User login
Photo by Aaron Logan
Research in mice suggests it’s feasible to use an immunotherapy conditioning regimen rather than radiation or chemotherapy prior to hematopoietic stem cell transplant (HSCT).
Investigators found that combining an antibody against the HSC receptor c-Kit with a CD47-blocking therapy could eliminate host HSCs and allow for successful engraftment of donor HSCs in immunocompetent recipient mice.
Adding T-cell-depleting antibodies to the mix allowed for robust HSC engraftment in a clinically relevant model of allogeneic HSCT.
Irving Weissman, MD, of Stanford University School of Medicine in California, and his colleagues conducted this research and reported the results in Science Translational Medicine.
The researchers first found that ACK2, an antibody against c-Kit, successfully depleted HSCs 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,” said study author Akanksha Chhabra, PhD, of Stanford University School of Medicine.
So the researchers sought to enhance the effectiveness of ACK2 by combining it with antibodies or biologic agents that block CD47. They found that blocking CD47—particularly with an antagonist known as CV1mb—liberated macrophages to engulf target cells.
In this way, the immune system effectively depleted host HSCs in the immunocompetent mice, clearing the way for donor HSCs to take up residence in the bone marrow.
Finally, the researchers set out to determine whether conditioning with an anti-c-Kit antibody and CD47-blocking therapy could be extended to a clinically relevant model of allogeneic HSCT, in which the donor and recipient are matched through human leukocyte antigen alleles but mismatched at minor histocompatibility complex (mHC) antigens.
So the team conditioned mice with either ACK2 and CV1mb or ACK2 and the anti-CD47 antibody MIAP410. And they achieved immune ablation with T-cell-depleting antibodies—GK1.5 (anti-CD4) and YTS169.4 (anti-CD8). The mice then received mHC-mismatched HSCs.
The researchers found that either conditioning regimen, when combined with a T-cell-depleting regimen, resulted in substantial granulocyte, B-cell, T-cell, and NK-cell chimerism, as well as HSC engraftment in the bone marrow.
The success of these techniques in mice raises the researchers’ hopes that similar techniques will succeed in humans.
“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% to effectively 0,” said study author Judith Shizuru, MD, PhD, of Stanford University School of Medicine.
“If and when this is accomplished, it will be a whole new era in disease treatment and regenerative medicine,” Dr Weissman said. 
Photo by Aaron Logan
Research in mice suggests it’s feasible to use an immunotherapy conditioning regimen rather than radiation or chemotherapy prior to hematopoietic stem cell transplant (HSCT).
Investigators found that combining an antibody against the HSC receptor c-Kit with a CD47-blocking therapy could eliminate host HSCs and allow for successful engraftment of donor HSCs in immunocompetent recipient mice.
Adding T-cell-depleting antibodies to the mix allowed for robust HSC engraftment in a clinically relevant model of allogeneic HSCT.
Irving Weissman, MD, of Stanford University School of Medicine in California, and his colleagues conducted this research and reported the results in Science Translational Medicine.
The researchers first found that ACK2, an antibody against c-Kit, successfully depleted HSCs 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,” said study author Akanksha Chhabra, PhD, of Stanford University School of Medicine.
So the researchers sought to enhance the effectiveness of ACK2 by combining it with antibodies or biologic agents that block CD47. They found that blocking CD47—particularly with an antagonist known as CV1mb—liberated macrophages to engulf target cells.
In this way, the immune system effectively depleted host HSCs in the immunocompetent mice, clearing the way for donor HSCs to take up residence in the bone marrow.
Finally, the researchers set out to determine whether conditioning with an anti-c-Kit antibody and CD47-blocking therapy could be extended to a clinically relevant model of allogeneic HSCT, in which the donor and recipient are matched through human leukocyte antigen alleles but mismatched at minor histocompatibility complex (mHC) antigens.
So the team conditioned mice with either ACK2 and CV1mb or ACK2 and the anti-CD47 antibody MIAP410. And they achieved immune ablation with T-cell-depleting antibodies—GK1.5 (anti-CD4) and YTS169.4 (anti-CD8). The mice then received mHC-mismatched HSCs.
The researchers found that either conditioning regimen, when combined with a T-cell-depleting regimen, resulted in substantial granulocyte, B-cell, T-cell, and NK-cell chimerism, as well as HSC engraftment in the bone marrow.
The success of these techniques in mice raises the researchers’ hopes that similar techniques will succeed in humans.
“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% to effectively 0,” said study author Judith Shizuru, MD, PhD, of Stanford University School of Medicine.
“If and when this is accomplished, it will be a whole new era in disease treatment and regenerative medicine,” Dr Weissman said.
Photo by Aaron Logan
Research in mice suggests it’s feasible to use an immunotherapy conditioning regimen rather than radiation or chemotherapy prior to hematopoietic stem cell transplant (HSCT).
Investigators found that combining an antibody against the HSC receptor c-Kit with a CD47-blocking therapy could eliminate host HSCs and allow for successful engraftment of donor HSCs in immunocompetent recipient mice.
Adding T-cell-depleting antibodies to the mix allowed for robust HSC engraftment in a clinically relevant model of allogeneic HSCT.
Irving Weissman, MD, of Stanford University School of Medicine in California, and his colleagues conducted this research and reported the results in Science Translational Medicine.
The researchers first found that ACK2, an antibody against c-Kit, successfully depleted HSCs 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,” said study author Akanksha Chhabra, PhD, of Stanford University School of Medicine.
So the researchers sought to enhance the effectiveness of ACK2 by combining it with antibodies or biologic agents that block CD47. They found that blocking CD47—particularly with an antagonist known as CV1mb—liberated macrophages to engulf target cells.
In this way, the immune system effectively depleted host HSCs in the immunocompetent mice, clearing the way for donor HSCs to take up residence in the bone marrow.
Finally, the researchers set out to determine whether conditioning with an anti-c-Kit antibody and CD47-blocking therapy could be extended to a clinically relevant model of allogeneic HSCT, in which the donor and recipient are matched through human leukocyte antigen alleles but mismatched at minor histocompatibility complex (mHC) antigens.
So the team conditioned mice with either ACK2 and CV1mb or ACK2 and the anti-CD47 antibody MIAP410. And they achieved immune ablation with T-cell-depleting antibodies—GK1.5 (anti-CD4) and YTS169.4 (anti-CD8). The mice then received mHC-mismatched HSCs.
The researchers found that either conditioning regimen, when combined with a T-cell-depleting regimen, resulted in substantial granulocyte, B-cell, T-cell, and NK-cell chimerism, as well as HSC engraftment in the bone marrow.
The success of these techniques in mice raises the researchers’ hopes that similar techniques will succeed in humans.
“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% to effectively 0,” said study author Judith Shizuru, MD, PhD, of Stanford University School of Medicine.
“If and when this is accomplished, it will be a whole new era in disease treatment and regenerative medicine,” Dr Weissman said.