Promising new experimental approach for replacing bone marrow stem cells

Bone marrow is the spongy tissue within our bones, predominantly located within our breast, hip and thigh bones. This tissue contains a special type of cell: blood stem or elemental cell. Normally, stem cells within our bone marrow give rise to all blood cell types, including white blood cells (fight infection, produce antibodies), red blood cells (carry oxygen) and platelets (coagulate).

Stem cell transplant may be the treatment of choice for patients with blood malignancies such as leukemia, lymphoma and myeloma1. In these malignancies, specific types of white blood cells are abnormal and replicate rapidly. Consequently, the normal primary function of white blood cells in fighting infection or disease is impaired. Moreover, accumulation of abnormal blood cells may affect the normal production of other blood cell types.

Replacing stem cells within the bone marrow, with stem cells from compatible donors, may cure blood malignancies or at least provide long remission (disease free-state). Nevertheless, conventional stem cell transplant requires chemotherapy and/or radiotherapy to: (1) eliminate abnormal cells, (2) reduce rejection by the immune system of the recipient, and (3) to free space within the bone marrow for the new transplanted stem cells to flourish1. A significant level of toxicity is associated with this initial treatment or conditioning. For example, radiotherapy as a conditioning treatment prior to stem cell transplantation is associated with increased risk of developing cataracts, diabetes and hypertension2,3. Moreover, another long-term side effect of conditioning treatment is the development of secondary tumors2,3.

Conditioning treatments have evolved over the decades since their inception in the 1950s1. In the 1980s, it was discovered that patients benefit from the immunity conferred by the graft or implant. Observations at the clinic and from clinical trials confirmed that the transplanted T-cells help in the process of eliminating residual malignant blood cells in the recipient1. The immune benefits of the graft have been exploited over the ensuing decades, and have allowed the use of lower intensity chemotherapy and/or radiotherapy for conditioning.

Therefore, immunotherapy strategies have made possible the use of less toxic conditioning treatments prior to stem cell transplantation. A recent study in mice suggests that immune-based treatments could be further exploited, allowing conditioning without the need for chemotherapy and/or radiotherapy (doi.org/10.1126/scitranslmed.aae0501)4.

A group at Stanford University School of Medicine recently demonstrated, in an experimental animal model, that immunotherapy strategies might be used to eliminate bone marrow stem and stem-derived cells (https://med.stanford.edu/news/all-news/2016/08/researchers-devise-safer-method-for-bone-marrow-transplants.html). Investigators showed that the host immune system could be activated to eliminate stem cells by using biological agents, specifically antibodies, targeting receptors or proteins within the membrane of bone marrow stem cells.

To implement this strategy, investigators targeted two critical membrane proteins on stem cells: c-kit and CD47. c-kit is essential for bone marrow stem cells to multiply and survive, while CD47 protects stem cells from elimination by the immune system4. Thus, by simultaneously blocking these proteins with specific antibodies, investigators could eliminate bone marrow stem cells in recipient animals, providing favorable conditions for transplant of new stem cells.

Patients requiring stem cell transplant for blood malignancies often depend on donor stem cells obtained from patients with similar genetic markers, but not identical to donors. Investigators mimicked the human clinical scenario by using immunologically normal host animals, and stem cell transplants grafted from genetically similar, but not identical donors. Under these conditions, successful stem cell engraftment was achieved by combined treatment with c-kit, CD47 and T-cell depleting antibodies.

Early-phase clinical trials are already in progress to evaluate the safety and effectiveness of CD47 blocking antibodies (https://med.stanford.edu/stemcell/CD47.html) and c-kit (https://www.cancer.gov/news-events/cancer-currents-blog/2016/safer-stem-cell-transplant). If these strategies are successful in humans, it may be possible to extend the use of bone marrow transplantation to other non-malignant diseases, such as metabolic disorders or specific types of anemia1. Currently the toxicity associated with chemotherapy and/or radiotherapy as conditioning treatment represents a considerable barrier to the treatment of non-malignant diseases.

References

1. Henig I. & Zuckerman T. (2014) ‘Hematopoietic Stem Cell Transplantation—50 Years of Evolution and Future Perspectives’. Rambam Maimonides Med J. 5 (4):e0028. doi:10.5041/RMMJ.10162.

2. Baker K. S. et al., (2007) ‘Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a report from the bone marrow transplantation survivor study’. Blood 109:1765-1772, doi:10.1182/blood-2006-05-022335.

3. Mohty B & Mohty M. (2011) ‘Long-term complications and side effects after allogeneic hematopoietic stem cell transplantation: an update’. Blood Cancer Journal 1, e16; doi:10.1038/bcj.2011.1

4. Chhabra A. et al., (2016) ‘Hematopoietic stem cell transplantation in immunocompetent hosts without radiation or chemotherapy’. Sci. Transl. Med. 8, 351ra105.

Link to article: Unique microbiome in breast tissue

A group of researchers at the Mayo Clinic recently discovered that breast tissue contains a distinct microbiome (DOI: 10.1038/srep30751). For this study, breast tissue was collected from patients with benign or malignant breast conditions. By analyzing the microbial genetic material in these tissue samples, investigators found that the microbiome within breast tissue differs from the microbiome present in other parts of our body. More importantly, the microorganisms found in healthy breast tissue are different from those found in cancerous breast tissue. The role of specific microorganisms in carcinogenesis is well established particularly in the gastrointestinal tract. These new findings present the opportunity to uncover the role that the unique breast microbiome may play in health and disease.

http://newsnetwork.mayoclinic.org/discussion/mayo-researchers-identify-unique-breast-microbiome-and-bacterial-differences-between-healthy-and-cancerous-tissue/