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Nature retracts STAP cell papers
Credit: Haruko Obokata
The journal Nature has retracted the papers it published several months ago on stimulus-triggered acquisition of pluripotency (STAP) cells.
In January, Nature published an article and a letter in which researchers claimed they could create STAP cells—ie, induce pluripotency in somatic cells by exposing them to a low-pH environment.
Not long after the papers were published, however, members of the scientific community began to question the validity of the research.
They voiced concerns about published images, possible plagiarism, and an inability to replicate the experiments described.
So the Japanese institute RIKEN, where most of the study’s investigators are employed, launched an investigation.
In April, RIKEN’s investigative committee concluded that lead study author Haruko Obokata, PhD, and some of her colleagues were guilty of misconduct and/or negligence.
Dr Obokata appealed the findings, saying the acts of misconduct were simply mistakes and that STAP cells do exist.
But the committee decided another investigation is not warranted, and RIKEN called for a retraction of the Nature papers.
Today, Nature published the retractions, which can be viewed here and here. An editorial on the subject is available here.
As for the future of STAP cells, RIKEN is currently attempting to recreate Dr Obokata’s experiments and determine if the cells do exist. The organization plans to release an interim report on this attempt in late July or early August.
Other researchers said they have tried and failed to replicate Dr Obokata’s experiments. One group detailed their failed attempt in F1000Research. 
Credit: Haruko Obokata
The journal Nature has retracted the papers it published several months ago on stimulus-triggered acquisition of pluripotency (STAP) cells.
In January, Nature published an article and a letter in which researchers claimed they could create STAP cells—ie, induce pluripotency in somatic cells by exposing them to a low-pH environment.
Not long after the papers were published, however, members of the scientific community began to question the validity of the research.
They voiced concerns about published images, possible plagiarism, and an inability to replicate the experiments described.
So the Japanese institute RIKEN, where most of the study’s investigators are employed, launched an investigation.
In April, RIKEN’s investigative committee concluded that lead study author Haruko Obokata, PhD, and some of her colleagues were guilty of misconduct and/or negligence.
Dr Obokata appealed the findings, saying the acts of misconduct were simply mistakes and that STAP cells do exist.
But the committee decided another investigation is not warranted, and RIKEN called for a retraction of the Nature papers.
Today, Nature published the retractions, which can be viewed here and here. An editorial on the subject is available here.
As for the future of STAP cells, RIKEN is currently attempting to recreate Dr Obokata’s experiments and determine if the cells do exist. The organization plans to release an interim report on this attempt in late July or early August.
Other researchers said they have tried and failed to replicate Dr Obokata’s experiments. One group detailed their failed attempt in F1000Research.
Credit: Haruko Obokata
The journal Nature has retracted the papers it published several months ago on stimulus-triggered acquisition of pluripotency (STAP) cells.
In January, Nature published an article and a letter in which researchers claimed they could create STAP cells—ie, induce pluripotency in somatic cells by exposing them to a low-pH environment.
Not long after the papers were published, however, members of the scientific community began to question the validity of the research.
They voiced concerns about published images, possible plagiarism, and an inability to replicate the experiments described.
So the Japanese institute RIKEN, where most of the study’s investigators are employed, launched an investigation.
In April, RIKEN’s investigative committee concluded that lead study author Haruko Obokata, PhD, and some of her colleagues were guilty of misconduct and/or negligence.
Dr Obokata appealed the findings, saying the acts of misconduct were simply mistakes and that STAP cells do exist.
But the committee decided another investigation is not warranted, and RIKEN called for a retraction of the Nature papers.
Today, Nature published the retractions, which can be viewed here and here. An editorial on the subject is available here.
As for the future of STAP cells, RIKEN is currently attempting to recreate Dr Obokata’s experiments and determine if the cells do exist. The organization plans to release an interim report on this attempt in late July or early August.
Other researchers said they have tried and failed to replicate Dr Obokata’s experiments. One group detailed their failed attempt in F1000Research.
Company recalls lots of warfarin
Bristol-Myers Squibb has announced a recall of 6 lots of the anticoagulant warfarin, sold as Coumadin for Injection in 5 mg single-use vials, in the US.
The company is recalling these lots after discovering visible particulate matter in unreleased samples of the drug.
The company said the safety risk to patients is likely low and is further mitigated by the product’s prescribing information, which advises that intravenous products be inspected visually before administration.
However, injected particulate metallic and non-metallic cellulose material can cause serious and potentially fatal adverse reactions, such as embolization. Allergic reactions to the foreign material could also occur.
To date, there have been no product complaints or adverse events reported to Bristol-Myers Squibb related to particulate matter in Coumadin for Injection.
Coumadin for Injection was discontinued in early April 2014. The oral formulation of Coumadin is not impacted by this recall.
Coumadin for Injection is packaged in cartons of six 5-mg single-use vials. The affected product includes the following 6 lots distributed to hospitals and pharmacies from November 2011 through January 2014:
Lot # Description NDC Expiration
201125 COUMADIN LINJ 5MG (6VL) US 0590-0324-35 Sept. 2014
201126 COUMADIN LINJ 5MG (6VL) US 0590-0324-35 Nov. 2014
201127 COUMADIN LINJ 5MG (6VL) US 0590-0324-35 Dec. 2014
201228 COUMADIN LINJ 5MG (6VL) US 0590-0324-35 June 2015
201229 COUMADIN LINJ 5MG (6VL) US 0590-0324-35 July 2015
201230 COUMADIN LINJ 5MG (6VL) US 0590-0324-35 Sept. 2015
Anyone with the aforementioned lots of Coumadin for Injection should stop using or distributing the product and contact Bristol-Myers Squibb’s recall vendor, GENCO, at 1-855-838-5784 to arrange for the return of remaining stock.
Customers with questions about the recall may contact the Bristol-Myers Squibb Customer Information Center at 1-800-332-2056.
Adverse reactions or quality problems associated with the use of this product can be reported to the FDA’s MedWatch Adverse Event Reporting Program.
Bristol-Myers Squibb has announced a recall of 6 lots of the anticoagulant warfarin, sold as Coumadin for Injection in 5 mg single-use vials, in the US.
The company is recalling these lots after discovering visible particulate matter in unreleased samples of the drug.
The company said the safety risk to patients is likely low and is further mitigated by the product’s prescribing information, which advises that intravenous products be inspected visually before administration.
However, injected particulate metallic and non-metallic cellulose material can cause serious and potentially fatal adverse reactions, such as embolization. Allergic reactions to the foreign material could also occur.
To date, there have been no product complaints or adverse events reported to Bristol-Myers Squibb related to particulate matter in Coumadin for Injection.
Coumadin for Injection was discontinued in early April 2014. The oral formulation of Coumadin is not impacted by this recall.
