[Multibilly]

Stem cell transplants without high-dose chemotherapy

by Multibilly on Mon Aug 15, 2016 8:21 pm

This is a pretty novel approach to doing a transplant without high-dose chemotherapy.

Remember, it's really the high-dose chemo which is at the heart of the treatment when it comes to transplant procedures, and the chemo used in this process hasn't changed much over the years.

"Researchers devise method for bone marrow transplants without using chemotherapy," Stanford School of Medicine press release, Aug. 10, 2016 (link to original text)

Full text of press release:

Blood stem cell transplantation, widely known as bone marrow transplantation, is a powerful technique that potentially can provide a lifelong cure for a variety of diseases. But the procedure is so toxic that it is currently used to treat only the most critical cases.

Now, researchers at the Stanford University School of Medicine have come up with a way of conducting the therapy that, in mice, dramatically lowers its toxicity. If the method eventually proves safe and effective for humans, it potentially could be used to cure autoimmune diseases like lupus, juvenile diabetes and multiple sclerosis; fix congenital metabolic disorders like “bubble boy” disease; and treat many more kinds of cancer, as well as make organ transplants safer and more successful.

“There is almost no category of disease or organ transplant that is not impacted by this research,” said Irving Weissman, MD, a co-author of the research and professor of pathology and of developmental biology at Stanford. A paper describing the technique was published Aug. 10 in Science Translational Medicine.

The paper’s senior author is Judith Shizuru, MD, PhD, professor of medicine. The lead authors are research associate Akanksha Chhabra, PhD; former graduate student Aaron Ring, MD, PhD, who is now on the faculty at Yale; and Kipp Weiskopf, MD, PhD, a former graduate student who is now a resident at Brigham and Women’s Hospital.

Noxious treatment

To successfully transplant blood stem cells, a patient’s own population of blood stem cells must be killed. Currently, this is done using chemotherapy or radiotherapy, treatments that are toxic enough to damage a variety of organs and even result in death.

“The chemotherapy and radiation used for transplant damage DNA and can cause both immediate problems and long-term damage to many tissues in the body,” Shizuru said. “Among the many known toxic side effects, these treatments can cause damage to the liver, reproductive organs and brain, potentially causing seizures and impairing neurological development and growth in children.” For these reasons, blood stem cell transplantation is used only when the risks of serious disease outweigh the com­pli­ca­tions from the transplant.

To avoid these terrible side effects, the Stanford researchers composed a symphony of biological instruments that clear the way for blood stem cell transplantation without the use of chemotherapy or radiotherapy.

Using antibodies

The scientists started with an antibody against a cell surface protein called c-kit, which is a primary marker of blood stem cells. Attaching the antibody to c-kit resulted in depletion of blood stem cells in immune-deficient mice. “However, this antibody alone would not be effective in immune-competent recipients, who represent a majority of potential bone marrow transplant recipients,” Chhabra said. The researchers sought to enhance the effectiveness by combining it with antibodies or with biologic agents that block another cell surface protein called CD47. Blocking CD47 liberated macrophages to “eat” target cells covered with c-kit antibody, Chhabra said.

With the CD47 marker blocked and the antibody attached to c-kit proteins, the immune system effectively depleted the animals’ blood-forming stem cells, clearing the way for transplanted blood stem cells from a donor to take up residence in the bone marrow and generate a whole new blood and immune system.

Comparing blood stem cell transplants to planting a new field of crops, Shizuru noted that the researchers not only found a safer way to clear the field for planting, but “we also used safer techniques to seed the new blood-generating cells.” Currently, bone marrow transplants involve a mix of cells that includes blood stem cells as well as various immune cells from the donor, which can attack the tissue of the transplant recipient. This immune attack results in what is called graft-versus-host disease, which can damage tissues and even kill patients.

Building on knowledge gained from previous research, the team purified the donor tissue so that it contained only blood stem cells and not the other immune cells that cause graft-versus-host disease.

The success of these techniques in mice raises hopes that similar techniques will succeed in human patients. “If it works in humans like it did in mice, we would expect that the risk of death from blood stem cell transplant would drop from 20 percent to effectively zero,” Shizuru said.

‘New era in disease treatment’

“If and when this is accomplished, it will be a whole new era in disease treatment and regenerative medicine,” said Weissman, who is director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine, as well as the director of the Ludwig Center for Cancer Stem Cell Research and Medicine.

Once a patient’s blood and immune system can safely be replaced, any disease caused by the patient’s own blood and immune cells could potentially be cured by a one-time application of blood stem cell transplantation, they said. Safely replacing a patient’s blood and immune cells will get rid of the cells that attack their own tissues and produce disease like rheumatoid arthritis and Type 1 diabetes.

A method of safely doing blood stem cell transplants would also potentially make organ transplantation safer and easier, the researchers said. Currently, people who get an organ transplant must for the rest of their lives stay on drugs that keep their immune systems from attacking the transplanted organ.

