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Increasing metabolite levels may prevent GVHD
Photo by Aaron Logan
Increasing levels of a gut microbiome-derived metabolite could help prevent graft-versus-host disease (GVHD) after hematopoietic stem cell transplant (HSCT), according to preclinical research published in Nature Immunology.
For this study, researchers searched for alterations in the gut microbiome to see whether metabolites could impact outcomes after HSCT.
They found that levels of a metabolite called butyrate were significantly reduced in the intestinal tract of mice that received a transplant.
When the researchers increased butyrate levels in these mice, they saw a decrease in the incidence and severity of GVHD.
“Our findings suggest we can prevent graft-vs-host disease by bolstering the amount of the microbiome-derived metabolite butyrate,” said study author Pavan Reddy, MD, of the University of Michigan Comprehensive Cancer Center in Ann Arbor.
He and his colleagues found they could mitigate GVHD by administering butyrate to mice or by altering the composition of indigenous gastrointestinal microbiota so they produced high levels of butyrate.
The team noted that diet is another way to control butyrate production by the gut microbiome—specifically, through resistant starch such as that found in potatoes.
The researchers hope to begin a clinical trial later this year in which they will combine resistant starch with current methods of preventing GVHD to assess whether they can increase butyrate and reduce the incidence and severity of GVHD in HSCT recipients.
“This is a whole new approach,” Dr Reddy said. “The idea is to make the host cells stronger, to be able to withstand the assault of the donor immune cells while reducing the risk of infection or [disease] relapse.” 
Photo by Aaron Logan
Increasing levels of a gut microbiome-derived metabolite could help prevent graft-versus-host disease (GVHD) after hematopoietic stem cell transplant (HSCT), according to preclinical research published in Nature Immunology.
For this study, researchers searched for alterations in the gut microbiome to see whether metabolites could impact outcomes after HSCT.
They found that levels of a metabolite called butyrate were significantly reduced in the intestinal tract of mice that received a transplant.
When the researchers increased butyrate levels in these mice, they saw a decrease in the incidence and severity of GVHD.
“Our findings suggest we can prevent graft-vs-host disease by bolstering the amount of the microbiome-derived metabolite butyrate,” said study author Pavan Reddy, MD, of the University of Michigan Comprehensive Cancer Center in Ann Arbor.
He and his colleagues found they could mitigate GVHD by administering butyrate to mice or by altering the composition of indigenous gastrointestinal microbiota so they produced high levels of butyrate.
The team noted that diet is another way to control butyrate production by the gut microbiome—specifically, through resistant starch such as that found in potatoes.
The researchers hope to begin a clinical trial later this year in which they will combine resistant starch with current methods of preventing GVHD to assess whether they can increase butyrate and reduce the incidence and severity of GVHD in HSCT recipients.
“This is a whole new approach,” Dr Reddy said. “The idea is to make the host cells stronger, to be able to withstand the assault of the donor immune cells while reducing the risk of infection or [disease] relapse.”
Photo by Aaron Logan
Increasing levels of a gut microbiome-derived metabolite could help prevent graft-versus-host disease (GVHD) after hematopoietic stem cell transplant (HSCT), according to preclinical research published in Nature Immunology.
For this study, researchers searched for alterations in the gut microbiome to see whether metabolites could impact outcomes after HSCT.
They found that levels of a metabolite called butyrate were significantly reduced in the intestinal tract of mice that received a transplant.
When the researchers increased butyrate levels in these mice, they saw a decrease in the incidence and severity of GVHD.
“Our findings suggest we can prevent graft-vs-host disease by bolstering the amount of the microbiome-derived metabolite butyrate,” said study author Pavan Reddy, MD, of the University of Michigan Comprehensive Cancer Center in Ann Arbor.
He and his colleagues found they could mitigate GVHD by administering butyrate to mice or by altering the composition of indigenous gastrointestinal microbiota so they produced high levels of butyrate.
The team noted that diet is another way to control butyrate production by the gut microbiome—specifically, through resistant starch such as that found in potatoes.
The researchers hope to begin a clinical trial later this year in which they will combine resistant starch with current methods of preventing GVHD to assess whether they can increase butyrate and reduce the incidence and severity of GVHD in HSCT recipients.
“This is a whole new approach,” Dr Reddy said. “The idea is to make the host cells stronger, to be able to withstand the assault of the donor immune cells while reducing the risk of infection or [disease] relapse.”
Four genes control growth of HSCs, team says
Image by John Perry
Four genes govern the growth and multiplication of hematopoietic stem cells (HSCs), according to a study published in Cell Reports.
Investigators conducted a genome-wide RNA interference screen in cells derived from human cord blood, looking for genes whose knockdown maintained the HSC phenotype during culture.
This revealed the 4 genes—STAG2, RAD21, STAG1, and SMC3—which are all members of the cohesin complex.
“The discovery showed that this protein complex is crucial and has an overarching function in the growth of the blood stem cells,” said study author Jonas Larsson, MD, PhD, of Lund University in Sweden.
Dr Larsson and his colleagues screened 15,000 genes for this study and found 20 candidates with a strong capacity to affect the balance of growth in HSCs.
Four of the genes—STAG2, RAD21, STAG1, and SMC3—were physically connected through cooperation in the cohesin complex. This complex forms a sort of brace that holds different parts of the DNA strand together in the cell.
The researchers believe this allows the cohesin complex to control access to the “on/off switches” in the DNA and to change the impulses that HSCs receive from various genes, thereby affecting whether an HSC multiplies or matures.
“Clarifying what regulates the balance between multiplication and maturation of blood stem cells could provide the right keys to expanding them outside the body,” said Roman Galeev, a doctoral student at Lund University.
“In addition, it would enable the identification of new points of attack for the treatment of blood cancer, which is precisely a disruption of the balance between multiplication and maturation.”
Galeev noted that research by other groups has revealed mutations in the cohesin complex genes in patients with hematologic malignancies (Mazumdar C, Cell Stem Cell 2015; Mullenders J, J Exp Med 2015; and Viny AD, J Exp Med 2015).
“This is incredibly exciting,” Galeev said. “Together with the results from our study, this indicates that the cohesin genes are directly and crucially significant in the development of blood cancer.”
“Our findings entail a new understanding of how the expansion of blood stem cells is controlled. Eventually, this can lead to new ways of affecting the process, either to prevent the development of cancer or to expand the stem cells for transplant.”
Image by John Perry
Four genes govern the growth and multiplication of hematopoietic stem cells (HSCs), according to a study published in Cell Reports.
Investigators conducted a genome-wide RNA interference screen in cells derived from human cord blood, looking for genes whose knockdown maintained the HSC phenotype during culture.
This revealed the 4 genes—STAG2, RAD21, STAG1, and SMC3—which are all members of the cohesin complex.
“The discovery showed that this protein complex is crucial and has an overarching function in the growth of the blood stem cells,” said study author Jonas Larsson, MD, PhD, of Lund University in Sweden.
Dr Larsson and his colleagues screened 15,000 genes for this study and found 20 candidates with a strong capacity to affect the balance of growth in HSCs.
Four of the genes—STAG2, RAD21, STAG1, and SMC3—were physically connected through cooperation in the cohesin complex. This complex forms a sort of brace that holds different parts of the DNA strand together in the cell.
The researchers believe this allows the cohesin complex to control access to the “on/off switches” in the DNA and to change the impulses that HSCs receive from various genes, thereby affecting whether an HSC multiplies or matures.
“Clarifying what regulates the balance between multiplication and maturation of blood stem cells could provide the right keys to expanding them outside the body,” said Roman Galeev, a doctoral student at Lund University.
“In addition, it would enable the identification of new points of attack for the treatment of blood cancer, which is precisely a disruption of the balance between multiplication and maturation.”
Galeev noted that research by other groups has revealed mutations in the cohesin complex genes in patients with hematologic malignancies (Mazumdar C, Cell Stem Cell 2015; Mullenders J, J Exp Med 2015; and Viny AD, J Exp Med 2015).
“This is incredibly exciting,” Galeev said. “Together with the results from our study, this indicates that the cohesin genes are directly and crucially significant in the development of blood cancer.”
“Our findings entail a new understanding of how the expansion of blood stem cells is controlled. Eventually, this can lead to new ways of affecting the process, either to prevent the development of cancer or to expand the stem cells for transplant.”
Image by John Perry
Four genes govern the growth and multiplication of hematopoietic stem cells (HSCs), according to a study published in Cell Reports.
Investigators conducted a genome-wide RNA interference screen in cells derived from human cord blood, looking for genes whose knockdown maintained the HSC phenotype during culture.
This revealed the 4 genes—STAG2, RAD21, STAG1, and SMC3—which are all members of the cohesin complex.
“The discovery showed that this protein complex is crucial and has an overarching function in the growth of the blood stem cells,” said study author Jonas Larsson, MD, PhD, of Lund University in Sweden.
Dr Larsson and his colleagues screened 15,000 genes for this study and found 20 candidates with a strong capacity to affect the balance of growth in HSCs.
Four of the genes—STAG2, RAD21, STAG1, and SMC3—were physically connected through cooperation in the cohesin complex. This complex forms a sort of brace that holds different parts of the DNA strand together in the cell.
The researchers believe this allows the cohesin complex to control access to the “on/off switches” in the DNA and to change the impulses that HSCs receive from various genes, thereby affecting whether an HSC multiplies or matures.
“Clarifying what regulates the balance between multiplication and maturation of blood stem cells could provide the right keys to expanding them outside the body,” said Roman Galeev, a doctoral student at Lund University.
“In addition, it would enable the identification of new points of attack for the treatment of blood cancer, which is precisely a disruption of the balance between multiplication and maturation.”