Coumadin for Injection is packaged in cartons of six 5-mg single-use vials. The affected product includes the following 6 lots distributed to hospitals and pharmacies from November 2011 through January 2014:
Lot # Description NDC Expiration
201125 COUMADIN LINJ 5MG (6VL) US 0590-0324-35 Sept. 2014
201126 COUMADIN LINJ 5MG (6VL) US 0590-0324-35 Nov. 2014
201127 COUMADIN LINJ 5MG (6VL) US 0590-0324-35 Dec. 2014
201228 COUMADIN LINJ 5MG (6VL) US 0590-0324-35 June 2015
201229 COUMADIN LINJ 5MG (6VL) US 0590-0324-35 July 2015
201230 COUMADIN LINJ 5MG (6VL) US 0590-0324-35 Sept. 2015
Anyone with the aforementioned lots of Coumadin for Injection should stop using or distributing the product and contact Bristol-Myers Squibb’s recall vendor, GENCO, at 1-855-838-5784 to arrange for the return of remaining stock.
Customers with questions about the recall may contact the Bristol-Myers Squibb Customer Information Center at 1-800-332-2056.
Adverse reactions or quality problems associated with the use of this product can be reported to the FDA’s MedWatch Adverse Event Reporting Program.
Bristol-Myers Squibb has announced a recall of 6 lots of the anticoagulant warfarin, sold as Coumadin for Injection in 5 mg single-use vials, in the US.
The company is recalling these lots after discovering visible particulate matter in unreleased samples of the drug.
The company said the safety risk to patients is likely low and is further mitigated by the product’s prescribing information, which advises that intravenous products be inspected visually before administration.
However, injected particulate metallic and non-metallic cellulose material can cause serious and potentially fatal adverse reactions, such as embolization. Allergic reactions to the foreign material could also occur.
To date, there have been no product complaints or adverse events reported to Bristol-Myers Squibb related to particulate matter in Coumadin for Injection.
Coumadin for Injection was discontinued in early April 2014. The oral formulation of Coumadin is not impacted by this recall.
Coumadin for Injection is packaged in cartons of six 5-mg single-use vials. The affected product includes the following 6 lots distributed to hospitals and pharmacies from November 2011 through January 2014:
Lot # Description NDC Expiration
201125 COUMADIN LINJ 5MG (6VL) US 0590-0324-35 Sept. 2014
201126 COUMADIN LINJ 5MG (6VL) US 0590-0324-35 Nov. 2014
201127 COUMADIN LINJ 5MG (6VL) US 0590-0324-35 Dec. 2014
201228 COUMADIN LINJ 5MG (6VL) US 0590-0324-35 June 2015
201229 COUMADIN LINJ 5MG (6VL) US 0590-0324-35 July 2015
201230 COUMADIN LINJ 5MG (6VL) US 0590-0324-35 Sept. 2015
Anyone with the aforementioned lots of Coumadin for Injection should stop using or distributing the product and contact Bristol-Myers Squibb’s recall vendor, GENCO, at 1-855-838-5784 to arrange for the return of remaining stock.
Customers with questions about the recall may contact the Bristol-Myers Squibb Customer Information Center at 1-800-332-2056.
Adverse reactions or quality problems associated with the use of this product can be reported to the FDA’s MedWatch Adverse Event Reporting Program.
Phase 2 results lead to breakthrough designation
The US Food and Drug Administration (FDA) has granted the bispecific antibody blinatumomab breakthrough designation for the treatment of adults with relapsed or refractory B-precursor acute lymphoblastic leukemia (B-ALL).
The decision was based on promising results of a phase 2 trial, which were presented at the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO) and the 19th Congress of the European Hematology Association (EHA).
According to the FDA, breakthrough designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.
For a treatment to receive this designation, there must be preliminary clinical evidence suggesting the drug may offer substantial improvement over currently available therapy on at least one clinically significant endpoint.
Trial results
Nicola Gökbuget, MD, of Goethe University in Frankfurt, Germany, and Max Topp, MD, of the University of Wuerzberg in Germany, presented phase 2 results with blinatumomab at the EHA Congress as abstracts S1314 and S722. The trial was sponsored by Amgen, the company developing blinatumomab.
“Blinatumomab is a bispecific antibody which has two parts,” Dr Gökbuget noted. “With one part—the CD3 part—it attracts T cells, and with the other part, it binds to CD19. And CD19 is a target available on the vast majority of B-precursor ALL blast cells.”
To test this mechanism, Dr Gökbuget and her colleagues evaluated blinatumomab monotherapy in 189 patients with relapsed or refractory B-ALL and a median age of 39 (range, 18-79).
The patients received blinatumomab by continuous intravenous infusion—4 weeks on and 2 weeks off—for up to 5 cycles.
Safety
Dr Gökbuget noted that major toxicities were related to cytokine release syndrome—for example, fever and headache—but cytopenias were also common.
“Another side effect observed with this compound—and this is something seen often with other T-cell therapies—was [central nervous system] events,” she added.
The most frequent adverse events (AEs) were pyrexia (59%), headache (35%) and febrile neutropenia (29%). The most frequent grade 3 or higher AEs were febrile neutropenia (26%), anemia (15%), and neutropenia (15%). Two percent of patients had grade 3 or higher cytokine release syndrome.
The most common grade 3 or higher nervous system AEs were headache (4%), encephalopathy (3%), and ataxia (2%). Three patients (2%) had grade 5 AEs considered treatment-related—2 with sepsis and 1 with Candida infection.
Efficacy
The study’s primary endpoint was complete remission (CR) or CR with partial hematologic recovery (CRh) within the first 2 cycles.
An exploratory endpoint was minimal residual disease (MRD) response (<10-4) within the first 2 cycles. If a patient was MRD-negative, he was classified as having a complete MRD response.
In all, 43% (81/189) of patients achieved a CR/CRh within 2 cycles of therapy. Thirty-three percent (63/189) achieved a CR, and 9% (18/189) achieved a CRh.
Eighty-two percent (60/73) of patients with a CR/CRh who were evaluable for an MRD assessment achieved an MRD response. This included 86% (50/58) of CR patients and 67% (10/15) of CRh patients. Seventy-one percent (51/73) of patients with CR/CRh had a complete MRD response.
The median relapse-free survival was 5.9 months.
“So to conclude, we have observed considerable antileukemic activity for this single-drug therapy,” Dr Gökbuget said. “We have to keep in mind this is a single drug, and, usually, these patients receive many different chemotherapy compounds.”
“Also, although these patients were poorly selected, this is, so far, the largest trial in adult ALL where standardized PCR-based MRD detection was tested in the relapsed setting. So these data will be very important.”
The US Food and Drug Administration (FDA) has granted the bispecific antibody blinatumomab breakthrough designation for the treatment of adults with relapsed or refractory B-precursor acute lymphoblastic leukemia (B-ALL).
The decision was based on promising results of a phase 2 trial, which were presented at the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO) and the 19th Congress of the European Hematology Association (EHA).
According to the FDA, breakthrough designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.
For a treatment to receive this designation, there must be preliminary clinical evidence suggesting the drug may offer substantial improvement over currently available therapy on at least one clinically significant endpoint.
Trial results
Nicola Gökbuget, MD, of Goethe University in Frankfurt, Germany, and Max Topp, MD, of the University of Wuerzberg in Germany, presented phase 2 results with blinatumomab at the EHA Congress as abstracts S1314 and S722. The trial was sponsored by Amgen, the company developing blinatumomab.
