Bench to Bedside: Disruptive Innovation

While allogeneic transplantation can be life saving for patients with hematologic malignancies, or inherited disorders such as several forms of immuno-deficiency, the transplant-related side effects and complications remain the biggest hurdles. One of the sources for side effect/complication is the conditioning regimen patients receive prior to the donor graft infusion. The conditioning regimen is usually composed of a combination of chemotherapies with or without radiation, and is designed to get rid of the hematopoietic cells in the recipient so the donor hematopoietic cells can take a hold (engraftment) after infusion. In addition, the donor grafts usually contain mature blood cells (T-cells, B-cells, NK cells), which are necessary to facilitate engraftment. However, these mature donor blood cells can also cause graft-versus-host disease (GVHD). Ideally, transplants should be performed using a chemotherapy/radiation-free conditioning regimen with purified donor hematopoietic stem cells without mature blood cells. In this scenario, patients could avoid the toxicities brought by traditional conditioning and the GVHD caused by mature donor blood cells carried over in the standard graft. It turns out that this is not an easy task. For successful donor cell engraftment, two obstacles must be overcome. First, the recipient immune system has to be contained so it will not reject the incoming donor cells. Second, the donor hematopoietic cells must be able to enter the niche space in the recipient bone marrow. In Dr. Judith Shizuru’s laboratory, efforts were devoted to finding antibodies that can deplete the recipient hematopoietic stem cells in the bone marrow to open the niche for the donor cells. After extensive testing of different molecules on the stem cells, they found that monoclonal antibodies against c-Kit (CD117) are able to achieve that goal. In an animal model, anti-c-Kit antibody alone was sufficient to promote successful engraftment of purified donor stem cells in immuno-compromised mice. In these animals, there were limited number of immune cells to reject the donor stem cells. However, as expected, anti-c-Kit treatment alone is not enough for stem cells engraftment in immune-competent mice due to the robust recipient immune cells. To overcome that challenge, Dr. Shizuru’s team used an additional antibody against CD47 to enhance the effect of anti-c-Kit. With the combination of anti-c-Kit and anti-CD47, purified donor stem cells can successfully engraft in immuno-competent mice without any other treatment. In these animals, no GVHD was observed since no mature donor blood cells were infused. While this is only a pre-clinical study, the promise from this innovation is limitless.
To bring this disruptive innovation to patient care, a phase I study has recently been opened to treat children with severe combined immunodeficiency (SCID) using anti-human-c-Kit antibody and purified donor hematopoietic stem cells. As Dr. Shizuru put it, “I want to make the transplantation procedure an order of magnitude safer, and to achieve the end-goal that cures cancer, immunodeficiency and autoimmune disease.