Galeev noted that research by other groups has revealed mutations in the cohesin complex genes in patients with hematologic malignancies (Mazumdar C, Cell Stem Cell 2015; Mullenders J, J Exp Med 2015; and Viny AD, J Exp Med 2015).
“This is incredibly exciting,” Galeev said. “Together with the results from our study, this indicates that the cohesin genes are directly and crucially significant in the development of blood cancer.”
“Our findings entail a new understanding of how the expansion of blood stem cells is controlled. Eventually, this can lead to new ways of affecting the process, either to prevent the development of cancer or to expand the stem cells for transplant.”
Computer models simulate HSCT recovery
Photo by Darren Baker
New research indicates that computer models can simulate the recovery of the immune system in patients undergoing hematopoietic stem cell transplant (HSCT).
The study suggests the possibility of using DNA sequencing and computer modeling to predict which HSCT recipients might suffer complications such as graft-versus-host-disease.
The research was published in Biology of Blood and Marrow Transplantation.
The study builds upon prior research, which showed that the immune system may be modeled as a dynamical system. Dynamical systems are mathematical objects used to model physical phenomena that change over time. These systems can be used to predict future states via observations of past and present states.
Researchers say the ability to predict immune system recovery after HSCT could potentially allow doctors to refine donor selection and better personalize post-transplant care to improve outcomes.
With this in mind, the team sequenced the DNA of 34 HSCT donor-recipient pairs and used the resulting information in a computer model to simulate how the recipient’s T-cell repertoire will recover following transplant.
“This study is the first to simulate the growth of the T-cell repertoire following transplantation using variables that aren’t accounted for in typical HLA donor-recipient matching,” said study author Amir Ahmed Toor, MD, of Virginia Commonwealth University in Richmond.
“Using a larger cohort of patients than in previous studies, we were able to mathematically predict the interactions of these variables, which led to simulations that appear to be very similar to clinically observed post-transplantation T-cell repertoire development.”
Previous research by Dr Toor and his colleagues revealed large variations between donor-recipient minor histocompatibility antigens that could potentially contribute to transplant complications not accounted for by HLA testing.
The models used in the computer simulations were driven by population growth formulas developed from past studies by Dr Toor and his colleagues that revealed distinct patterns of lymphocyte recovery in HSCT recipients.
Using matrix mathematics to develop the simulations, the researchers observed competition among T cells as the T-cell repertoire develops.
This competition leads to certain families of T cells becoming dominant and more numerous, which crowds out weaker T-cell families, causing them to develop later and in fewer numbers.
“We are attempting to account for the many variables that could impact T-cell repertoire development and, in turn, patient outcomes,” Dr Toor said.
“In future studies, we hope to explore the impact of organ-specific antigen expression. The knowledge gained from this research could potentially allow more accurate predictions of which organs could be most affected by graft-versus-host-disease.”
Photo by Darren Baker
New research indicates that computer models can simulate the recovery of the immune system in patients undergoing hematopoietic stem cell transplant (HSCT).
The study suggests the possibility of using DNA sequencing and computer modeling to predict which HSCT recipients might suffer complications such as graft-versus-host-disease.
The research was published in Biology of Blood and Marrow Transplantation.
The study builds upon prior research, which showed that the immune system may be modeled as a dynamical system. Dynamical systems are mathematical objects used to model physical phenomena that change over time. These systems can be used to predict future states via observations of past and present states.
Researchers say the ability to predict immune system recovery after HSCT could potentially allow doctors to refine donor selection and better personalize post-transplant care to improve outcomes.
With this in mind, the team sequenced the DNA of 34 HSCT donor-recipient pairs and used the resulting information in a computer model to simulate how the recipient’s T-cell repertoire will recover following transplant.
“This study is the first to simulate the growth of the T-cell repertoire following transplantation using variables that aren’t accounted for in typical HLA donor-recipient matching,” said study author Amir Ahmed Toor, MD, of Virginia Commonwealth University in Richmond.
“Using a larger cohort of patients than in previous studies, we were able to mathematically predict the interactions of these variables, which led to simulations that appear to be very similar to clinically observed post-transplantation T-cell repertoire development.”
Previous research by Dr Toor and his colleagues revealed large variations between donor-recipient minor histocompatibility antigens that could potentially contribute to transplant complications not accounted for by HLA testing.
The models used in the computer simulations were driven by population growth formulas developed from past studies by Dr Toor and his colleagues that revealed distinct patterns of lymphocyte recovery in HSCT recipients.
Using matrix mathematics to develop the simulations, the researchers observed competition among T cells as the T-cell repertoire develops.
This competition leads to certain families of T cells becoming dominant and more numerous, which crowds out weaker T-cell families, causing them to develop later and in fewer numbers.
“We are attempting to account for the many variables that could impact T-cell repertoire development and, in turn, patient outcomes,” Dr Toor said.
“In future studies, we hope to explore the impact of organ-specific antigen expression. The knowledge gained from this research could potentially allow more accurate predictions of which organs could be most affected by graft-versus-host-disease.”
Photo by Darren Baker
New research indicates that computer models can simulate the recovery of the immune system in patients undergoing hematopoietic stem cell transplant (HSCT).
The study suggests the possibility of using DNA sequencing and computer modeling to predict which HSCT recipients might suffer complications such as graft-versus-host-disease.
The research was published in Biology of Blood and Marrow Transplantation.
The study builds upon prior research, which showed that the immune system may be modeled as a dynamical system. Dynamical systems are mathematical objects used to model physical phenomena that change over time. These systems can be used to predict future states via observations of past and present states.
Researchers say the ability to predict immune system recovery after HSCT could potentially allow doctors to refine donor selection and better personalize post-transplant care to improve outcomes.
With this in mind, the team sequenced the DNA of 34 HSCT donor-recipient pairs and used the resulting information in a computer model to simulate how the recipient’s T-cell repertoire will recover following transplant.
“This study is the first to simulate the growth of the T-cell repertoire following transplantation using variables that aren’t accounted for in typical HLA donor-recipient matching,” said study author Amir Ahmed Toor, MD, of Virginia Commonwealth University in Richmond.
“Using a larger cohort of patients than in previous studies, we were able to mathematically predict the interactions of these variables, which led to simulations that appear to be very similar to clinically observed post-transplantation T-cell repertoire development.”
Previous research by Dr Toor and his colleagues revealed large variations between donor-recipient minor histocompatibility antigens that could potentially contribute to transplant complications not accounted for by HLA testing.
The models used in the computer simulations were driven by population growth formulas developed from past studies by Dr Toor and his colleagues that revealed distinct patterns of lymphocyte recovery in HSCT recipients.
Using matrix mathematics to develop the simulations, the researchers observed competition among T cells as the T-cell repertoire develops.
This competition leads to certain families of T cells becoming dominant and more numerous, which crowds out weaker T-cell families, causing them to develop later and in fewer numbers.
“We are attempting to account for the many variables that could impact T-cell repertoire development and, in turn, patient outcomes,” Dr Toor said.
“In future studies, we hope to explore the impact of organ-specific antigen expression. The knowledge gained from this research could potentially allow more accurate predictions of which organs could be most affected by graft-versus-host-disease.”
FDA approves drug for 2 indications in MM
Photo courtesy of
Spectrum Pharmaceuticals
The US Food and Drug Administration (FDA) has approved a new formulation of melphalan for injection (Evomela) for 2 indications.
The drug is now approved for use as a high-dose conditioning treatment prior to autologous hematopoietic stem cell transplant (HSCT) in patients with multiple myeloma (MM) and for the palliative treatment of patients with MM for whom oral therapy is not appropriate.
Evomela is the first product to be FDA-approved for the high-dose conditioning indication in MM. The FDA previously granted the drug orphan designation for this indication.
About Evomela
Evomela is a Captisol-enabled, propylene glycol-free melphalan formulation. This formulation eliminates the need to use a propylene glycol-containing custom diluent, which is required with other intravenous melphalan formulations and has been reported to cause renal and cardiac side effects.
Captisol is a chemically modified cyclodextrin with a structure designed to optimize the solubility and stability of drugs.
The use of Captisol technology to reformulate melphalan is reported to improve the drug’s stability, extending its use time. The technology allows the admixture solution to be stable for 4 hours at room temperature, in addition to the 1 hour following reconstitution, and for 24 hours at refrigerated temperature (5°C).
This is anticipated to simplify preparation and administration logistics and allow for slower infusion rates and longer administration durations for pre-transplant chemotherapy.
The full prescribing information for Evomela is available at www.evomela.com.
Spectrum Pharmaceuticals gained global development and commercialization rights to Evomela from Ligand Pharmaceuticals Incorporated in March 2013.
Spectrum assumed responsibility for completing the pivotal phase 2 trial of Evomela and was responsible for filing the new drug application. Spectrum filed the application in December 2014, and the FDA accepted it the following March.
Phase 2 study
Evomela was approved by the FDA based on its bioequivalence to the standard melphalan formulation (Alkeran) in a phase 2 study.
Initial results from this trial (phase 2a) were published in Bone Marrow Transplantation in June 2014. Phase 2b results were published in Biology of Blood and Marrow Transplantation in September 2015.
Phase 2b included 61 patients. Fifty-six had newly diagnosed MM, and 5 had relapsed MM following prior HSCT.
The patients received Evomela at 200 mg/m2, given as 2 doses on day -3 and day -2 prior to autologous HSCT (day 0).
All 61 patients achieved myeloablation at a median of 5 days post-HSCT. And all patients had successful neutrophil and platelet engraftment at a median of 12 days and 13 days post-HSCT, respectively.
Efficacy was assessed by clinical response at day 100. According to investigator assessment, the overall response rate was 95%, and the complete response (CR) rate was 31%.