“Blinatumomab is a bispecific antibody which has two parts,” Dr Gökbuget noted. “With one part—the CD3 part—it attracts T cells, and with the other part, it binds to CD19. And CD19 is a target available on the vast majority of B-precursor ALL blast cells.”
To test this mechanism, Dr Gökbuget and her colleagues evaluated blinatumomab monotherapy in 189 patients with relapsed or refractory B-ALL and a median age of 39 (range, 18-79).
The patients received blinatumomab by continuous intravenous infusion—4 weeks on and 2 weeks off—for up to 5 cycles.
Safety
Dr Gökbuget noted that major toxicities were related to cytokine release syndrome—for example, fever and headache—but cytopenias were also common.
“Another side effect observed with this compound—and this is something seen often with other T-cell therapies—was [central nervous system] events,” she added.
The most frequent adverse events (AEs) were pyrexia (59%), headache (35%) and febrile neutropenia (29%). The most frequent grade 3 or higher AEs were febrile neutropenia (26%), anemia (15%), and neutropenia (15%). Two percent of patients had grade 3 or higher cytokine release syndrome.
The most common grade 3 or higher nervous system AEs were headache (4%), encephalopathy (3%), and ataxia (2%). Three patients (2%) had grade 5 AEs considered treatment-related—2 with sepsis and 1 with Candida infection.
Efficacy
The study’s primary endpoint was complete remission (CR) or CR with partial hematologic recovery (CRh) within the first 2 cycles.
An exploratory endpoint was minimal residual disease (MRD) response (<10-4) within the first 2 cycles. If a patient was MRD-negative, he was classified as having a complete MRD response.
In all, 43% (81/189) of patients achieved a CR/CRh within 2 cycles of therapy. Thirty-three percent (63/189) achieved a CR, and 9% (18/189) achieved a CRh.
Eighty-two percent (60/73) of patients with a CR/CRh who were evaluable for an MRD assessment achieved an MRD response. This included 86% (50/58) of CR patients and 67% (10/15) of CRh patients. Seventy-one percent (51/73) of patients with CR/CRh had a complete MRD response.
The median relapse-free survival was 5.9 months.
“So to conclude, we have observed considerable antileukemic activity for this single-drug therapy,” Dr Gökbuget said. “We have to keep in mind this is a single drug, and, usually, these patients receive many different chemotherapy compounds.”
“Also, although these patients were poorly selected, this is, so far, the largest trial in adult ALL where standardized PCR-based MRD detection was tested in the relapsed setting. So these data will be very important.”
The US Food and Drug Administration (FDA) has granted the bispecific antibody blinatumomab breakthrough designation for the treatment of adults with relapsed or refractory B-precursor acute lymphoblastic leukemia (B-ALL).
The decision was based on promising results of a phase 2 trial, which were presented at the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO) and the 19th Congress of the European Hematology Association (EHA).
According to the FDA, breakthrough designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.
For a treatment to receive this designation, there must be preliminary clinical evidence suggesting the drug may offer substantial improvement over currently available therapy on at least one clinically significant endpoint.
Trial results
Nicola Gökbuget, MD, of Goethe University in Frankfurt, Germany, and Max Topp, MD, of the University of Wuerzberg in Germany, presented phase 2 results with blinatumomab at the EHA Congress as abstracts S1314 and S722. The trial was sponsored by Amgen, the company developing blinatumomab.
“Blinatumomab is a bispecific antibody which has two parts,” Dr Gökbuget noted. “With one part—the CD3 part—it attracts T cells, and with the other part, it binds to CD19. And CD19 is a target available on the vast majority of B-precursor ALL blast cells.”
To test this mechanism, Dr Gökbuget and her colleagues evaluated blinatumomab monotherapy in 189 patients with relapsed or refractory B-ALL and a median age of 39 (range, 18-79).
The patients received blinatumomab by continuous intravenous infusion—4 weeks on and 2 weeks off—for up to 5 cycles.
Safety
Dr Gökbuget noted that major toxicities were related to cytokine release syndrome—for example, fever and headache—but cytopenias were also common.
“Another side effect observed with this compound—and this is something seen often with other T-cell therapies—was [central nervous system] events,” she added.
The most frequent adverse events (AEs) were pyrexia (59%), headache (35%) and febrile neutropenia (29%). The most frequent grade 3 or higher AEs were febrile neutropenia (26%), anemia (15%), and neutropenia (15%). Two percent of patients had grade 3 or higher cytokine release syndrome.
The most common grade 3 or higher nervous system AEs were headache (4%), encephalopathy (3%), and ataxia (2%). Three patients (2%) had grade 5 AEs considered treatment-related—2 with sepsis and 1 with Candida infection.
Efficacy
The study’s primary endpoint was complete remission (CR) or CR with partial hematologic recovery (CRh) within the first 2 cycles.
An exploratory endpoint was minimal residual disease (MRD) response (<10-4) within the first 2 cycles. If a patient was MRD-negative, he was classified as having a complete MRD response.
In all, 43% (81/189) of patients achieved a CR/CRh within 2 cycles of therapy. Thirty-three percent (63/189) achieved a CR, and 9% (18/189) achieved a CRh.
Eighty-two percent (60/73) of patients with a CR/CRh who were evaluable for an MRD assessment achieved an MRD response. This included 86% (50/58) of CR patients and 67% (10/15) of CRh patients. Seventy-one percent (51/73) of patients with CR/CRh had a complete MRD response.
The median relapse-free survival was 5.9 months.
“So to conclude, we have observed considerable antileukemic activity for this single-drug therapy,” Dr Gökbuget said. “We have to keep in mind this is a single drug, and, usually, these patients receive many different chemotherapy compounds.”
“Also, although these patients were poorly selected, this is, so far, the largest trial in adult ALL where standardized PCR-based MRD detection was tested in the relapsed setting. So these data will be very important.”
Artificial platelets increase survival in injured mice
Credit: Aaron Logan
New research suggests artificial platelets can aid natural platelets in the clotting process, thereby halting internal bleeding faster.
The artificial platelets, called hemostatic nanoparticles, dramatically increased survival rates in mouse models of blast trauma (hemorrhaging resulting from exposure to an explosion).
And the hemostatic nanoparticles did not appear to interfere with healing or cause any other complications for up to 3 weeks after injection.
Erin Lavik, ScD, of Case Western Reserve University in Cleveland, Ohio, and her colleagues recounted these results in Proceedings of the National Academy of Sciences.
Side effects and survival
The researchers developed a full-body-blast mouse model that replicates the injuries seen in people exposed to explosions. And they used these mice to compare the safety and efficacy of the hemostatic nanoparticles to no treatment, control nanoparticles, lactated Ringer’s solution, and rFVIIa.
The survival rate in mice treated with hemostatic nanoparticles increased to 95% at 1 hour post-trauma, compared to 60% for untreated mice. The odds ratio (OR) was 13.
