Highlights

Is HLA Matching at the C Locus Necessary?

 

Claudio Brunstein, MD, PhD, and Karen Ballen, MD
Friday, June 15, 2018
8:45 AM - 9:30 PM
Hilton San Diego Resort - International Ballroom

What to do with HLA-C?

By Kerri Wachter
AABB Staff Writer

Claudio Brunstein

Claudio Brunstein, MD, PhD

The ability to further refine matching of umbilical cord blood units (UCB), particularly for HLA-C, leaves many wondering just what to do with that information. While allele-specific matching at several loci has had significant implications for improving outcomes for unrelated adult donor (URD) hematopoietic cell transplantation (HCT), UCB grafts have traditionally been matched at HLA-A and HLA-B at the antigen level. So how is HLA-C being used at transplant centers? Claudio Brunstein, MD, PhD, hopes to generate an open discussion about HLA-C matching practices during a Friday morning talk at the 16th Annual International Cord Blood Symposium.

Brunstein said that he expects the discussion to focus on when it’s appropriate to use HLA-C and when it’s not necessary for UCB units. Brunstein is the Director of the Adult Blood and Marrow Transplantation Program, Medical Director of the Unrelated Donor Transplantation Program, and an Associate Professor of Medicine in Division of Hematology, Oncology and Transplantation at the University of Minnesota.

“Historically cord blood selection has considered only HLA-A, HLA-B, and HLA-DRB1. Over the years this has allowed most, if not all, patients to go on to a cord blood transplant,” he said. “As the number of cord blood transplants grew, we were able to tease out that better-matched cord blood transplants do better than the less well-matched. It’s not that you can’t do a less well-matched transplant when it’s the only thing that you have — and sometimes it’s the only option for an individual patient — but if you match it better, patients do better.”

“Cord blood is much more forgiving than adult URD transplants,” said Brunstein. “So in cord blood you can have a fairly mismatched unit and patients are still going to do OK. Patients will not have horrible graft-vs-host disease or a very high risk of rejection, as you normally have with a mismatched unrelated donor ... You can mismatch and you still get engraftment.”

But HLA-C matching can confer a benefit in some cases. Recent research has shown that among patients undergoing double UCB transplantation and who received at least one unit of 2-4 out of 6 UCB matched at the allele level, antigen level HLA C matching improved survival and reduced non-relapse mortality1. The authors concluded that in these patients additional HLA-C matching “should be pursued whenever possible.” However, for patients receiving well-matched units (i.e. at least 5 out of 6), additional matching at HLA-C does not improve outcomes. Additional research from other groups supports these finding.

HLA-C matching, high-resolution typing of all loci and greater CD34 doses allow better matches than traditional criteria. “If you ask me what are the minimal criteria to use a cord blood unit — well it has to be at least a 4 out of 6 match; considering HLA-A and -B at intermediate resolution and HLA-DR at high resolution; and then having a certain cell dose [greater than 2.5 x 107 TNC/kg],” he said. “HLA-C comes as a refinement to that, as does high resolution typing. CD34 dose is yet another refinement.”

1Brunstein CG, Cutler CS, DeFor TE, et al. Matching HLA-C improved the outcomes after double umbilical cord blood transplantation for recipients of 2-4/6 HLA-matched grafts. Biol Blood Marrow Transplant. 2017;23:126-33. doi: 10.1016/j.bbmt.2016.10.018.

 

Cord Tissue Derived MSCs for the Treatment of Lupus in Adults

 

Gary Gilkeson, MD
Medical University of South Carolina
Saturday, June 16, 2018
11:00 AM - 12:30 PM
Hilton San Diego Resort

Early Research Suggests Cord-Derived MSCs Could Provide Another Therapeutic Option for Systemic Lupus Erythematosus

By Kerri Wachter
AABB Staff Writer

Gary Gilkeson

Gary Gilkeson, MD

With the potential to affect almost any organ, a widely variable prognosis and a menu of standard therapies with potentially serious side effects, systemic lupus erythematosus (SLE) is a particularly challenging disease to treat.