According to independent pathology review, the overall response rate was 100%, and the CR rate was 21%. The lower rate of confirmed CRs in the independent review was due to missing data.
Treatment-related mortality was 0%, and non-hematologic adverse events were mostly grade 1 and 2 in severity. The incidence of grade 3 mucositis and grade 3 stomatitis were 10% and 5%, respectively, with no grade 4 mucositis or stomatitis reported.
Twenty percent of patients experienced treatment-emergent serious adverse events, most of which were grade 3 and consisted of events commonly reported in patients undergoing myeloablative chemotherapy. No new safety signals were identified.
Photo courtesy of
Spectrum Pharmaceuticals
The US Food and Drug Administration (FDA) has approved a new formulation of melphalan for injection (Evomela) for 2 indications.
The drug is now approved for use as a high-dose conditioning treatment prior to autologous hematopoietic stem cell transplant (HSCT) in patients with multiple myeloma (MM) and for the palliative treatment of patients with MM for whom oral therapy is not appropriate.
Evomela is the first product to be FDA-approved for the high-dose conditioning indication in MM. The FDA previously granted the drug orphan designation for this indication.
About Evomela
Evomela is a Captisol-enabled, propylene glycol-free melphalan formulation. This formulation eliminates the need to use a propylene glycol-containing custom diluent, which is required with other intravenous melphalan formulations and has been reported to cause renal and cardiac side effects.
Captisol is a chemically modified cyclodextrin with a structure designed to optimize the solubility and stability of drugs.
The use of Captisol technology to reformulate melphalan is reported to improve the drug’s stability, extending its use time. The technology allows the admixture solution to be stable for 4 hours at room temperature, in addition to the 1 hour following reconstitution, and for 24 hours at refrigerated temperature (5°C).
This is anticipated to simplify preparation and administration logistics and allow for slower infusion rates and longer administration durations for pre-transplant chemotherapy.
The full prescribing information for Evomela is available at www.evomela.com.
Spectrum Pharmaceuticals gained global development and commercialization rights to Evomela from Ligand Pharmaceuticals Incorporated in March 2013.
Spectrum assumed responsibility for completing the pivotal phase 2 trial of Evomela and was responsible for filing the new drug application. Spectrum filed the application in December 2014, and the FDA accepted it the following March.
Phase 2 study
Evomela was approved by the FDA based on its bioequivalence to the standard melphalan formulation (Alkeran) in a phase 2 study.
Initial results from this trial (phase 2a) were published in Bone Marrow Transplantation in June 2014. Phase 2b results were published in Biology of Blood and Marrow Transplantation in September 2015.
Phase 2b included 61 patients. Fifty-six had newly diagnosed MM, and 5 had relapsed MM following prior HSCT.
The patients received Evomela at 200 mg/m2, given as 2 doses on day -3 and day -2 prior to autologous HSCT (day 0).
All 61 patients achieved myeloablation at a median of 5 days post-HSCT. And all patients had successful neutrophil and platelet engraftment at a median of 12 days and 13 days post-HSCT, respectively.
Efficacy was assessed by clinical response at day 100. According to investigator assessment, the overall response rate was 95%, and the complete response (CR) rate was 31%.
According to independent pathology review, the overall response rate was 100%, and the CR rate was 21%. The lower rate of confirmed CRs in the independent review was due to missing data.
Treatment-related mortality was 0%, and non-hematologic adverse events were mostly grade 1 and 2 in severity. The incidence of grade 3 mucositis and grade 3 stomatitis were 10% and 5%, respectively, with no grade 4 mucositis or stomatitis reported.
Twenty percent of patients experienced treatment-emergent serious adverse events, most of which were grade 3 and consisted of events commonly reported in patients undergoing myeloablative chemotherapy. No new safety signals were identified.
Photo courtesy of
Spectrum Pharmaceuticals
The US Food and Drug Administration (FDA) has approved a new formulation of melphalan for injection (Evomela) for 2 indications.
The drug is now approved for use as a high-dose conditioning treatment prior to autologous hematopoietic stem cell transplant (HSCT) in patients with multiple myeloma (MM) and for the palliative treatment of patients with MM for whom oral therapy is not appropriate.
Evomela is the first product to be FDA-approved for the high-dose conditioning indication in MM. The FDA previously granted the drug orphan designation for this indication.
About Evomela
Evomela is a Captisol-enabled, propylene glycol-free melphalan formulation. This formulation eliminates the need to use a propylene glycol-containing custom diluent, which is required with other intravenous melphalan formulations and has been reported to cause renal and cardiac side effects.
Captisol is a chemically modified cyclodextrin with a structure designed to optimize the solubility and stability of drugs.
The use of Captisol technology to reformulate melphalan is reported to improve the drug’s stability, extending its use time. The technology allows the admixture solution to be stable for 4 hours at room temperature, in addition to the 1 hour following reconstitution, and for 24 hours at refrigerated temperature (5°C).
This is anticipated to simplify preparation and administration logistics and allow for slower infusion rates and longer administration durations for pre-transplant chemotherapy.
The full prescribing information for Evomela is available at www.evomela.com.
Spectrum Pharmaceuticals gained global development and commercialization rights to Evomela from Ligand Pharmaceuticals Incorporated in March 2013.
Spectrum assumed responsibility for completing the pivotal phase 2 trial of Evomela and was responsible for filing the new drug application. Spectrum filed the application in December 2014, and the FDA accepted it the following March.
Phase 2 study
Evomela was approved by the FDA based on its bioequivalence to the standard melphalan formulation (Alkeran) in a phase 2 study.
Initial results from this trial (phase 2a) were published in Bone Marrow Transplantation in June 2014. Phase 2b results were published in Biology of Blood and Marrow Transplantation in September 2015.
Phase 2b included 61 patients. Fifty-six had newly diagnosed MM, and 5 had relapsed MM following prior HSCT.
The patients received Evomela at 200 mg/m2, given as 2 doses on day -3 and day -2 prior to autologous HSCT (day 0).
All 61 patients achieved myeloablation at a median of 5 days post-HSCT. And all patients had successful neutrophil and platelet engraftment at a median of 12 days and 13 days post-HSCT, respectively.
Efficacy was assessed by clinical response at day 100. According to investigator assessment, the overall response rate was 95%, and the complete response (CR) rate was 31%.
According to independent pathology review, the overall response rate was 100%, and the CR rate was 21%. The lower rate of confirmed CRs in the independent review was due to missing data.
Treatment-related mortality was 0%, and non-hematologic adverse events were mostly grade 1 and 2 in severity. The incidence of grade 3 mucositis and grade 3 stomatitis were 10% and 5%, respectively, with no grade 4 mucositis or stomatitis reported.
Twenty percent of patients experienced treatment-emergent serious adverse events, most of which were grade 3 and consisted of events commonly reported in patients undergoing myeloablative chemotherapy. No new safety signals were identified.
Combo appears superior to G-CSF for mobilizing HSCs
in the bone marrow
A 2-drug combination can be more effective than granulocyte colony-stimulating factor (G-CSF) for mobilizing hematopoietic stem cells (HSCs), according to preclinical research published in Nature Communications.
The combination consists of the dual α9β1/α4β1 antagonist BOP and the CXCR4 antagonist AMD3100, also known as plerixafor.
In experiments with mice, researchers found that treatment with BOP and AMD3100 directly impacts HSCs so they can be seen in the blood stream within an hour.
And when these HSCs are transplanted into recipient mice, they can replenish the entire hematopoietic system.
“Current treatment requires [a transplant donor] to have growth factor injections for several days leading up to the [harvesting] procedure,” said study author Susie Nilsson, PhD, of Monash University in Clayton, Victoria, Australia.
“Using the [2-drug combination] eliminates the need for this, meaning a procedure that once took days can be reduced to around an hour.”
Combination vs monotherapy
Dr Nilsson and her colleagues found that, when given alone, AMD3100 and BOP produced similar increases in white blood cell (WBC) counts and the proportion of progenitors (LSK cells) in the peripheral blood (PB) of mice.
However, BOP produced a significantly greater increase in the proportion of HSCs (LSKSLAM cells) in the PB. The researchers said this suggests that AMD3100 predominantly mobilizes progenitors, and BOP predominantly mobilizes HSCs.
The team also found that, in combination, BOP and AMD3100 mobilized WBCs, progenitors, and HSCs more effectively than either agent alone.
To determine if these drugs could mobilize HSCs and progenitors with long-term multi-lineage engraftment potential, the researchers performed limiting dilution transplant analysis using BOP, AMD3100, or both drugs.
The team observed superior survival in mice that received 30 ml of PB mobilized using the combination, when compared to either drug alone.
In addition, PB mobilized with the combination resulted in a greater repopulation frequency (1 HSC in 23 ml PB) than PB mobilized with BOP (1 HSC in 327 ml) or AMD3100 (1 HSC in 351 ml).
The researchers said this was a more than 10-fold improvement with the combination, as compared to monotherapy.
Comparisons with G-CSF
Treating mice with a single dose of BOP following 4 days of G-CSF treatment resulted in significant synergistic increases in HSCs (LSKSLAM cells) and progenitors (LSK cells), when compared to G-CSF alone.
BOP and AMD3100 in combination produced equivalent numbers of HSCs and progenitors as G-CSF alone.
And the combination of G-CSF and AMD3100 mobilized significantly more HSCs and progenitors than G-CSF alone.
But the greatest number of HSCs and progenitors were mobilized with the combination of G-CSF, AMD3100, and BOP. This combination produced a significant increase in cells when compared with G-CSF alone or the combination of AMD3100 and BOP.