When the researchers compared the hemostatic nanoparticles and lactated Ringer’s solution, the OR was 8.5. For hemostatic nanoparticles vs control nanoparticles, the OR was 7.1. And for hemostatic nanoparticles vs rFVIIa, the OR was 5.5.
Most mice were killed at the 1-hour time point, but the researchers maintained some mice in the nanoparticle groups so they could assess survival at 1 week and 3 weeks after the blast injury and examine the long-term effects of the nanoparticles.
The team said the vast majority of animals that survived at 1 hour lived to the end of the 3-week study. Differences in lethality at 1 week and 3 weeks were not statistically significant.
Furthermore, there were no unwanted side effects, such as accumulation of the nanoparticles, clot formation, or aberrant healing, during examinations at the 1-week and 3-week time points.
About the nanoparticles
The nanoparticles are made from short polymer chains already approved for other uses by the US Food and Drug Administration.
“They are incredibly simple . . . spheres with arms of peptides that react with activated blood platelets in damaged tissues to help clots form more quickly,” Dr Lavik said.
The dry particles remained viable after 2 weeks on a shelf. A medic in the field or an ambulance crew would add saline, shake and inject them, according to the researchers.
In earlier testing, rat models injected with the nanoparticles stopped bleeding faster than untreated models. Further research and testing are underway, and clinical trials are likely at least 5 years out, Dr Lavik said. 
Credit: Aaron Logan
New research suggests artificial platelets can aid natural platelets in the clotting process, thereby halting internal bleeding faster.
The artificial platelets, called hemostatic nanoparticles, dramatically increased survival rates in mouse models of blast trauma (hemorrhaging resulting from exposure to an explosion).
And the hemostatic nanoparticles did not appear to interfere with healing or cause any other complications for up to 3 weeks after injection.
Erin Lavik, ScD, of Case Western Reserve University in Cleveland, Ohio, and her colleagues recounted these results in Proceedings of the National Academy of Sciences.
Side effects and survival
The researchers developed a full-body-blast mouse model that replicates the injuries seen in people exposed to explosions. And they used these mice to compare the safety and efficacy of the hemostatic nanoparticles to no treatment, control nanoparticles, lactated Ringer’s solution, and rFVIIa.
The survival rate in mice treated with hemostatic nanoparticles increased to 95% at 1 hour post-trauma, compared to 60% for untreated mice. The odds ratio (OR) was 13.
When the researchers compared the hemostatic nanoparticles and lactated Ringer’s solution, the OR was 8.5. For hemostatic nanoparticles vs control nanoparticles, the OR was 7.1. And for hemostatic nanoparticles vs rFVIIa, the OR was 5.5.
Most mice were killed at the 1-hour time point, but the researchers maintained some mice in the nanoparticle groups so they could assess survival at 1 week and 3 weeks after the blast injury and examine the long-term effects of the nanoparticles.
The team said the vast majority of animals that survived at 1 hour lived to the end of the 3-week study. Differences in lethality at 1 week and 3 weeks were not statistically significant.
Furthermore, there were no unwanted side effects, such as accumulation of the nanoparticles, clot formation, or aberrant healing, during examinations at the 1-week and 3-week time points.
About the nanoparticles
The nanoparticles are made from short polymer chains already approved for other uses by the US Food and Drug Administration.
“They are incredibly simple . . . spheres with arms of peptides that react with activated blood platelets in damaged tissues to help clots form more quickly,” Dr Lavik said.
The dry particles remained viable after 2 weeks on a shelf. A medic in the field or an ambulance crew would add saline, shake and inject them, according to the researchers.
In earlier testing, rat models injected with the nanoparticles stopped bleeding faster than untreated models. Further research and testing are underway, and clinical trials are likely at least 5 years out, Dr Lavik said.
Credit: Aaron Logan
New research suggests artificial platelets can aid natural platelets in the clotting process, thereby halting internal bleeding faster.
The artificial platelets, called hemostatic nanoparticles, dramatically increased survival rates in mouse models of blast trauma (hemorrhaging resulting from exposure to an explosion).
And the hemostatic nanoparticles did not appear to interfere with healing or cause any other complications for up to 3 weeks after injection.
Erin Lavik, ScD, of Case Western Reserve University in Cleveland, Ohio, and her colleagues recounted these results in Proceedings of the National Academy of Sciences.
Side effects and survival
The researchers developed a full-body-blast mouse model that replicates the injuries seen in people exposed to explosions. And they used these mice to compare the safety and efficacy of the hemostatic nanoparticles to no treatment, control nanoparticles, lactated Ringer’s solution, and rFVIIa.
The survival rate in mice treated with hemostatic nanoparticles increased to 95% at 1 hour post-trauma, compared to 60% for untreated mice. The odds ratio (OR) was 13.
When the researchers compared the hemostatic nanoparticles and lactated Ringer’s solution, the OR was 8.5. For hemostatic nanoparticles vs control nanoparticles, the OR was 7.1. And for hemostatic nanoparticles vs rFVIIa, the OR was 5.5.
Most mice were killed at the 1-hour time point, but the researchers maintained some mice in the nanoparticle groups so they could assess survival at 1 week and 3 weeks after the blast injury and examine the long-term effects of the nanoparticles.
The team said the vast majority of animals that survived at 1 hour lived to the end of the 3-week study. Differences in lethality at 1 week and 3 weeks were not statistically significant.
Furthermore, there were no unwanted side effects, such as accumulation of the nanoparticles, clot formation, or aberrant healing, during examinations at the 1-week and 3-week time points.
About the nanoparticles
The nanoparticles are made from short polymer chains already approved for other uses by the US Food and Drug Administration.
“They are incredibly simple . . . spheres with arms of peptides that react with activated blood platelets in damaged tissues to help clots form more quickly,” Dr Lavik said.
The dry particles remained viable after 2 weeks on a shelf. A medic in the field or an ambulance crew would add saline, shake and inject them, according to the researchers.
In earlier testing, rat models injected with the nanoparticles stopped bleeding faster than untreated models. Further research and testing are underway, and clinical trials are likely at least 5 years out, Dr Lavik said.
QOL data support ATRA-ATO in APL
MILAN—Quality of life (QOL) data support the use of all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) in patients with acute promyelocytic leukemia (APL), a GIMEMA researcher has reported.
Previously released data from a phase 3 study showed that ATRA-ATO can improve survival rates in APL patients when compared to ATRA plus chemotherapy.
Now, a QOL assessment of these same patients suggests ATO can confer additional benefits.
Researchers observed post-induction improvements in fatigue, cognitive functioning, and other QOL outcome measures among patients treated with ATRA-ATO. However, there were no major differences in post-consolidation results between the ATO arm and the chemotherapy arm.
Nevertheless, the results suggest ATRA-ATO should be considered the preferred first-line therapy in APL, according to Fabio Efficace, PhD, of the GIMEMA Data Center and Health Outcomes Research Unit in Rome, Italy.
Dr Efficace presented QOL data for ATRA-ATO at the 19th Annual Congress of the European Hematology Association (EHA) as abstract S1330.