“We do have drugs that patients respond to, but there is still a large percentage of patients who do not respond, and these drugs are relatively toxic,” said Gary Gilkeson, MD. Gilkeson is a Professor of Medicine in the Department of Microbiology and Immunology at the Medical University of South Carolina (MUSC), and will speak at the 16th International Cord Blood Symposium (ICBS), to be held June 14-16, 2018, in San Diego. Gilkeson added, “So the big goal is to find treatments that are not as toxic, especially because most of the patients are young women in their childbearing years. We want to avoid drugs that may affect their fertility.”

Mesenchymal stromal cells (MSCs) derived from cord tissue are now being actively investigated as a treatment for autoimmune diseases, such as SLE. “Prior studies have recognized for a few years that mesenchymal stromal cells have prominent immune suppressive ability,” said Gilkeson. In fact, MSCs were first used clinically to treat acute graft-versus-host disease following allogeneic hematopoietic stem cell transplant and have since been investigated for the treatment of autoimmune disorders, including Sjogren’s syndrome, systemic sclerosis and dermatomyositis/polymyositis.

Several papers published by Gilkeson’s collaborator, Lingyun Sun, MD, PhD, from The Affiliated Drum Tower Hospital of Nanjing University Medical School in China, showed good response rates when these cells were given to patients with SLE who had not responded well to other therapies. Gilkeson and his colleagues also conducted a number of studies in mouse models and found that MSCs did indeed seem to be active suppressing agents.

A phase-I trial was launched in the United States with MSCs obtained from the umbilical cords of healthy donors having an elective Caesarean section. The cells were processed at MUSC’s good manufacturing practice- (GMP) quality clean-cell facility to ensure the quality and safety of the MSCs prior to infusing into patients.

While the phase-I results are uncontrolled, the preliminary data is encouraging. In general, patients had good responses with no significant side effects. Gilkeson will be presenting some of this soon-to-be published data at ICBS. A phase-II trial is scheduled to start in May, with funding from the Lupus Foundation of America and the National Institutes of Health.

So far, the response seen in patients in the Chinese trials seems to be quite durable, with some patients doing well off of medication at 5, 6, and 7 years post-treatment, said Gilkeson. While it’s too soon to say if similar results will be seen in the U.S. trial, Gilkeson said “we have two patients who are out 8 or 9 months and are still doing fine. We are just giving one infusion, so we’ll have to see how long it lasts.”

The optimal dose also remains to be seen with investigational doses so far ranging from 1 million cells per kilogram to 10 million — with no differences in the side effect profile. It’s also too early to say whether certain patients may respond better than others. No discernable patterns have been seen in the Chinese trials so far.

“We are also doing very intense mechanistic studies, looking at everything we can think of regarding the immune system,” Gilkeson said. “The phase-I trial showed that we do see very marked changes in the immune profile of the patients. The key question is whether this might be predictive of who will respond.”

 

Unproven Therapies: From Do It Yourself Gene Editing to Stem Cell Tourism

 

Leigh Turner, PhD
University of Minnesota Center for Bioethics, School of Public Health and College of Pharmacy
09:30 AM - 10:00 AM
Thursday, June 14, 2018
Hilton San Diego Resort

When Caveat Emptor Isn’t Enough

Direct-to-Consumer Stem Cell Clinics Pose Novel Medical, Ethical and Regulatory Challenges

By Kerri Wachter
AABB Staff Writer

Leigh Turner

Leigh Turner, PhD

The principle of caveat emptor — let the buyer beware — dates back to ancient Rome, but today the maxim has commonly come to mean that a buyer assumes the risk of a purchase and would be well-served to do some research prior to the transaction. The idea has worked fairly well for real estate and tangible items for centuries. However, the growing number of stem-cell clinics in the United States that market directly to consumers (DTC) poses a serious challenge to this sage advice. Patient education, a mainstay for savvy medical consumers, isn’t enough for individuals who turn to these companies seeking treatment for a large number of conditions and injuries.