The researchers also compared the hematopoietic potential of PB mobilized with multiple doses of G-CSF to PB mobilized with a single dose of BOP and AMD3100 in combination.
Although equivalent numbers of HSCs were mobilized, BOP and AMD3100 significantly enhanced short-term and long-term multi-lineage engraftment, when compared to G-CSF.
To determine whether the HSC mobilization observed in these experiments is equivalent in humans, the researchers tested the mobilizing agents in humanized NSG mice.
They found that a single dose of BOP or AMD3100 alone, or multiple doses of G-CSF for 4 days, did not significantly increase human WBCs or human CD34+ stem and progenitor cells.
However, a single dose of BOP and AMD3100 in combination produced a significant increase in both WBCs and stem and progenitor cells.
The researchers said the next step is a phase 1 trial assessing the combination of BOP with G-CSF before they can test the combination of BOP and AMD3100 in humans.
in the bone marrow
A 2-drug combination can be more effective than granulocyte colony-stimulating factor (G-CSF) for mobilizing hematopoietic stem cells (HSCs), according to preclinical research published in Nature Communications.
The combination consists of the dual α9β1/α4β1 antagonist BOP and the CXCR4 antagonist AMD3100, also known as plerixafor.
In experiments with mice, researchers found that treatment with BOP and AMD3100 directly impacts HSCs so they can be seen in the blood stream within an hour.
And when these HSCs are transplanted into recipient mice, they can replenish the entire hematopoietic system.
“Current treatment requires [a transplant donor] to have growth factor injections for several days leading up to the [harvesting] procedure,” said study author Susie Nilsson, PhD, of Monash University in Clayton, Victoria, Australia.
“Using the [2-drug combination] eliminates the need for this, meaning a procedure that once took days can be reduced to around an hour.”
Combination vs monotherapy
Dr Nilsson and her colleagues found that, when given alone, AMD3100 and BOP produced similar increases in white blood cell (WBC) counts and the proportion of progenitors (LSK cells) in the peripheral blood (PB) of mice.
However, BOP produced a significantly greater increase in the proportion of HSCs (LSKSLAM cells) in the PB. The researchers said this suggests that AMD3100 predominantly mobilizes progenitors, and BOP predominantly mobilizes HSCs.
The team also found that, in combination, BOP and AMD3100 mobilized WBCs, progenitors, and HSCs more effectively than either agent alone.
To determine if these drugs could mobilize HSCs and progenitors with long-term multi-lineage engraftment potential, the researchers performed limiting dilution transplant analysis using BOP, AMD3100, or both drugs.
The team observed superior survival in mice that received 30 ml of PB mobilized using the combination, when compared to either drug alone.
In addition, PB mobilized with the combination resulted in a greater repopulation frequency (1 HSC in 23 ml PB) than PB mobilized with BOP (1 HSC in 327 ml) or AMD3100 (1 HSC in 351 ml).
The researchers said this was a more than 10-fold improvement with the combination, as compared to monotherapy.
Comparisons with G-CSF
Treating mice with a single dose of BOP following 4 days of G-CSF treatment resulted in significant synergistic increases in HSCs (LSKSLAM cells) and progenitors (LSK cells), when compared to G-CSF alone.
BOP and AMD3100 in combination produced equivalent numbers of HSCs and progenitors as G-CSF alone.
And the combination of G-CSF and AMD3100 mobilized significantly more HSCs and progenitors than G-CSF alone.
But the greatest number of HSCs and progenitors were mobilized with the combination of G-CSF, AMD3100, and BOP. This combination produced a significant increase in cells when compared with G-CSF alone or the combination of AMD3100 and BOP.
The researchers also compared the hematopoietic potential of PB mobilized with multiple doses of G-CSF to PB mobilized with a single dose of BOP and AMD3100 in combination.
Although equivalent numbers of HSCs were mobilized, BOP and AMD3100 significantly enhanced short-term and long-term multi-lineage engraftment, when compared to G-CSF.
To determine whether the HSC mobilization observed in these experiments is equivalent in humans, the researchers tested the mobilizing agents in humanized NSG mice.
They found that a single dose of BOP or AMD3100 alone, or multiple doses of G-CSF for 4 days, did not significantly increase human WBCs or human CD34+ stem and progenitor cells.
However, a single dose of BOP and AMD3100 in combination produced a significant increase in both WBCs and stem and progenitor cells.
The researchers said the next step is a phase 1 trial assessing the combination of BOP with G-CSF before they can test the combination of BOP and AMD3100 in humans.
in the bone marrow
A 2-drug combination can be more effective than granulocyte colony-stimulating factor (G-CSF) for mobilizing hematopoietic stem cells (HSCs), according to preclinical research published in Nature Communications.
The combination consists of the dual α9β1/α4β1 antagonist BOP and the CXCR4 antagonist AMD3100, also known as plerixafor.
In experiments with mice, researchers found that treatment with BOP and AMD3100 directly impacts HSCs so they can be seen in the blood stream within an hour.
And when these HSCs are transplanted into recipient mice, they can replenish the entire hematopoietic system.
“Current treatment requires [a transplant donor] to have growth factor injections for several days leading up to the [harvesting] procedure,” said study author Susie Nilsson, PhD, of Monash University in Clayton, Victoria, Australia.
“Using the [2-drug combination] eliminates the need for this, meaning a procedure that once took days can be reduced to around an hour.”
Combination vs monotherapy
Dr Nilsson and her colleagues found that, when given alone, AMD3100 and BOP produced similar increases in white blood cell (WBC) counts and the proportion of progenitors (LSK cells) in the peripheral blood (PB) of mice.
However, BOP produced a significantly greater increase in the proportion of HSCs (LSKSLAM cells) in the PB. The researchers said this suggests that AMD3100 predominantly mobilizes progenitors, and BOP predominantly mobilizes HSCs.
The team also found that, in combination, BOP and AMD3100 mobilized WBCs, progenitors, and HSCs more effectively than either agent alone.
To determine if these drugs could mobilize HSCs and progenitors with long-term multi-lineage engraftment potential, the researchers performed limiting dilution transplant analysis using BOP, AMD3100, or both drugs.
The team observed superior survival in mice that received 30 ml of PB mobilized using the combination, when compared to either drug alone.
In addition, PB mobilized with the combination resulted in a greater repopulation frequency (1 HSC in 23 ml PB) than PB mobilized with BOP (1 HSC in 327 ml) or AMD3100 (1 HSC in 351 ml).
The researchers said this was a more than 10-fold improvement with the combination, as compared to monotherapy.
Comparisons with G-CSF
Treating mice with a single dose of BOP following 4 days of G-CSF treatment resulted in significant synergistic increases in HSCs (LSKSLAM cells) and progenitors (LSK cells), when compared to G-CSF alone.
BOP and AMD3100 in combination produced equivalent numbers of HSCs and progenitors as G-CSF alone.
And the combination of G-CSF and AMD3100 mobilized significantly more HSCs and progenitors than G-CSF alone.
But the greatest number of HSCs and progenitors were mobilized with the combination of G-CSF, AMD3100, and BOP. This combination produced a significant increase in cells when compared with G-CSF alone or the combination of AMD3100 and BOP.
The researchers also compared the hematopoietic potential of PB mobilized with multiple doses of G-CSF to PB mobilized with a single dose of BOP and AMD3100 in combination.
Although equivalent numbers of HSCs were mobilized, BOP and AMD3100 significantly enhanced short-term and long-term multi-lineage engraftment, when compared to G-CSF.
To determine whether the HSC mobilization observed in these experiments is equivalent in humans, the researchers tested the mobilizing agents in humanized NSG mice.
They found that a single dose of BOP or AMD3100 alone, or multiple doses of G-CSF for 4 days, did not significantly increase human WBCs or human CD34+ stem and progenitor cells.
However, a single dose of BOP and AMD3100 in combination produced a significant increase in both WBCs and stem and progenitor cells.
The researchers said the next step is a phase 1 trial assessing the combination of BOP with G-CSF before they can test the combination of BOP and AMD3100 in humans.
Intervention helps parents cope with kids’ HSCT
Photo by Chad McNeeley
A new social-cognitive intervention can reduce stress in parents of children undergoing hematopoietic stem cell transplant (HSCT), according to research published in the Journal of Consulting and Clinical Psychology.
In the short-term, the parent social-cognitive intervention program (P-SCIP) appeared more effective than the current best-practice psychosocial care (BPC) for reducing anxiety, depression, and traumatic distress.
However, there was not much difference between P-SCIP and BPC when it came to long-term results.
Certain subgroups of parents seemed to derive more benefit from P-SCIP than other parents.
“[P]revious research from our team and others has shown that between 20% and 66% of caregivers have elevated depression and/or anxiety prior to their child’s transplant procedure,” said study author Sharon Manne, PhD, of the Rutgers Cancer Institute of New Jersey in New Brunswick.
“It was our aim in this study to develop and test an individual intervention program that targets cognitive and social processing strategies associated with caregiver adjustment and compare that to available best-practice psychosocial care.”
Interventions
This study included 218 biological or foster parents of HSCT recipients under age 19. The parents were assigned to receive P-SCIP or BPC.
P-SCIP required parents to view an interactive CD-ROM for five 60-minute sessions over a 2- to 3-week period following the child’s transplant.
The CD-ROM addressed parents’ worries about their child, coping with solvable concerns related to HSCT, coping with unchangeable problems related to HSCT, and communication and the importance of expressing feelings and needs.
Parents receiving BPC viewed a 1-hour video guide to pediatric HSCT and received a pamphlet covering common caregiver issues. The parents were also given the option of having someone watch their child for up to 5 hours and the use of walkie-talkies so the parents could communicate with their child when they were not in the room.