“When conducting a clinical trial—especially a randomized, phase 3 study—it is of paramount importance to include quality of life assessment,” Dr Efficace said. “If quality of life is assessed in a robust way . . ., it will always provide very important information to [help us] judge the overall treatment effectiveness.”
To that end, he and his colleagues performed QOL assessments of patients enrolled in a randomized, phase 3 trial. The study was designed to show that ATRA-ATO was non-inferior to ATRA- chemo with respect to event-free survival rates at 2 years.
The trial actually showed that ATRA-ATO was superior to ATRA-chemo with regard to both event-free and overall survival.
To assess differences in QOL measures, Dr Efficace and his colleagues asked patients to complete the EORTC QLQ-C30 questionnaire post-induction and post-consolidation.
The questionnaire is used to assess functional aspects, including cognitive functioning, emotional functioning, physical functioning, role functioning, and social functioning. It’s also used to evaluate core symptoms, including pain, fatigue, dyspnea, nausea/vomiting, constipation, diarrhea, insomnia, and appetite loss.
In all, 156 patients received at least 1 dose of their assigned therapy. In the ATRA-chemo group, 62 patients completed the QOL questionnaire post-induction, and 61 did so post-consolidation. In the ATRA-ATO group, 53 patients completed the questionnaire post-induction, and 58 did so post-consolidation.
Post-induction, patients treated with ATRA-ATO reported significantly less fatigue than patients in the ATRA-chemo arm. ATO-treated patients also reported clinically meaningful improvements in appetite loss, nausea/vomiting, constipation, diarrhea, physical functioning, and cognitive functioning.
“We know that when you’re doing chemotherapy, one of the possible effects is loss of cognitive functioning,” Dr Efficace noted. “And we found, for those not receiving chemotherapy, a benefit in cognitive function. So this is something that has to be explored in further studies.”
Dr Efficace also pointed out that, post-consolidation, there were “no major differences” in QOL measures between the 2 treatment arms. Nevertheless, he believes the initial benefits in fatigue and other symptoms support ATRA-ATO as the preferred first-line therapy for APL patients.
“The clinician should be reassured that [ATRA-]ATO as first-line therapy not only provides benefits in terms of event-free survival and overall survival, but it also provides advantages in terms of side effects of therapy,” Dr Efficace said.
“In this trial, we assessed toxicity, but toxicity is physician-reported data. Now, we have patient-reported data. [ATRA-]ATO should be the preferred first-line therapy because it is optimal from the patient perspective.”
MILAN—Quality of life (QOL) data support the use of all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) in patients with acute promyelocytic leukemia (APL), a GIMEMA researcher has reported.
Previously released data from a phase 3 study showed that ATRA-ATO can improve survival rates in APL patients when compared to ATRA plus chemotherapy.
Now, a QOL assessment of these same patients suggests ATO can confer additional benefits.
Researchers observed post-induction improvements in fatigue, cognitive functioning, and other QOL outcome measures among patients treated with ATRA-ATO. However, there were no major differences in post-consolidation results between the ATO arm and the chemotherapy arm.
Nevertheless, the results suggest ATRA-ATO should be considered the preferred first-line therapy in APL, according to Fabio Efficace, PhD, of the GIMEMA Data Center and Health Outcomes Research Unit in Rome, Italy.
Dr Efficace presented QOL data for ATRA-ATO at the 19th Annual Congress of the European Hematology Association (EHA) as abstract S1330.
“When conducting a clinical trial—especially a randomized, phase 3 study—it is of paramount importance to include quality of life assessment,” Dr Efficace said. “If quality of life is assessed in a robust way . . ., it will always provide very important information to [help us] judge the overall treatment effectiveness.”
To that end, he and his colleagues performed QOL assessments of patients enrolled in a randomized, phase 3 trial. The study was designed to show that ATRA-ATO was non-inferior to ATRA- chemo with respect to event-free survival rates at 2 years.
The trial actually showed that ATRA-ATO was superior to ATRA-chemo with regard to both event-free and overall survival.
To assess differences in QOL measures, Dr Efficace and his colleagues asked patients to complete the EORTC QLQ-C30 questionnaire post-induction and post-consolidation.
The questionnaire is used to assess functional aspects, including cognitive functioning, emotional functioning, physical functioning, role functioning, and social functioning. It’s also used to evaluate core symptoms, including pain, fatigue, dyspnea, nausea/vomiting, constipation, diarrhea, insomnia, and appetite loss.
In all, 156 patients received at least 1 dose of their assigned therapy. In the ATRA-chemo group, 62 patients completed the QOL questionnaire post-induction, and 61 did so post-consolidation. In the ATRA-ATO group, 53 patients completed the questionnaire post-induction, and 58 did so post-consolidation.
Post-induction, patients treated with ATRA-ATO reported significantly less fatigue than patients in the ATRA-chemo arm. ATO-treated patients also reported clinically meaningful improvements in appetite loss, nausea/vomiting, constipation, diarrhea, physical functioning, and cognitive functioning.
“We know that when you’re doing chemotherapy, one of the possible effects is loss of cognitive functioning,” Dr Efficace noted. “And we found, for those not receiving chemotherapy, a benefit in cognitive function. So this is something that has to be explored in further studies.”
Dr Efficace also pointed out that, post-consolidation, there were “no major differences” in QOL measures between the 2 treatment arms. Nevertheless, he believes the initial benefits in fatigue and other symptoms support ATRA-ATO as the preferred first-line therapy for APL patients.
“The clinician should be reassured that [ATRA-]ATO as first-line therapy not only provides benefits in terms of event-free survival and overall survival, but it also provides advantages in terms of side effects of therapy,” Dr Efficace said.
“In this trial, we assessed toxicity, but toxicity is physician-reported data. Now, we have patient-reported data. [ATRA-]ATO should be the preferred first-line therapy because it is optimal from the patient perspective.”
MILAN—Quality of life (QOL) data support the use of all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) in patients with acute promyelocytic leukemia (APL), a GIMEMA researcher has reported.
Previously released data from a phase 3 study showed that ATRA-ATO can improve survival rates in APL patients when compared to ATRA plus chemotherapy.
Now, a QOL assessment of these same patients suggests ATO can confer additional benefits.
Researchers observed post-induction improvements in fatigue, cognitive functioning, and other QOL outcome measures among patients treated with ATRA-ATO. However, there were no major differences in post-consolidation results between the ATO arm and the chemotherapy arm.
Nevertheless, the results suggest ATRA-ATO should be considered the preferred first-line therapy in APL, according to Fabio Efficace, PhD, of the GIMEMA Data Center and Health Outcomes Research Unit in Rome, Italy.
Dr Efficace presented QOL data for ATRA-ATO at the 19th Annual Congress of the European Hematology Association (EHA) as abstract S1330.
“When conducting a clinical trial—especially a randomized, phase 3 study—it is of paramount importance to include quality of life assessment,” Dr Efficace said. “If quality of life is assessed in a robust way . . ., it will always provide very important information to [help us] judge the overall treatment effectiveness.”
