn’t happen until 1968, and the first success with an unrelated donor occurred five years later.
The science of stem cell transplant continues to evolve with success in terms of added healthy years — and even cures — becoming far more frequent. Blood stem cell transplantation for such hematologic disorders as multiple myeloma, lymphoma and specific leukemias is clearly beneficial and no longer considered experimental. Insurance often covers these transplants, although not always. When a patient is turned down by his or her company, Rubin says their team fights for coverage on a case-by-case basis.