All participants were asked to complete an in-person survey within a month’s time of their child receiving the transplant and to complete follow-up surveys by phone or mail at 1 month, 6 months, and 1 year post-HSCT.
One hundred and ten parents were randomized to P-SCIP and 108 to BPC. Sixty-six parents completed P-SCIP through the last follow-up, as did 72 parents assigned to BPC.
Results
The researchers found that P-SCIP could reduce anxiety, depression, and—to a marginal degree—traumatic distress more than BPC.
However, the beneficial effects of P-SCIP relative to BPC were only seen at the first follow-up. The overall psychological benefits of P-SCIP were no longer evident at the 6-month or 1-year follow ups.
Still, anxiety, depression, and traumatic distress declined among all the parents over the 1-year follow-up period, which is consistent with other research on caregiver distress after pediatric HSCT.
“Our study suggests that our intervention had an impact when primary caregivers were experiencing high levels of trauma and stress—during the time of the actual transplant and hospitalization—and that the intervention was more beneficial for specific subgroups of caregivers,” Dr Manne said.
P-SCIP had a stronger effect than BPC among parents who began the study reporting higher depression and anxiety and among parents whose children developed graft-versus-host disease.
Similarly, P-SCIP had long-term effects on traumatic distress among parents who reported higher anxiety pre-HSCT and among parents whose children had graft-versus-host disease at HSCT discharge.
“Our findings suggest that screening caregivers for elevations in anxiety and targeting interventions specifically to them may prove beneficial,” Dr Manne said.
She added that a next step for this research might be to examine possible differences between mothers and fathers in the caregiver role, as most of the primary caregivers in this study were mothers.
Additionally, if this intervention is carried into the clinical setting, methods of improving intervention attendance might be considered. Utilizing phone or web-based contact that would allow the parent to remain in the room with the child during hospitalization might help the caregivers more easily access the intervention.
Photo by Chad McNeeley
A new social-cognitive intervention can reduce stress in parents of children undergoing hematopoietic stem cell transplant (HSCT), according to research published in the Journal of Consulting and Clinical Psychology.
In the short-term, the parent social-cognitive intervention program (P-SCIP) appeared more effective than the current best-practice psychosocial care (BPC) for reducing anxiety, depression, and traumatic distress.
However, there was not much difference between P-SCIP and BPC when it came to long-term results.
Certain subgroups of parents seemed to derive more benefit from P-SCIP than other parents.
“[P]revious research from our team and others has shown that between 20% and 66% of caregivers have elevated depression and/or anxiety prior to their child’s transplant procedure,” said study author Sharon Manne, PhD, of the Rutgers Cancer Institute of New Jersey in New Brunswick.
“It was our aim in this study to develop and test an individual intervention program that targets cognitive and social processing strategies associated with caregiver adjustment and compare that to available best-practice psychosocial care.”
Interventions
This study included 218 biological or foster parents of HSCT recipients under age 19. The parents were assigned to receive P-SCIP or BPC.
P-SCIP required parents to view an interactive CD-ROM for five 60-minute sessions over a 2- to 3-week period following the child’s transplant.
The CD-ROM addressed parents’ worries about their child, coping with solvable concerns related to HSCT, coping with unchangeable problems related to HSCT, and communication and the importance of expressing feelings and needs.
Parents receiving BPC viewed a 1-hour video guide to pediatric HSCT and received a pamphlet covering common caregiver issues. The parents were also given the option of having someone watch their child for up to 5 hours and the use of walkie-talkies so the parents could communicate with their child when they were not in the room.
All participants were asked to complete an in-person survey within a month’s time of their child receiving the transplant and to complete follow-up surveys by phone or mail at 1 month, 6 months, and 1 year post-HSCT.
One hundred and ten parents were randomized to P-SCIP and 108 to BPC. Sixty-six parents completed P-SCIP through the last follow-up, as did 72 parents assigned to BPC.
Results
The researchers found that P-SCIP could reduce anxiety, depression, and—to a marginal degree—traumatic distress more than BPC.
However, the beneficial effects of P-SCIP relative to BPC were only seen at the first follow-up. The overall psychological benefits of P-SCIP were no longer evident at the 6-month or 1-year follow ups.
Still, anxiety, depression, and traumatic distress declined among all the parents over the 1-year follow-up period, which is consistent with other research on caregiver distress after pediatric HSCT.
“Our study suggests that our intervention had an impact when primary caregivers were experiencing high levels of trauma and stress—during the time of the actual transplant and hospitalization—and that the intervention was more beneficial for specific subgroups of caregivers,” Dr Manne said.
P-SCIP had a stronger effect than BPC among parents who began the study reporting higher depression and anxiety and among parents whose children developed graft-versus-host disease.
Similarly, P-SCIP had long-term effects on traumatic distress among parents who reported higher anxiety pre-HSCT and among parents whose children had graft-versus-host disease at HSCT discharge.
“Our findings suggest that screening caregivers for elevations in anxiety and targeting interventions specifically to them may prove beneficial,” Dr Manne said.
She added that a next step for this research might be to examine possible differences between mothers and fathers in the caregiver role, as most of the primary caregivers in this study were mothers.
Additionally, if this intervention is carried into the clinical setting, methods of improving intervention attendance might be considered. Utilizing phone or web-based contact that would allow the parent to remain in the room with the child during hospitalization might help the caregivers more easily access the intervention.
Photo by Chad McNeeley
A new social-cognitive intervention can reduce stress in parents of children undergoing hematopoietic stem cell transplant (HSCT), according to research published in the Journal of Consulting and Clinical Psychology.
In the short-term, the parent social-cognitive intervention program (P-SCIP) appeared more effective than the current best-practice psychosocial care (BPC) for reducing anxiety, depression, and traumatic distress.
However, there was not much difference between P-SCIP and BPC when it came to long-term results.
Certain subgroups of parents seemed to derive more benefit from P-SCIP than other parents.
“[P]revious research from our team and others has shown that between 20% and 66% of caregivers have elevated depression and/or anxiety prior to their child’s transplant procedure,” said study author Sharon Manne, PhD, of the Rutgers Cancer Institute of New Jersey in New Brunswick.
“It was our aim in this study to develop and test an individual intervention program that targets cognitive and social processing strategies associated with caregiver adjustment and compare that to available best-practice psychosocial care.”
Interventions
This study included 218 biological or foster parents of HSCT recipients under age 19. The parents were assigned to receive P-SCIP or BPC.
P-SCIP required parents to view an interactive CD-ROM for five 60-minute sessions over a 2- to 3-week period following the child’s transplant.
The CD-ROM addressed parents’ worries about their child, coping with solvable concerns related to HSCT, coping with unchangeable problems related to HSCT, and communication and the importance of expressing feelings and needs.
Parents receiving BPC viewed a 1-hour video guide to pediatric HSCT and received a pamphlet covering common caregiver issues. The parents were also given the option of having someone watch their child for up to 5 hours and the use of walkie-talkies so the parents could communicate with their child when they were not in the room.
All participants were asked to complete an in-person survey within a month’s time of their child receiving the transplant and to complete follow-up surveys by phone or mail at 1 month, 6 months, and 1 year post-HSCT.
One hundred and ten parents were randomized to P-SCIP and 108 to BPC. Sixty-six parents completed P-SCIP through the last follow-up, as did 72 parents assigned to BPC.
Results
The researchers found that P-SCIP could reduce anxiety, depression, and—to a marginal degree—traumatic distress more than BPC.
However, the beneficial effects of P-SCIP relative to BPC were only seen at the first follow-up. The overall psychological benefits of P-SCIP were no longer evident at the 6-month or 1-year follow ups.
Still, anxiety, depression, and traumatic distress declined among all the parents over the 1-year follow-up period, which is consistent with other research on caregiver distress after pediatric HSCT.
“Our study suggests that our intervention had an impact when primary caregivers were experiencing high levels of trauma and stress—during the time of the actual transplant and hospitalization—and that the intervention was more beneficial for specific subgroups of caregivers,” Dr Manne said.
P-SCIP had a stronger effect than BPC among parents who began the study reporting higher depression and anxiety and among parents whose children developed graft-versus-host disease.
Similarly, P-SCIP had long-term effects on traumatic distress among parents who reported higher anxiety pre-HSCT and among parents whose children had graft-versus-host disease at HSCT discharge.
“Our findings suggest that screening caregivers for elevations in anxiety and targeting interventions specifically to them may prove beneficial,” Dr Manne said.
She added that a next step for this research might be to examine possible differences between mothers and fathers in the caregiver role, as most of the primary caregivers in this study were mothers.
Additionally, if this intervention is carried into the clinical setting, methods of improving intervention attendance might be considered. Utilizing phone or web-based contact that would allow the parent to remain in the room with the child during hospitalization might help the caregivers more easily access the intervention.
Team finds precursors to HSPCs in mice
Image by Matthias Zepper
Researchers have reportedly identified precursor cells that can be matured into transplantable hematopoietic stem/progenitor cells (HSPCs) in the lab.
The investigators discovered the precursor cells in the placentas and embryos of mice, but the team believes their findings could aid the development of patient-specific HSPCs and more differentiated blood products for cell-replacement therapy in humans.
“To cure disease in the long-term, we need to be able to transplant something that can keep producing new blood cells and won’t be rejected by the patient’s body,” said study author Kateri Moore, DVM, of the Icahn School of Medicine at Mount Sinai in New York, New York.
“We are excited by the results of our study. The precursor cells can be matured in the lab to transplantable HSPCs. Our reprogramming process can inform developmental hematopoiesis and vice-versa.”
Dr Moore and her colleagues described this work in Developmental Cell.