To that end, he and his colleagues performed QOL assessments of patients enrolled in a randomized, phase 3 trial. The study was designed to show that ATRA-ATO was non-inferior to ATRA- chemo with respect to event-free survival rates at 2 years.
The trial actually showed that ATRA-ATO was superior to ATRA-chemo with regard to both event-free and overall survival.
To assess differences in QOL measures, Dr Efficace and his colleagues asked patients to complete the EORTC QLQ-C30 questionnaire post-induction and post-consolidation.
The questionnaire is used to assess functional aspects, including cognitive functioning, emotional functioning, physical functioning, role functioning, and social functioning. It’s also used to evaluate core symptoms, including pain, fatigue, dyspnea, nausea/vomiting, constipation, diarrhea, insomnia, and appetite loss.
In all, 156 patients received at least 1 dose of their assigned therapy. In the ATRA-chemo group, 62 patients completed the QOL questionnaire post-induction, and 61 did so post-consolidation. In the ATRA-ATO group, 53 patients completed the questionnaire post-induction, and 58 did so post-consolidation.
Post-induction, patients treated with ATRA-ATO reported significantly less fatigue than patients in the ATRA-chemo arm. ATO-treated patients also reported clinically meaningful improvements in appetite loss, nausea/vomiting, constipation, diarrhea, physical functioning, and cognitive functioning.
“We know that when you’re doing chemotherapy, one of the possible effects is loss of cognitive functioning,” Dr Efficace noted. “And we found, for those not receiving chemotherapy, a benefit in cognitive function. So this is something that has to be explored in further studies.”
Dr Efficace also pointed out that, post-consolidation, there were “no major differences” in QOL measures between the 2 treatment arms. Nevertheless, he believes the initial benefits in fatigue and other symptoms support ATRA-ATO as the preferred first-line therapy for APL patients.
“The clinician should be reassured that [ATRA-]ATO as first-line therapy not only provides benefits in terms of event-free survival and overall survival, but it also provides advantages in terms of side effects of therapy,” Dr Efficace said.
“In this trial, we assessed toxicity, but toxicity is physician-reported data. Now, we have patient-reported data. [ATRA-]ATO should be the preferred first-line therapy because it is optimal from the patient perspective.”
HIV+ cancer patients more likely to go untreated
lymphocyte; Credit: CDC
Cancer patients infected with HIV are less likely than their uninfected peers to receive cancer treatment, according to research published in the Journal of Clinical Oncology.
Results showed that HIV-positive patients were roughly twice as likely to go untreated for lymphomas and other cancers.
The researchers believe a lack of clinical trial data and treatment guidelines for HIV patients with cancer may contribute to this health disparity.
To assess the role of HIV status on cancer treatment, Gita Suneja, MD, of the University of Pennsylvania in Philadelphia, and her colleagues used data from the National Cancer Institute’s HIV/AIDS Cancer Match Study.
This included 3045 HIV-infected patients and 1,087,648 uninfected patients. The patients had been diagnosed with Hodgkin lymphoma, diffuse large B-cell lymphoma, or cervical, lung, anal, prostate, colorectal, or breast cancer from 1996 through 2010.
For each cancer type, the researchers assessed the relationship between HIV status and cancer treatment, adjusted for cancer stage, sex, age at cancer diagnosis, race/ethnicity, year of cancer diagnosis, and US state.
For all but 1 cancer type, there was a significantly higher proportion of HIV-infected patients who did not receive cancer treatment when compared with uninfected patients.
The adjusted odds ratios (aORs) were 1.67 for diffuse large B-cell lymphoma, 1.77 for Hodgkin lymphoma, 1.60 for cervical cancer, 1.79 for prostate cancer, 1.81 for breast cancer, 2.18 for lung cancer, and 2.27 for colorectal cancer.
Anal cancer was the only malignancy for which HIV status did not appear to impact treatment. The aOR was 1.01.
Among HIV-infected individuals, factors independently associated with a lack of cancer treatment included low CD4 count, male sex with injection drug use as mode of HIV exposure, age 45 to 64 years, black race, and distant or unknown cancer stage.
“In my clinical experience, I have seen uncertainty surrounding treatment of HIV-infected cancer patients,” Dr Suneja said. “Patients with HIV have typically been excluded from clinical trials, and, therefore, oncologists do not know if the best available treatments are equally safe and effective in those with HIV.”
“Many oncologists rely on guidelines based on such trials for treatment decision-making, and, in the absence of guidance, they may elect not to treat HIV-infected cancer patients due to concerns about adverse side effects or poor survival. This could help explain, in part, why many HIV-positive cancer patients are not receiving appropriate cancer care.”
Therefore, Dr Suneja and her colleagues recommend that cancer trials begin enrolling HIV-infected patients and cancer management guidelines incorporate recommendations for HIV-infected patients.
lymphocyte; Credit: CDC
Cancer patients infected with HIV are less likely than their uninfected peers to receive cancer treatment, according to research published in the Journal of Clinical Oncology.
Results showed that HIV-positive patients were roughly twice as likely to go untreated for lymphomas and other cancers.
The researchers believe a lack of clinical trial data and treatment guidelines for HIV patients with cancer may contribute to this health disparity.
To assess the role of HIV status on cancer treatment, Gita Suneja, MD, of the University of Pennsylvania in Philadelphia, and her colleagues used data from the National Cancer Institute’s HIV/AIDS Cancer Match Study.
This included 3045 HIV-infected patients and 1,087,648 uninfected patients. The patients had been diagnosed with Hodgkin lymphoma, diffuse large B-cell lymphoma, or cervical, lung, anal, prostate, colorectal, or breast cancer from 1996 through 2010.
For each cancer type, the researchers assessed the relationship between HIV status and cancer treatment, adjusted for cancer stage, sex, age at cancer diagnosis, race/ethnicity, year of cancer diagnosis, and US state.
For all but 1 cancer type, there was a significantly higher proportion of HIV-infected patients who did not receive cancer treatment when compared with uninfected patients.
The adjusted odds ratios (aORs) were 1.67 for diffuse large B-cell lymphoma, 1.77 for Hodgkin lymphoma, 1.60 for cervical cancer, 1.79 for prostate cancer, 1.81 for breast cancer, 2.18 for lung cancer, and 2.27 for colorectal cancer.
Anal cancer was the only malignancy for which HIV status did not appear to impact treatment. The aOR was 1.01.
Among HIV-infected individuals, factors independently associated with a lack of cancer treatment included low CD4 count, male sex with injection drug use as mode of HIV exposure, age 45 to 64 years, black race, and distant or unknown cancer stage.
“In my clinical experience, I have seen uncertainty surrounding treatment of HIV-infected cancer patients,” Dr Suneja said. “Patients with HIV have typically been excluded from clinical trials, and, therefore, oncologists do not know if the best available treatments are equally safe and effective in those with HIV.”
“Many oncologists rely on guidelines based on such trials for treatment decision-making, and, in the absence of guidance, they may elect not to treat HIV-infected cancer patients due to concerns about adverse side effects or poor survival. This could help explain, in part, why many HIV-positive cancer patients are not receiving appropriate cancer care.”