“It’s hard to argue with creating resources that will help people better understand stem cells, better understand what a clinical study is ... but I think we can’t just say ‘Well, buyer beware. It’s a complicated marketplace. Educate yourself and best of luck,’ and then give people a pat on the head and think that they’re going to be safe,” said bioethicist Leigh Turner, PhD, who will give a talk at the 16th International Cord Blood Symposium.

These DTC stem cell companies often make vague promises about the benefits of stem cells, but fail to disclose that the efficacy and safety of these treatments have yet to be rigorously tested. Companies can be downright misleading, said Turner. If a clinic offers an autologous procedure for example, they’ll say that because they use the patient’s own cells, there’s no possibility of an immunological reaction, and that there’s really no risk attached to it. The companies are careful not to make claims about curing people, as well. Instead, the companies will claim that many of their clients have found the procedure beneficial or seen an X% improvement.

“Anyone could look at that and say, ‘well, the only real downside is that maybe I spend several thousand dollars and I don’t see improvement. But it doesn’t seem like I’m at risk of real physical harm, and they’re telling me that there’s a good chance that I’ll benefit,’” said Turner, who is an associate professor at the University of Minnesota Center for Bioethics, School of Public Health and College of Pharmacy.

Not only can advertising for the stem-cell therapies — an ambiguous term — on offer be misleading, the information sources that are considered to be reliable and accurate aren’t always. Patients, clinicians and researchers alike go to the ClinicalTrials.gov website run by NIH’s National Library of Medicine that provides easy access to information about clinical trials for a host of conditions, diseases and injuries. What many of them don’t realize is that pretty much anyone can list a trial on the website. Inclusion on ClinicalTrials.gov isn’t a stamp of legitimate, rigorous, quality research. And stem cell clinics take advantage of this fact.

Turner, too, was surprised when he learned this about ClinicalTrials.gov during the course of his research into DTC stem cell clinics in the United States. “It kind of dawned on me gradually. I kept seeing things that looked strange and yet they were on Clinicaltrials.gov… I get queries from people who are thinking about going to a clinic and or have questions and are reaching out trying to get someone to help them. I used to think, ‘well, a sensible piece of advice to give people is that if you want to make a distinction between legitimate clinical research/a credible clinical trial and this marketplace of unproven and unlicensed risky interventions, then go to ClinicalTrials.gov and it will help you make those distinctions,” he said.

Turner coauthored a landmark study of DTC stem cell clinics in 2016 with stem-cell researcher Paul Knoepfler, PhD, of the University of California at Davis. In the study, the duo tried to quantify and catalog these clinics in the United States — the first systematic attempt1. They identified 351 U.S.-based businesses offering stem cell therapies direct to consumers at 571 clinics.

ClinicalTrials.gov now includes a disclaimer prominently located at the top of the website advising users that “ClinicalTrials.gov is a database of privately and publicly funded clinical studies conducted around the world.”

The difficulty in finding reliable information about legitimate stem cell trials highlights the need for regulation of the stem cell therapy marketplace. According to Turner, the FDA has a key role to play. “We need something very old-fashioned. We need an FDA that plays a more meaningful role in regulating the marketplace.” This means that when companies and clinics offer treatments for numerous diseases and injuries, the agency investigates those claims and ensures that there is meaningful science behind them.

But there’s a role for other federal and state agencies as well. While a lot of these businesses fall under the purview of the FDA, “this can’t just be a story about the FDA and whether or not it’s doing an adequate job,” he said. The Federal Trade Commission needs to take a more active role in investigating and penalizing businesses that make fraudulent advertising claims.

At the state level, medical boards regulate the practice of medicine and advertising claims that medical practices make. In many states there are also a consumer protection agencies. Both have a role to play in ensuring the safety of patients seeking stem cell treatments and protecting their wallets from untested or ineffective therapies.

1Turner L, Knoepfler P. Selling Stem Cells in the USA: Assessing the Direct-to-Consumer Industry. Cell Stem Cell. 2016;19:154-7.