With previous work, the researchers reprogrammed mouse fibroblasts to become HSPCs. They showed that this process occurred through hemogenic precursors that are Prom1+Sca1+CD34+CD45− (PS34CD45−).
So for the current study, the investigators examined mouse placentas and embryos, looking for cells with the same phenotype. They were able to find and analyze PS34CD45− cells.
Investigation revealed that PS34CD45− cells express endothelial and hematopoietic markers. And the cells originate in embryonic tissue and localize to the vascular labyrinth.
Furthermore, the researchers said global gene expression profiles of PS34CD45− cells correlate with reprogrammed precursors and establish a hemogenic precursor cell molecular signature.
In culture, PS34CD45− cells gave rise to multi-lineage hematopoietic colonies. PS34CD45− cells generated B and T lymphocytes and engrafted in primary and secondary immunodeficient mice.
The investigators said the next step is to test these findings in humans.
“Our ultimate goal is to grow blood-forming cells in the lab and improve efficiencies to generate patient-specific blood cells,” Dr Moore said. “This study brings us a step closer to reaching this goal.”
Image by Matthias Zepper
Researchers have reportedly identified precursor cells that can be matured into transplantable hematopoietic stem/progenitor cells (HSPCs) in the lab.
The investigators discovered the precursor cells in the placentas and embryos of mice, but the team believes their findings could aid the development of patient-specific HSPCs and more differentiated blood products for cell-replacement therapy in humans.
“To cure disease in the long-term, we need to be able to transplant something that can keep producing new blood cells and won’t be rejected by the patient’s body,” said study author Kateri Moore, DVM, of the Icahn School of Medicine at Mount Sinai in New York, New York.
“We are excited by the results of our study. The precursor cells can be matured in the lab to transplantable HSPCs. Our reprogramming process can inform developmental hematopoiesis and vice-versa.”
Dr Moore and her colleagues described this work in Developmental Cell.
With previous work, the researchers reprogrammed mouse fibroblasts to become HSPCs. They showed that this process occurred through hemogenic precursors that are Prom1+Sca1+CD34+CD45− (PS34CD45−).
So for the current study, the investigators examined mouse placentas and embryos, looking for cells with the same phenotype. They were able to find and analyze PS34CD45− cells.
Investigation revealed that PS34CD45− cells express endothelial and hematopoietic markers. And the cells originate in embryonic tissue and localize to the vascular labyrinth.
Furthermore, the researchers said global gene expression profiles of PS34CD45− cells correlate with reprogrammed precursors and establish a hemogenic precursor cell molecular signature.
In culture, PS34CD45− cells gave rise to multi-lineage hematopoietic colonies. PS34CD45− cells generated B and T lymphocytes and engrafted in primary and secondary immunodeficient mice.
The investigators said the next step is to test these findings in humans.
“Our ultimate goal is to grow blood-forming cells in the lab and improve efficiencies to generate patient-specific blood cells,” Dr Moore said. “This study brings us a step closer to reaching this goal.”
Image by Matthias Zepper
Researchers have reportedly identified precursor cells that can be matured into transplantable hematopoietic stem/progenitor cells (HSPCs) in the lab.
The investigators discovered the precursor cells in the placentas and embryos of mice, but the team believes their findings could aid the development of patient-specific HSPCs and more differentiated blood products for cell-replacement therapy in humans.
“To cure disease in the long-term, we need to be able to transplant something that can keep producing new blood cells and won’t be rejected by the patient’s body,” said study author Kateri Moore, DVM, of the Icahn School of Medicine at Mount Sinai in New York, New York.
“We are excited by the results of our study. The precursor cells can be matured in the lab to transplantable HSPCs. Our reprogramming process can inform developmental hematopoiesis and vice-versa.”
Dr Moore and her colleagues described this work in Developmental Cell.
With previous work, the researchers reprogrammed mouse fibroblasts to become HSPCs. They showed that this process occurred through hemogenic precursors that are Prom1+Sca1+CD34+CD45− (PS34CD45−).
So for the current study, the investigators examined mouse placentas and embryos, looking for cells with the same phenotype. They were able to find and analyze PS34CD45− cells.
Investigation revealed that PS34CD45− cells express endothelial and hematopoietic markers. And the cells originate in embryonic tissue and localize to the vascular labyrinth.
Furthermore, the researchers said global gene expression profiles of PS34CD45− cells correlate with reprogrammed precursors and establish a hemogenic precursor cell molecular signature.
In culture, PS34CD45− cells gave rise to multi-lineage hematopoietic colonies. PS34CD45− cells generated B and T lymphocytes and engrafted in primary and secondary immunodeficient mice.
The investigators said the next step is to test these findings in humans.
“Our ultimate goal is to grow blood-forming cells in the lab and improve efficiencies to generate patient-specific blood cells,” Dr Moore said. “This study brings us a step closer to reaching this goal.”
FDA issues new guidance on Zika virus transmission
Photo courtesy of NHS
The US Food and Drug Administration (FDA) has issued a guidance document intended to help reduce the risk of Zika virus transmission via human cells, tissues, and cellular and tissue-based products (HCT/Ps).
The guidance addresses donation of HCT/Ps from both living and deceased donors, including donors of umbilical cord blood and hematopoietic stem/progenitor cells.
In this document, the FDA recommends a 6-month deferral period for most HCT/P donors who may have been exposed to the Zika virus.
The exception is donors of gestational tissues, who should be considered ineligible if they were at risk of contracting the virus at any time during their pregnancy.
The new guidance is a part of the FDA’s ongoing efforts to protect HCT/Ps and blood products from Zika virus transmission. Last month, the agency issued recommendations for reducing the risk of Zika virus transmission via blood transfusion.
There is a potential risk that Zika virus can be transmitted by HCT/Ps used as part of a medical, surgical, or reproductive procedure. HCT/Ps include products such as corneas, bone, skin, heart valves, hematopoietic stem/progenitor cells, gestational tissues such as amniotic membrane, and reproductive tissues such as semen and oocytes.
According to the Centers for Disease Control and Prevention, Zika virus can be spread by a man to his sexual partners. To date, there have been several cases of sexual transmission in the US.
Current information about Zika virus detection in semen suggests the period of deferral for HCT/P donors should be longer than the period recommended for donors of whole blood and blood components.
Therefore, the FDA has recommended that living donors of HCT/Ps be considered ineligible if they were diagnosed with Zika virus infection, were in an area with active Zika virus transmission, or had sex with a male with either of those risk factors within the past 6 months.
Donors of umbilical cord blood, placenta, or other gestational tissues should be considered ineligible if they have had any of the above risk factors at any point during their pregnancy.
Deceased donors should be considered ineligible if they were diagnosed with Zika virus infection in the past 6 months.
A deferral period of 6 months was chosen because of the limited data available on the length of time the virus can persist in all tissues. Zika virus has been detected in tissues and body fluids after the virus is no longer detectable in the blood stream and has been detected in semen possibly up to 10 weeks after the onset of symptoms.
Less evidence exists regarding the potential for transmission of Zika virus by HCT/Ps typically recovered from deceased donors. As more information becomes available, the understanding of the risks to recipients of HCT/Ps, including HCT/Ps recovered from deceased donors, may evolve.
The FDA said it will continue to monitor the situation and evaluate new information regarding the associated risks as it becomes available.
In addition, the FDA said it is prioritizing the development of blood donor screening and diagnostic tests that may be useful for identifying the presence of or recent infection with the Zika virus. The agency is prepared to evaluate investigational vaccines and therapeutics that might be developed and review technology that may help suppress populations of the mosquitoes that can spread the virus.
Photo courtesy of NHS
The US Food and Drug Administration (FDA) has issued a guidance document intended to help reduce the risk of Zika virus transmission via human cells, tissues, and cellular and tissue-based products (HCT/Ps).
The guidance addresses donation of HCT/Ps from both living and deceased donors, including donors of umbilical cord blood and hematopoietic stem/progenitor cells.
In this document, the FDA recommends a 6-month deferral period for most HCT/P donors who may have been exposed to the Zika virus.
The exception is donors of gestational tissues, who should be considered ineligible if they were at risk of contracting the virus at any time during their pregnancy.
The new guidance is a part of the FDA’s ongoing efforts to protect HCT/Ps and blood products from Zika virus transmission. Last month, the agency issued recommendations for reducing the risk of Zika virus transmission via blood transfusion.
There is a potential risk that Zika virus can be transmitted by HCT/Ps used as part of a medical, surgical, or reproductive procedure. HCT/Ps include products such as corneas, bone, skin, heart valves, hematopoietic stem/progenitor cells, gestational tissues such as amniotic membrane, and reproductive tissues such as semen and oocytes.
According to the Centers for Disease Control and Prevention, Zika virus can be spread by a man to his sexual partners. To date, there have been several cases of sexual transmission in the US.
Current information about Zika virus detection in semen suggests the period of deferral for HCT/P donors should be longer than the period recommended for donors of whole blood and blood components.
Therefore, the FDA has recommended that living donors of HCT/Ps be considered ineligible if they were diagnosed with Zika virus infection, were in an area with active Zika virus transmission, or had sex with a male with either of those risk factors within the past 6 months.
Donors of umbilical cord blood, placenta, or other gestational tissues should be considered ineligible if they have had any of the above risk factors at any point during their pregnancy.
Deceased donors should be considered ineligible if they were diagnosed with Zika virus infection in the past 6 months.
A deferral period of 6 months was chosen because of the limited data available on the length of time the virus can persist in all tissues. Zika virus has been detected in tissues and body fluids after the virus is no longer detectable in the blood stream and has been detected in semen possibly up to 10 weeks after the onset of symptoms.