Therefore, Dr Suneja and her colleagues recommend that cancer trials begin enrolling HIV-infected patients and cancer management guidelines incorporate recommendations for HIV-infected patients.
lymphocyte; Credit: CDC
Cancer patients infected with HIV are less likely than their uninfected peers to receive cancer treatment, according to research published in the Journal of Clinical Oncology.
Results showed that HIV-positive patients were roughly twice as likely to go untreated for lymphomas and other cancers.
The researchers believe a lack of clinical trial data and treatment guidelines for HIV patients with cancer may contribute to this health disparity.
To assess the role of HIV status on cancer treatment, Gita Suneja, MD, of the University of Pennsylvania in Philadelphia, and her colleagues used data from the National Cancer Institute’s HIV/AIDS Cancer Match Study.
This included 3045 HIV-infected patients and 1,087,648 uninfected patients. The patients had been diagnosed with Hodgkin lymphoma, diffuse large B-cell lymphoma, or cervical, lung, anal, prostate, colorectal, or breast cancer from 1996 through 2010.
For each cancer type, the researchers assessed the relationship between HIV status and cancer treatment, adjusted for cancer stage, sex, age at cancer diagnosis, race/ethnicity, year of cancer diagnosis, and US state.
For all but 1 cancer type, there was a significantly higher proportion of HIV-infected patients who did not receive cancer treatment when compared with uninfected patients.
The adjusted odds ratios (aORs) were 1.67 for diffuse large B-cell lymphoma, 1.77 for Hodgkin lymphoma, 1.60 for cervical cancer, 1.79 for prostate cancer, 1.81 for breast cancer, 2.18 for lung cancer, and 2.27 for colorectal cancer.
Anal cancer was the only malignancy for which HIV status did not appear to impact treatment. The aOR was 1.01.
Among HIV-infected individuals, factors independently associated with a lack of cancer treatment included low CD4 count, male sex with injection drug use as mode of HIV exposure, age 45 to 64 years, black race, and distant or unknown cancer stage.
“In my clinical experience, I have seen uncertainty surrounding treatment of HIV-infected cancer patients,” Dr Suneja said. “Patients with HIV have typically been excluded from clinical trials, and, therefore, oncologists do not know if the best available treatments are equally safe and effective in those with HIV.”
“Many oncologists rely on guidelines based on such trials for treatment decision-making, and, in the absence of guidance, they may elect not to treat HIV-infected cancer patients due to concerns about adverse side effects or poor survival. This could help explain, in part, why many HIV-positive cancer patients are not receiving appropriate cancer care.”
Therefore, Dr Suneja and her colleagues recommend that cancer trials begin enrolling HIV-infected patients and cancer management guidelines incorporate recommendations for HIV-infected patients.
Group engineers versatile RBCs
Researchers say they’ve modified red blood cells (RBCs) to carry a range of payloads—from drugs to vaccines to imaging agents.
“We wanted to create high-value red cells that do more than simply carry oxygen,” said study author Harvey Lodish, PhD, of the Whitehead Institute in Cambridge, Massachusetts.
“Here, we’ve laid out the technology to make mouse and human red blood cells in culture that can express what we want and potentially be used for therapeutic or diagnostic purposes.”
Dr Lodish and his colleagues detailed the technology in Proceedings of the National Academy of Sciences.
The team noted that RBCs are an attractive vehicle for a variety of reasons, including their abundance and their long lifespan.
Perhaps most importantly, during RBC production, progenitor cells jettison their nuclei and all DNA therein. Without a nucleus, a mature RBC lacks any genetic material or any signs of earlier genetic manipulation that could result in tumor formation or other adverse effects.
Exploiting this characteristic, Dr Lodish and his colleagues introduced into early stage RBC progenitors genes coding for specific, slightly modified, normal red cell surface proteins.
As the RBCs approach maturity and enucleate, the proteins remain on the cell surface, where they are modified by a protein-labeling technique known as sortagging.
The technique relies on the bacterial enzyme sortase A to establish a strong chemical bond between the surface protein and a substance of choice, be it a small-molecule therapeutic or an antibody capable of binding a toxin. The modifications leave the cells and their surfaces unharmed.
“Because the modified human red blood cells can circulate in the body for up to 4 months, one could envision a scenario in which the cells are used to introduce antibodies that neutralize a toxin,” said Hidde L. Ploegh, PhD, also of the Whitehead Institute. “The result would be long-lasting reserves of antitoxin antibodies.”
The approach has captured the attention of the US military and its Defense Advanced Research Projects Agency, which is supporting the research in the interest of developing treatments or vaccines effective against biological weapons.
Dr Lodish believes the applications are potentially vast and may include RBCs modified to bind and remove bad cholesterol from the bloodstream, carry clot-busting proteins to treat ischemic strokes or deep-vein thrombosis, or deliver anti-inflammatory antibodies to alleviate chronic inflammation.
Dr Ploegh said there is evidence to suggest that modified RBCs could be used to suppress the unwanted immune response that often accompanies treatment with protein-based therapies.
He is exploring whether these RBCs could be used to prime the immune system to allow patients to better tolerate treatment with such therapies.
Researchers say they’ve modified red blood cells (RBCs) to carry a range of payloads—from drugs to vaccines to imaging agents.
“We wanted to create high-value red cells that do more than simply carry oxygen,” said study author Harvey Lodish, PhD, of the Whitehead Institute in Cambridge, Massachusetts.
“Here, we’ve laid out the technology to make mouse and human red blood cells in culture that can express what we want and potentially be used for therapeutic or diagnostic purposes.”
Dr Lodish and his colleagues detailed the technology in Proceedings of the National Academy of Sciences.
The team noted that RBCs are an attractive vehicle for a variety of reasons, including their abundance and their long lifespan.
Perhaps most importantly, during RBC production, progenitor cells jettison their nuclei and all DNA therein. Without a nucleus, a mature RBC lacks any genetic material or any signs of earlier genetic manipulation that could result in tumor formation or other adverse effects.
Exploiting this characteristic, Dr Lodish and his colleagues introduced into early stage RBC progenitors genes coding for specific, slightly modified, normal red cell surface proteins.
As the RBCs approach maturity and enucleate, the proteins remain on the cell surface, where they are modified by a protein-labeling technique known as sortagging.
The technique relies on the bacterial enzyme sortase A to establish a strong chemical bond between the surface protein and a substance of choice, be it a small-molecule therapeutic or an antibody capable of binding a toxin. The modifications leave the cells and their surfaces unharmed.
“Because the modified human red blood cells can circulate in the body for up to 4 months, one could envision a scenario in which the cells are used to introduce antibodies that neutralize a toxin,” said Hidde L. Ploegh, PhD, also of the Whitehead Institute. “The result would be long-lasting reserves of antitoxin antibodies.”
The approach has captured the attention of the US military and its Defense Advanced Research Projects Agency, which is supporting the research in the interest of developing treatments or vaccines effective against biological weapons.
