Stem Cell Transplant Approaches for Patients With Blood Cancers

March 13, 2019

Dr. Scadden discusses which blood cancer patients are eligible for stem cell transplantation, as well as the latest advances in the field.

Click here to read an expert perspective from Will Donnellan, MD.

Stem cell transplantation is used to treat patients with blood cancers and various blood diseases. However, the procedure is most common for blood cancers. ONCOLOGY spoke with David T. Scadden, MD, to discuss which patients are eligible, as well as the latest advances in the field.

Q:Can you describe how a typical autologous stem cell transplant and an allogeneic stem cell transplant are done and how they differ?

DR. SCADDEN:The allogeneic stem cell transplant is the process of receiving stem cells from someone else. This can be a relative or a donor who just happens to be an immunologic match. An autologous stem cell transplant means that you are donating your own stem cells. So, you can imagine that two different groups of people receive these kinds of transplants; however, each patient, whether they are receiving an autologous or an allogeneic stem cell transplant, undergoes a very similar set of steps, meaning that the stem cells are harvested, collected, and usually stored. Then, the patient goes through the process whereby their own stem cells are eliminated with the use of chemotherapy drugs, drugs plus radiation, or radiation alone. This is necessary both because you want to get rid of the abnormal cells, but you also need to make space for the new stem cells. The stem cells are given much like a blood transfusion: they go into the blood and find their way to “specialized niches,” where they start to produce new blood cells. These niches need to be empty or the cells won't find room and move on. This so-called conditioning is a part of what is necessary before a transplant can be done. After the transplant, clinicians try to manage the complications that arise from having someone else's cells in your body, or from the cells arriving but taking a long time to make the cells that the patient needs.

Q: Who are the blood cancer patients who are typically eligible for these two types of transplants?

DR. SCADDEN: To be clear, these transplants are not just for those with blood cancers, but can be for a range of different blood diseases. However, blood cancers are currently the most common setting in which these transplants are performed. If someone has an aggressive leukemia that involves cells that are not stem cells, but are very close to stem cells, you have to replace these cells that are abnormal or malignant. In this situation, you have to use someone else's stem cells, meaning an allogeneic stem cell transplant. If you are someone who had a blood disorder that is not affected so much by stem cells, but a population of differentiated blood cells, such as the B cells that can turn into lymphoma or the plasma cells that can turn into multiple myeloma, then we can give patients their own cells back. In these cases, the stem cells are harvested and put in the freezer, and then the patients are given intensive chemotherapy to wipe out their existing cells. The frozen stem cells are thawed, and when the chemotherapy drugs have cleared from the body, we infuse their stem cells back in and they begin to make new blood cells.

These approaches are also used in nonmalignant settings, often in people who have genetic disorders, including those who have sickle cell anemia or an immune deficiency. In these cases, you obviously have to use someone else's stem cells. Additionally, patients who develop aplastic anemia receive someone else's stem cells when theirs have failed. There are dozens and dozens of diseases for which transplant has now been used, but they typically occur in the settings of lymphoma, myeloma, and leukemia.

Q: Are there conditions or disorders that would preclude patients from being eligible for a stem cell transplant?

DR. SCADDEN: A lot of it has to do with the rigors of the transplant, which make the procedure quite difficult. Patients can be excluded if they have other medical problems such as heart, liver, or kidney disease. We do know that transplant is often a curative therapy. We know that it can be useful in a wide range of disorders for which transplants are not currently used, and the reason is because of the complexity of this treatment. The hope is that we can move beyond the current measures and identify new ways to do a transplant, such that additional people can be eligible for what can be a curative and life-saving therapy.

Q: Your lab works on new transplant approaches in which patients may be able to avoid cytotoxic conditioning, which many patients cannot withstand. Can you talk about some recent advances on this front, or novel approaches in development?

DR. SCADDEN: We know that stem cells can be killed by chemotherapy and radiation therapy. But we also know that in doing these treatments, there is a lot of collateral damage. Many other tissues are affected, which inevitably can result in genetic damage that affects the whole body. There are methods now where you can get a much more selective delivery of a toxin. In other words, we know that there are proteins on the surface of stem cells and many different cell types that distinguish them and make them different from other cells. Antibodies can recognize these very specific signature proteins on the cells you want to target. In my lab we try to leverage that as a way to reduce this collateral damage. We've loaded these antibodies with a toxin, so that they bind to the stem cells, causing the cells to internalize these toxins, meaning that just those cells are exposed to the toxin and only those cells die. This enables us to cause a much more selective but still powerful depletion of cells, so that the transplanted cells have a place to reside and where we can eliminate most or all of the diseased cells. This is something that has been demonstrated in animal models, and we certainly hope to advance that to humans. This strategy has been taken up by biotechnology companies, to move this approach into humans in the next year or so.

Q:Your lab studies the basic biology of hematopoietic stem cells that reside in the bone marrow. What have you learned in the last few years about the biology of these cells that may be useful for translation into novel therapies for those with hematologic malignancies?