Less evidence exists regarding the potential for transmission of Zika virus by HCT/Ps typically recovered from deceased donors. As more information becomes available, the understanding of the risks to recipients of HCT/Ps, including HCT/Ps recovered from deceased donors, may evolve.
The FDA said it will continue to monitor the situation and evaluate new information regarding the associated risks as it becomes available.
In addition, the FDA said it is prioritizing the development of blood donor screening and diagnostic tests that may be useful for identifying the presence of or recent infection with the Zika virus. The agency is prepared to evaluate investigational vaccines and therapeutics that might be developed and review technology that may help suppress populations of the mosquitoes that can spread the virus.
Photo courtesy of NHS
The US Food and Drug Administration (FDA) has issued a guidance document intended to help reduce the risk of Zika virus transmission via human cells, tissues, and cellular and tissue-based products (HCT/Ps).
The guidance addresses donation of HCT/Ps from both living and deceased donors, including donors of umbilical cord blood and hematopoietic stem/progenitor cells.
In this document, the FDA recommends a 6-month deferral period for most HCT/P donors who may have been exposed to the Zika virus.
The exception is donors of gestational tissues, who should be considered ineligible if they were at risk of contracting the virus at any time during their pregnancy.
The new guidance is a part of the FDA’s ongoing efforts to protect HCT/Ps and blood products from Zika virus transmission. Last month, the agency issued recommendations for reducing the risk of Zika virus transmission via blood transfusion.
There is a potential risk that Zika virus can be transmitted by HCT/Ps used as part of a medical, surgical, or reproductive procedure. HCT/Ps include products such as corneas, bone, skin, heart valves, hematopoietic stem/progenitor cells, gestational tissues such as amniotic membrane, and reproductive tissues such as semen and oocytes.
According to the Centers for Disease Control and Prevention, Zika virus can be spread by a man to his sexual partners. To date, there have been several cases of sexual transmission in the US.
Current information about Zika virus detection in semen suggests the period of deferral for HCT/P donors should be longer than the period recommended for donors of whole blood and blood components.
Therefore, the FDA has recommended that living donors of HCT/Ps be considered ineligible if they were diagnosed with Zika virus infection, were in an area with active Zika virus transmission, or had sex with a male with either of those risk factors within the past 6 months.
Donors of umbilical cord blood, placenta, or other gestational tissues should be considered ineligible if they have had any of the above risk factors at any point during their pregnancy.
Deceased donors should be considered ineligible if they were diagnosed with Zika virus infection in the past 6 months.
A deferral period of 6 months was chosen because of the limited data available on the length of time the virus can persist in all tissues. Zika virus has been detected in tissues and body fluids after the virus is no longer detectable in the blood stream and has been detected in semen possibly up to 10 weeks after the onset of symptoms.
Less evidence exists regarding the potential for transmission of Zika virus by HCT/Ps typically recovered from deceased donors. As more information becomes available, the understanding of the risks to recipients of HCT/Ps, including HCT/Ps recovered from deceased donors, may evolve.
The FDA said it will continue to monitor the situation and evaluate new information regarding the associated risks as it becomes available.
In addition, the FDA said it is prioritizing the development of blood donor screening and diagnostic tests that may be useful for identifying the presence of or recent infection with the Zika virus. The agency is prepared to evaluate investigational vaccines and therapeutics that might be developed and review technology that may help suppress populations of the mosquitoes that can spread the virus.
Agent can mobilize HSCs for transplant, study suggests
in the bone marrow
HONOLULU—Early results from a pilot study suggest an investigational agent can effectively mobilize hematopoietic stem cells (HSCs) in healthy transplant donors.
The agent, CDX-301 (recombinant human Flt3 ligand), is a hematopoietic cytokine designed to expand dendritic cells and HSCs.
For the study, researchers tested CDX-301 in sibling-matched donors for hematopoietic stem cell transplant (HSCT) recipients with hematologic malignancies.
The team reported early results with 4 donor/recipient pairs at the 2016 BMT Tandem Meetings (abstract 479). The research was sponsored by Celldex Therapeutics, Inc., the company developing CDX-301.
Donor results
The donors received CDX-301 at 75 μg/kg/day for 5 days. Leukapheresis began on day 6 if the peripheral blood CD34+ count was 7/μL or greater. The goal CD34+ yield was at least 2x106 per kilogram of recipient weight collected in 2 days of leukapheresis or less.
The donors could receive rescue plerixafor if the peripheral blood CD34+ count was less than 7/μL by day 8 or if the total CD34+ yield was less than 1x106/kg after the second day of leukapheresis.
The researchers analyzed CDX-301-mobilized cells by flow cytometry and compared them to historical data for peripheral blood grafts mobilized by granulocyte colony-stimulating factor (G-CSF).
Compared to the G-CSF-mobilized grafts, CDX-301-mobilized grafts had an increase in CD127+ (IL-7R) naïve T cells, γδ T cells, natural killer cells, and B cells.
The CDX-301-mobilized grafts were more enriched with plasmacytoid dendritic cells. And dendritic cells from the CDX-301 grafts had a more mature phenotype, expressing CD80 and CD86.
“From these data and preclinical studies, CDX-301 appears to be an effective, targeted approach to mobilization comparable to G-CSF,” said Steven Devine, MD, of The Ohio State Comprehensive Cancer Center in Columbus.
“With a relatively short course of treatment, we are observing specificity for mobilized stem cells and a lack of toxicity, instead of broad cellular mobilization and side effects.”
CDX-301 related adverse events included dizziness (grade 2), back pain (grade 1), arthralgia (grade 1), injection site reaction (2 grade 1), dyspepsia (1 grade 1, 1 grade 2), and decreased platelet count (2 grade 1). There were no grade 3/4 adverse events.
Recipient results
Thus far, 4 recipients have undergone HSCT with CDX-301-mobilized grafts. Recipient 1 had acute myeloid leukemia, recipients 2 and 3 had mantle cell lymphoma, and recipient 4 had chronic myeloid leukemia.
Recipients 1 through 3 received myeloablative conditioning, while recipient 4 received reduced-intensity conditioning. All patients received standard graft-vs-host disease (GVHD) prophylaxis (tacrolimus and methotrexate).
Recipient 4 has not yet engrafted. The other 3 had both neutrophil engraftment (day 17, 18, and 19) and platelet engraftment (day 14, 25, and 40).
There have been no infectious complications, and recipients 1 and 3 have not developed GVHD.
Recipient 2 developed steroid-responsive, grade 2, upper gastrointestinal GVHD on day 18, followed by grade 1 skin GVHD on day 50 that progressed to stage 3. Overall, the patient had grade 2 GVHD on day 64. The patient’s lymphoma has also progressed.
The researchers said these results suggest CDX-301 is well tolerated and can mobilize CD34+ cells when given as a single agent. They said recipients experienced successful engraftment in an expected time frame.
And the additional naïve T cells and plasmacytoid dendritic cells in CDX-301-mobilized grafts (compared to G-CSF-mobilized grafts) may provide better outcomes in HSCT recipients.
Now, the researchers plan to explore CDX-301 in combination with plerixafor. Additional donor/patient pairs are being accrued to a second study cohort.
in the bone marrow
HONOLULU—Early results from a pilot study suggest an investigational agent can effectively mobilize hematopoietic stem cells (HSCs) in healthy transplant donors.
The agent, CDX-301 (recombinant human Flt3 ligand), is a hematopoietic cytokine designed to expand dendritic cells and HSCs.
For the study, researchers tested CDX-301 in sibling-matched donors for hematopoietic stem cell transplant (HSCT) recipients with hematologic malignancies.
The team reported early results with 4 donor/recipient pairs at the 2016 BMT Tandem Meetings (abstract 479). The research was sponsored by Celldex Therapeutics, Inc., the company developing CDX-301.
Donor results
The donors received CDX-301 at 75 μg/kg/day for 5 days. Leukapheresis began on day 6 if the peripheral blood CD34+ count was 7/μL or greater. The goal CD34+ yield was at least 2x106 per kilogram of recipient weight collected in 2 days of leukapheresis or less.
The donors could receive rescue plerixafor if the peripheral blood CD34+ count was less than 7/μL by day 8 or if the total CD34+ yield was less than 1x106/kg after the second day of leukapheresis.
The researchers analyzed CDX-301-mobilized cells by flow cytometry and compared them to historical data for peripheral blood grafts mobilized by granulocyte colony-stimulating factor (G-CSF).
Compared to the G-CSF-mobilized grafts, CDX-301-mobilized grafts had an increase in CD127+ (IL-7R) naïve T cells, γδ T cells, natural killer cells, and B cells.
The CDX-301-mobilized grafts were more enriched with plasmacytoid dendritic cells. And dendritic cells from the CDX-301 grafts had a more mature phenotype, expressing CD80 and CD86.
“From these data and preclinical studies, CDX-301 appears to be an effective, targeted approach to mobilization comparable to G-CSF,” said Steven Devine, MD, of The Ohio State Comprehensive Cancer Center in Columbus.
“With a relatively short course of treatment, we are observing specificity for mobilized stem cells and a lack of toxicity, instead of broad cellular mobilization and side effects.”
CDX-301 related adverse events included dizziness (grade 2), back pain (grade 1), arthralgia (grade 1), injection site reaction (2 grade 1), dyspepsia (1 grade 1, 1 grade 2), and decreased platelet count (2 grade 1). There were no grade 3/4 adverse events.
Recipient results
Thus far, 4 recipients have undergone HSCT with CDX-301-mobilized grafts. Recipient 1 had acute myeloid leukemia, recipients 2 and 3 had mantle cell lymphoma, and recipient 4 had chronic myeloid leukemia.
Recipients 1 through 3 received myeloablative conditioning, while recipient 4 received reduced-intensity conditioning. All patients received standard graft-vs-host disease (GVHD) prophylaxis (tacrolimus and methotrexate).