“Even if you are on immunosuppressants, most organ transplants diminish in function or fail over time, and the immunosuppressive drugs themselves make the patient more susceptible to life-threatening infections or newly forming cancers,” Weissman said.

But if blood and immune stem cells from the organ donor can be transplanted at the same time as the organ, the new immune system will recognize the donated organ and not attack it, the researchers said. “The transplanted cells, the donated organ and the patient’s own tissues all learn to coexist,” Shizuru said. “The donor blood stem cells re-educate the immune system of the patient, and the transplanted organ doesn’t get kicked out.”

Blood and immune stem cell transplants may also be critical to making the new era of regenerative medicine a success. If stem cells for organs or tissues like heart or liver are grown for general transplantation — that is, not designed specifically for one patient — the patient will require immune conditioning through blood stem cell transplantation so that the stem cells are not rejected as foreign bodies, the researchers said.

Other Stanford-affiliated co-authors of the work are graduate student Sydney Gordon; research assistant Alan Le; research associate Hye-Sook Kwon, PhD; former medical fellow Nan Guo Ring, MD; Jens-Peter Volkmer, MD, an instructor at the Institute for Stem Cell Biology and Regenerative Medicine; and former research assistants Serena Tseng, Peter John Schnorr and Po Yi Ho.

Support for this research came from the Virginia and D.K. Ludwig Fund for Cancer Research, the California Institute for Regenerative Medicine, the National Institutes of Health (grants R01CA86065 and R01HL058770), the Stanford Medical Science Training Program, the Tom and Stacy Siebel Foun­da­tion, the Stinehart-Reed Foun­da­tion, the Gunn/Olivier Research Fund, and the HL Snyder Medical Foun­da­tion.

Stanford’s departments of Medicine, of Pathology and of Developmental Biology also sup­ported the work.

Related journal article:

Chhabra, A., et al, "Hematopoietic stem cell transplantation in immunocompetent hosts without radiation or chemotherapy," Science Translational Medicine, Aug. 10, 2016 (link to abstract)

Abstract of related journal article:

Hematopoietic stem cell (HSC) transplantation can cure diverse diseases of the blood system, includ­ing hematologic malignancies, anemias, and auto­immune disorders. However, patients must undergo toxic con­ditioning regimens that use chemo­therapy and/or radiation to eliminate host HSCs and enable donor HSC engraftment. Previous studies have shown that anti–c-Kit mono­clonal antibodies deplete HSCs from bone marrow niches, allowing donor HSC engraft­ment in immunodeficient mice. We show that host HSC clearance is dependent on Fc-mediated antibody effector functions, and enhancing effector activity through blockade of CD47, a myeloid-specific immune checkpoint, extends anti–c-Kit conditioning to fully immuno­com­petent mice. The com­bined treatment leads to elimination of >99% of host HSCs and robust multi­lineage blood re­con­sti­tu­tion after HSC trans­plantation. This targeted con­dition­ing regimen that uses only biologic agents has the po­ten­tial to trans­form the practice of HSC trans­plantation and enable its use in a wider spectrum of patients.

[Davidg]

Re: Stem cell transplants without high-dose chemotherapy

by Davidg on Wed Aug 17, 2016 11:19 am

Interesting paper. I'm just trying to work out if it has any application to plasma cell dyscrasias where the objective pretransplant is complete bone marrow ablation.

Another comparable approach also with minimal side affects is pre-targeted radio­immuno­therapy (RIT), which I believe Dr Green at Fred Hutchinson is working on.

[JPC]

Re: Stem cell transplants without high-dose chemotherapy

by JPC on Wed Aug 17, 2016 2:53 pm

I saw this too, Multibilly, and think the article is very interesting. As it is in the phase of animal study at present, it does seem somewhat speculative at this stage, just like all of the new drugs in multiple myeloma were also in that stage a number of years ago. Given the length of the approval process and the remaining obstacles to be worked out going forward (successful human testing, among other issues), I would say the development time would be something like in the range of 8 to 10 years.

If it works out, however, it could be quite significant. An added impetus is that multiple myeloma represents only a portion of the autologous and allogeneic transplants overall, and that presents an additional driver, as well as the concept of the potential benefit to scenarios of organ donation.

Thank you for posting.

[Mark11]

Re: Stem cell transplants without high-dose chemotherapy

by Mark11 on Thu Aug 18, 2016 9:39 am

Hi Multibilly,

Thanks for posting this article.