DR. SCADDEN: One of the reasons I got involved in this is that I am interested in being able to potentially modify the genes in these cells for people who have inherited disorders of the blood and also to be able to make the cells impervious to certain kinds of infections like HIV. However, some of the early studies were complicated because we just didn't know enough about blood stem cells. I think we have gained a tremendous amount of knowledge about how blood stem cells work and also the ways in which we can genetically modify them. People have heard of CRISPR, this really exciting new way in which we can edit genes, and find ways to modify damaged DNA and genes and correct them. This technology will be tremendously powerful if it can be applied to diseases where we know a lot about the cells that are affected. There are efforts to use this in the eye, for example, but blood will certainly be an area where gene editing will be used. We are starting to see and will see over the course of the next few years that this will really have an impact.

However, for people to be willing to go through this type of therapy, the process needs to be made much less toxic. We need better ways to be able to access patients' stem cells, better ways to use fewer numbers of patients' stem cells, and better ways to allow these modified cells to go in and engraft and remake blood. These are all things that we have been working on in the lab and things that are moving forward to clinical applications. I think these will be enabling technologies for all of the very exciting gene editing techniques that are being tested now.

Q:Are there clinical trials that you can highlight that are investigating novel stem cell transplant approaches?

DR. SCADDEN: The things that are being tested currently run the gamut. Often they are focused on mitigating immune complications such as graft-vs-host disease, which can occur when a patient undergoes an allogeneic transplant. There are lots of ongoing, very interesting studies that are happening now. These include the use of inhibitors of kinases like JAK and BTK, antibodies against immune costimulating molecules like cytotoxic T-lymphocyte–associated antigen 4, antibodies against adhesion molecules like P-selectin, and antibodies against B cells. There are also some studies coming up soon to test new ways in which cells can move into the blood more rapidly and efficiently, so that it is easier to be a donor. There are also some conditioning studies that will be using antibody approaches, which are for a very limited subset of patients, but that we hope will be available for clinical trials over the next year to year and a half. These latter programs include some from Magenta Therapeutics, where I am a founder. Most clinical studies in the area of stem cell transplantation can be found on BeTheMatch.org or on ClinicalTrials.gov.

Financial Disclosure:Dr. Scadden is director, shareholder, and consultant for Clear Creek Bio, Editas Medicine, Fate Therapeutics (co-founder), LifeVaultBio, Magenta Therapeutics (co-founder), and Red Oak Medicines; he is also a director and shareholder of Agios and a consultant for FOG Pharma.

PERSPECTIVE

Hematopoietic Stem Cell Transplantation: Relevant With Room for Improvement

Will Donnellan, MD

Despite the recent approval of multiple targeted agents and immunotherapies for malignant blood disorders, hematopoietic stem cell transplantation (HSCT) remains the only curative option for a significant number of patients. Dr. Scadden gives an excellent review of the types of, indications for, and complications arising from HSCT.

When it comes to disorders such as acute leukemia, myelodysplastic syndromes, and multiply relapsed lymphomas, an allogeneic donor is generally the preferred stem cell source. The mechanism by which allogeneic HSCT is curative is twofold. Initial disease control is achieved through administration of conditioning chemotherapy +/- radiation prior to the transplant. Tumor debulking as a result of the conditioning allows disease control that is long enough for the development of the graft-vs-leukemia (GVL) effect, in which the transplanted immune system recognizes and kills residual malignant cells. GVL then provides a sustained mechanism of long-term immunological surveillance and elimination of residual disease that might lead to relapse.

When allogeneic stem cell transplant fails, it is typically due to one of several factors. On the front end, intrinsic chemoresistance and/or inability to deliver fully ablative doses of conditioning due to patient-specific factors allows the disease to progress prior to the development of GVL. Alternatively, the conditioning provides sufficient upfront control, but the disease is subsequently able to escape the GVL effect by various mechanisms, such as human leukocyte antigen loss, tumor antigen downregulation, and induction of donor immune tolerance and exhaustion.

Taking this into account, attempts to improve outcomes from allogeneic HSCT have focused on these factors. By improving conditioning regimens, especially for less fit patients, it increases the likelihood of a progression-free window that is long enough for patients to reap the benefits of GVL. Alternatively, by augmenting the donor's immune system post-transplant, GVL can be boosted and tumor escape can be prevented. Specifically in regards to improving conditioning regimens, several promising compounds are at various stages of development. As Dr. Scadden points out, conditioning that incorporates antibody-based therapy allows precise delivery of a potent cytotoxin to the cell of interest, while sparing normal healthy tissues. As a result, tumoricidal effects are enhanced and toxicity is minimized.

In a treatment landscape where novel therapies are as promising as ever, the long-validated field of HSCT is not going away. For many patients, this remains their best chance of cure. Research focused on improving conditioning regimens and enhancing post-transplant immune function will hopefully lead to breakthroughs that will benefit patients with difficult-to-treat hematologic malignancies.

Financial Disclosure: Dr. Donnellan has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

Dr. Donnellan is Director of Acute Leukemia/Myelodysplastic Syndromes Research at Sarah Cannon Research Institute/Tennessee Oncology in Nashville, Tennessee.