Recipient 4 has not yet engrafted. The other 3 had both neutrophil engraftment (day 17, 18, and 19) and platelet engraftment (day 14, 25, and 40).
There have been no infectious complications, and recipients 1 and 3 have not developed GVHD.
Recipient 2 developed steroid-responsive, grade 2, upper gastrointestinal GVHD on day 18, followed by grade 1 skin GVHD on day 50 that progressed to stage 3. Overall, the patient had grade 2 GVHD on day 64. The patient’s lymphoma has also progressed.
The researchers said these results suggest CDX-301 is well tolerated and can mobilize CD34+ cells when given as a single agent. They said recipients experienced successful engraftment in an expected time frame.
And the additional naïve T cells and plasmacytoid dendritic cells in CDX-301-mobilized grafts (compared to G-CSF-mobilized grafts) may provide better outcomes in HSCT recipients.
Now, the researchers plan to explore CDX-301 in combination with plerixafor. Additional donor/patient pairs are being accrued to a second study cohort.
in the bone marrow
HONOLULU—Early results from a pilot study suggest an investigational agent can effectively mobilize hematopoietic stem cells (HSCs) in healthy transplant donors.
The agent, CDX-301 (recombinant human Flt3 ligand), is a hematopoietic cytokine designed to expand dendritic cells and HSCs.
For the study, researchers tested CDX-301 in sibling-matched donors for hematopoietic stem cell transplant (HSCT) recipients with hematologic malignancies.
The team reported early results with 4 donor/recipient pairs at the 2016 BMT Tandem Meetings (abstract 479). The research was sponsored by Celldex Therapeutics, Inc., the company developing CDX-301.
Donor results
The donors received CDX-301 at 75 μg/kg/day for 5 days. Leukapheresis began on day 6 if the peripheral blood CD34+ count was 7/μL or greater. The goal CD34+ yield was at least 2x106 per kilogram of recipient weight collected in 2 days of leukapheresis or less.
The donors could receive rescue plerixafor if the peripheral blood CD34+ count was less than 7/μL by day 8 or if the total CD34+ yield was less than 1x106/kg after the second day of leukapheresis.
The researchers analyzed CDX-301-mobilized cells by flow cytometry and compared them to historical data for peripheral blood grafts mobilized by granulocyte colony-stimulating factor (G-CSF).
Compared to the G-CSF-mobilized grafts, CDX-301-mobilized grafts had an increase in CD127+ (IL-7R) naïve T cells, γδ T cells, natural killer cells, and B cells.
The CDX-301-mobilized grafts were more enriched with plasmacytoid dendritic cells. And dendritic cells from the CDX-301 grafts had a more mature phenotype, expressing CD80 and CD86.
“From these data and preclinical studies, CDX-301 appears to be an effective, targeted approach to mobilization comparable to G-CSF,” said Steven Devine, MD, of The Ohio State Comprehensive Cancer Center in Columbus.
“With a relatively short course of treatment, we are observing specificity for mobilized stem cells and a lack of toxicity, instead of broad cellular mobilization and side effects.”
CDX-301 related adverse events included dizziness (grade 2), back pain (grade 1), arthralgia (grade 1), injection site reaction (2 grade 1), dyspepsia (1 grade 1, 1 grade 2), and decreased platelet count (2 grade 1). There were no grade 3/4 adverse events.
Recipient results
Thus far, 4 recipients have undergone HSCT with CDX-301-mobilized grafts. Recipient 1 had acute myeloid leukemia, recipients 2 and 3 had mantle cell lymphoma, and recipient 4 had chronic myeloid leukemia.
Recipients 1 through 3 received myeloablative conditioning, while recipient 4 received reduced-intensity conditioning. All patients received standard graft-vs-host disease (GVHD) prophylaxis (tacrolimus and methotrexate).
Recipient 4 has not yet engrafted. The other 3 had both neutrophil engraftment (day 17, 18, and 19) and platelet engraftment (day 14, 25, and 40).
There have been no infectious complications, and recipients 1 and 3 have not developed GVHD.
Recipient 2 developed steroid-responsive, grade 2, upper gastrointestinal GVHD on day 18, followed by grade 1 skin GVHD on day 50 that progressed to stage 3. Overall, the patient had grade 2 GVHD on day 64. The patient’s lymphoma has also progressed.
The researchers said these results suggest CDX-301 is well tolerated and can mobilize CD34+ cells when given as a single agent. They said recipients experienced successful engraftment in an expected time frame.
And the additional naïve T cells and plasmacytoid dendritic cells in CDX-301-mobilized grafts (compared to G-CSF-mobilized grafts) may provide better outcomes in HSCT recipients.
Now, the researchers plan to explore CDX-301 in combination with plerixafor. Additional donor/patient pairs are being accrued to a second study cohort.
Adjunct T-cell therapy granted orphan designation
The US Food and Drug Administration (FDA) has granted orphan drug designation for BPX-501, an adjunct T-cell therapy.
The designation is for the combination of BPX-501 genetically modified T cells and the activator agent rimiducid as replacement T-cell therapy for the treatment of immunodeficiency and graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplant (HSCT).
BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate cells in the event of toxicity.
The CaspaCIDe switch consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway. Infusion of rimiducid is designed to trigger activation of this domain of caspase-9 (iCasp9), which leads to selective apoptosis of the CaspaCIDe-containing cells.
This technology is intended to provide a safety net to eliminate BPX-501 alloreactive T cells if severe GVHD occurs, ostensibly enabling physicians to more safely perform haploidentical HSCTs by adding back the BPX-501 genetically engineered T cells to speed immune reconstitution and provide control over viral infections.
Following an allogeneic HSCT, a lack of sufficient mature T cells constitutes immune deficiency that can contribute to infections, viral reactivation, and relapse.
The ability to correct this immune deficiency by adding back mature donor T cells, without raising the risk of uncontrollable GVHD, has the potential to change the risk profile of allogeneic transplant, according to Bellicum Pharmaceuticals, the company developing BPX-501.
BPX-501 is being evaluated in multiple phase 1/2 trials in adults and pediatric patients with leukemias, lymphomas, and genetic blood diseases in the US and Europe.
About orphan designation
The FDA’s Office of Orphan Products Development grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent rare diseases and disorders that affect fewer than 200,000 people in the US.
Orphan designation qualifies a company for various development incentives, including tax credits for qualified clinical testing and marketing exclusivity for a period of 7 years.
The US Food and Drug Administration (FDA) has granted orphan drug designation for BPX-501, an adjunct T-cell therapy.
The designation is for the combination of BPX-501 genetically modified T cells and the activator agent rimiducid as replacement T-cell therapy for the treatment of immunodeficiency and graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplant (HSCT).
BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate cells in the event of toxicity.
The CaspaCIDe switch consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway. Infusion of rimiducid is designed to trigger activation of this domain of caspase-9 (iCasp9), which leads to selective apoptosis of the CaspaCIDe-containing cells.
This technology is intended to provide a safety net to eliminate BPX-501 alloreactive T cells if severe GVHD occurs, ostensibly enabling physicians to more safely perform haploidentical HSCTs by adding back the BPX-501 genetically engineered T cells to speed immune reconstitution and provide control over viral infections.
Following an allogeneic HSCT, a lack of sufficient mature T cells constitutes immune deficiency that can contribute to infections, viral reactivation, and relapse.
The ability to correct this immune deficiency by adding back mature donor T cells, without raising the risk of uncontrollable GVHD, has the potential to change the risk profile of allogeneic transplant, according to Bellicum Pharmaceuticals, the company developing BPX-501.
BPX-501 is being evaluated in multiple phase 1/2 trials in adults and pediatric patients with leukemias, lymphomas, and genetic blood diseases in the US and Europe.
About orphan designation
The FDA’s Office of Orphan Products Development grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent rare diseases and disorders that affect fewer than 200,000 people in the US.
Orphan designation qualifies a company for various development incentives, including tax credits for qualified clinical testing and marketing exclusivity for a period of 7 years.
The US Food and Drug Administration (FDA) has granted orphan drug designation for BPX-501, an adjunct T-cell therapy.
The designation is for the combination of BPX-501 genetically modified T cells and the activator agent rimiducid as replacement T-cell therapy for the treatment of immunodeficiency and graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplant (HSCT).
BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate cells in the event of toxicity.
The CaspaCIDe switch consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway. Infusion of rimiducid is designed to trigger activation of this domain of caspase-9 (iCasp9), which leads to selective apoptosis of the CaspaCIDe-containing cells.
This technology is intended to provide a safety net to eliminate BPX-501 alloreactive T cells if severe GVHD occurs, ostensibly enabling physicians to more safely perform haploidentical HSCTs by adding back the BPX-501 genetically engineered T cells to speed immune reconstitution and provide control over viral infections.
Following an allogeneic HSCT, a lack of sufficient mature T cells constitutes immune deficiency that can contribute to infections, viral reactivation, and relapse.
The ability to correct this immune deficiency by adding back mature donor T cells, without raising the risk of uncontrollable GVHD, has the potential to change the risk profile of allogeneic transplant, according to Bellicum Pharmaceuticals, the company developing BPX-501.
BPX-501 is being evaluated in multiple phase 1/2 trials in adults and pediatric patients with leukemias, lymphomas, and genetic blood diseases in the US and Europe.
About orphan designation
The FDA’s Office of Orphan Products Development grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent rare diseases and disorders that affect fewer than 200,000 people in the US.
Orphan designation qualifies a company for various development incentives, including tax credits for qualified clinical testing and marketing exclusivity for a period of 7 years.