This article refers only to allogeneic transplants. The healthy functioning donor immune system is the most important part of the therapy, not the high dose chemotherapy. Of the few people here in the forum who have done an allogenic transplant, I am the only one that I am aware of that used a full dose of ablative chemotherapy. Here is an article that discusses conditioning for those interested. RIC stands for reduced intensity conditioning, NMA is nonmyeloablative and GVM stands for graft vs malignancy

"A general recommendation is to utilize the least toxic regimen that can achieve the optimal therapeutic result. Thus, RIC and NMA regimens are indicated for diagnoses that are highly sensitive to GVM effects. In diagnoses where higher-dose intensity improves eradication of malignancy, RIC regimens should be reserved for elderly patients or those with comorbidities who could not tolerate an ablative regimen.24 The decision to use ablative or RIC should consider the patient’s age, performance status, frailty and comorbid conditions. There is no clearly defined age cutoff. Most centers recommend RIC or NMA regimens for patients over age 60 and most centers consider patients up to 75 years of age."

Source: Pingali, S.R., and Champlin, R.E., "Pushing the envelope – nonmyeloablative and reduced intensity preparative regimens for allogeneic hematopoietic transplantation," Bone Marrow Transplantation, May 2015 (full text of article)

For patients receiving an allogeneic transplant for autoimmune diseases, this type of research could prove to be more beneficial, as they are not worried about early relapse like a blood cancer patient is prior to the donor immune system getting stronger / more mature. Allogeneic trans­plants are not a "one size fits all" type of therapy.

From the posted article:

"Comparing blood stem cell transplants to planting a new field of crops, Shizuru noted that the researchers not only found a safer way to clear the field for planting, but “we also used safer techniques to seed the new blood-generating cells.” Currently, bone marrow trans­plants involve a mix of cells that includes blood stem cells as well as various immune cells from the donor, which can attack the tissue of the trans­plant recipient. This immune attack results in what is called graft-versus-host disease, which can damage tissues and even kill patients."

I discuss graft manipulation all of the time. This is a very old concept. I used a polyclonal antibody called ATG to do this. In 2016, few patients that do an allogeneic transplant in first complete response will have a problem with extensive chronic GVHD using ATG or other techniques that are available. I will show this in a study published in 2016. I am picking this one because it separated those that do the transplant in first complete response out and it has a quality of life component. It is a study of AML and MDS patients.

"Twenty-five patients were transplanted for acute myeloid leukemia (AML) (n=20) or myelo­dys­plastic syndrome (MDS) (n=5), both in first complete remission (CR1). Fourteen (56%) were 60 years or older, 19 (76%) had an HCT-CI of three or more, and 8 (32%) had poor cytogenetics. Two-year cumulative incidence of relapse, PFS, and OS were 20%, 68% and 76%, respectively (Online Supplementary Figure S1). One year after allo-HSCT, 20 of 25 (80%) patients were alive and progression free. Among them, 18 (90%) were free of cGvHD, without IST (n=15) or with tapering IST (n=3). One patient (5%) was living with treated extensive cGvHD, and one patient (5%) was living with untreated limited cGvHD."

Source: Blaise, D., et al, "Low Non-Relapse Mortality And Long-Term Preserved Quality Of Life In Older Patients Undergoing Matched Related Donor Allogeneic Stem Cell Transplantation: A Prospective Multicenter Phase II Trial,"Haematologica, Feb 2015 (full text of article)

If one patient out of 20 needs therapy for chronic GVHD, I think it is safe to say that is not the biggest problem with the procedure. It seems obvious to me that the biggest cause of treatment failure is relapse – not "toxic" conditioning or GVHD. I do not see how the above study will help reduce the risk of relapse.

On to one of the most important topics - health related quality of life. The QOL section did not separate the first complete response group from the other patients.

"Global health-related quality of life, physical functioning, emotional functioning, and social func­tion­ing were not impaired compared to baseline for more than 75% of the patients (75%, 81.4%, 82.3%, and 75%, respectively). Thirty-four of the 46 (74%) progression-free patients at one year were living without persistent extensive chronic graft-versus-host disease. We conclude that the reduced-intensity conditioning regimen combining fludarabine, intra­venous busulfan, and rabbit anti­thy­mocyte globulins is well tolerated in patients older than 55 years with low non-relapse mortality and long-term preserved quality of life."

I enjoyed reading the study posted as this is my area of interest as opposed to reading about drugs that are not curative. Unfortunately I do not see how it would address the leading cause of treatment failure of an allogeneic transplant for blood cancer patients - relapse. Hopefully this technique can lead to solid organ transplant recipients being able to get off immuno­sup­pressive drugs like steroids. My experience as a patient that did an allo transplant in first com­plete response is in line with the 2nd study I posted. I have no signs of chronic GVHD despite having a transplant that is at high risk for it (female donor - male recipient) and my quality of life five years after the procedure is excellent. The main issue that needs to be addressed for blood cancer patients that do RIC / NMC transplants is reduction of the rate of relapse.

Mark

[Multibilly]

Re: Stem cell transplants without high-dose chemotherapy

by Multibilly on Thu Aug 18, 2016 9:46 pm

Mark,

Appreciate the followup. I re-read the article and agree with your points.