Dr Lodish believes the applications are potentially vast and may include RBCs modified to bind and remove bad cholesterol from the bloodstream, carry clot-busting proteins to treat ischemic strokes or deep-vein thrombosis, or deliver anti-inflammatory antibodies to alleviate chronic inflammation.
Dr Ploegh said there is evidence to suggest that modified RBCs could be used to suppress the unwanted immune response that often accompanies treatment with protein-based therapies.
He is exploring whether these RBCs could be used to prime the immune system to allow patients to better tolerate treatment with such therapies.
Researchers say they’ve modified red blood cells (RBCs) to carry a range of payloads—from drugs to vaccines to imaging agents.
“We wanted to create high-value red cells that do more than simply carry oxygen,” said study author Harvey Lodish, PhD, of the Whitehead Institute in Cambridge, Massachusetts.
“Here, we’ve laid out the technology to make mouse and human red blood cells in culture that can express what we want and potentially be used for therapeutic or diagnostic purposes.”
Dr Lodish and his colleagues detailed the technology in Proceedings of the National Academy of Sciences.
The team noted that RBCs are an attractive vehicle for a variety of reasons, including their abundance and their long lifespan.
Perhaps most importantly, during RBC production, progenitor cells jettison their nuclei and all DNA therein. Without a nucleus, a mature RBC lacks any genetic material or any signs of earlier genetic manipulation that could result in tumor formation or other adverse effects.
Exploiting this characteristic, Dr Lodish and his colleagues introduced into early stage RBC progenitors genes coding for specific, slightly modified, normal red cell surface proteins.
As the RBCs approach maturity and enucleate, the proteins remain on the cell surface, where they are modified by a protein-labeling technique known as sortagging.
The technique relies on the bacterial enzyme sortase A to establish a strong chemical bond between the surface protein and a substance of choice, be it a small-molecule therapeutic or an antibody capable of binding a toxin. The modifications leave the cells and their surfaces unharmed.
“Because the modified human red blood cells can circulate in the body for up to 4 months, one could envision a scenario in which the cells are used to introduce antibodies that neutralize a toxin,” said Hidde L. Ploegh, PhD, also of the Whitehead Institute. “The result would be long-lasting reserves of antitoxin antibodies.”
The approach has captured the attention of the US military and its Defense Advanced Research Projects Agency, which is supporting the research in the interest of developing treatments or vaccines effective against biological weapons.
Dr Lodish believes the applications are potentially vast and may include RBCs modified to bind and remove bad cholesterol from the bloodstream, carry clot-busting proteins to treat ischemic strokes or deep-vein thrombosis, or deliver anti-inflammatory antibodies to alleviate chronic inflammation.
Dr Ploegh said there is evidence to suggest that modified RBCs could be used to suppress the unwanted immune response that often accompanies treatment with protein-based therapies.
He is exploring whether these RBCs could be used to prime the immune system to allow patients to better tolerate treatment with such therapies.
Enhancing gene delivery to HSCs
Credit: Chad McNeeley
Scientists say they’ve overcome a major hurdle to developing gene therapies for blood disorders.
They found the drug rapamycin could help them bypass the natural defenses of hematopoietic stem cells (HSCs) and deliver therapeutic doses of disease-fighting genes, without compromising HSC function.
The team believes this discovery could lead to more effective and affordable long-term treatments for disorders such as leukemia and sickle cell anemia.
Bruce Torbett, PhD, of The Scripps Research Institute in La Jolla, California, and his colleagues reported their findings in Blood.
Past research showed that HIV vectors can deliver genes to HSCs. However, when scientists extract HSCs from the body for gene therapy, HIV vectors are usually able to deliver genes to about 30% to 40% of the cells.
For leukemia, leukodystrophy, or genetic diseases where treatment requires a reasonable number of healthy cells derived from stem cells, this number may be too low for therapeutic purposes.
This limitation prompted Dr Torbett and his colleagues to test whether rapamycin could improve delivery of a gene to HSCs. Rapamycin was selected based on its ability to control virus entry and slow cell growth.
The researchers began by isolating stem cells from cord blood samples. They exposed the HSCs to rapamycin and HIV vectors engineered to deliver a gene for a green florescent protein. This fluorescence provided a visual marker that helped the team track gene delivery.
They saw a big difference in both mouse and human stem cells treated with rapamycin, where therapeutic genes were inserted into up to 80% of cells. This property had never been connected to rapamycin before.
The researchers also found that rapamycin can keep HSCs from differentiating as quickly when taken out of the body for gene therapy.
“We wanted to make sure the conditions we will use preserve stem cells, so if we transplant them back into our animal models, they act just like the original stem cells,” Dr Torbett said. “We showed that, in 2 sets of animal models, stem cells remain and produce gene-modified cells.”
The scientists hope these methods could someday be useful in the clinic.
“Our methods could reduce costs and the amount of preparation that goes into modifying blood stem cells using viral vector gene therapy,” said Cathy Wang, also of The Scripps Research Institute. “It would make gene therapy accessible to a lot more patients.”
She said the team’s next steps are to carry out preclinical studies using rapamycin with stem cells in other animal models and then test the method in humans. The researchers are also working to delineate the dual pathways of rapamycin’s mechanism of action in HSCs.
Credit: Chad McNeeley
Scientists say they’ve overcome a major hurdle to developing gene therapies for blood disorders.
They found the drug rapamycin could help them bypass the natural defenses of hematopoietic stem cells (HSCs) and deliver therapeutic doses of disease-fighting genes, without compromising HSC function.
The team believes this discovery could lead to more effective and affordable long-term treatments for disorders such as leukemia and sickle cell anemia.
Bruce Torbett, PhD, of The Scripps Research Institute in La Jolla, California, and his colleagues reported their findings in Blood.
Past research showed that HIV vectors can deliver genes to HSCs. However, when scientists extract HSCs from the body for gene therapy, HIV vectors are usually able to deliver genes to about 30% to 40% of the cells.
For leukemia, leukodystrophy, or genetic diseases where treatment requires a reasonable number of healthy cells derived from stem cells, this number may be too low for therapeutic purposes.
This limitation prompted Dr Torbett and his colleagues to test whether rapamycin could improve delivery of a gene to HSCs. Rapamycin was selected based on its ability to control virus entry and slow cell growth.
The researchers began by isolating stem cells from cord blood samples. They exposed the HSCs to rapamycin and HIV vectors engineered to deliver a gene for a green florescent protein. This fluorescence provided a visual marker that helped the team track gene delivery.
They saw a big difference in both mouse and human stem cells treated with rapamycin, where therapeutic genes were inserted into up to 80% of cells. This property had never been connected to rapamycin before.
The researchers also found that rapamycin can keep HSCs from differentiating as quickly when taken out of the body for gene therapy.
“We wanted to make sure the conditions we will use preserve stem cells, so if we transplant them back into our animal models, they act just like the original stem cells,” Dr Torbett said. “We showed that, in 2 sets of animal models, stem cells remain and produce gene-modified cells.”
The scientists hope these methods could someday be useful in the clinic.
“Our methods could reduce costs and the amount of preparation that goes into modifying blood stem cells using viral vector gene therapy,” said Cathy Wang, also of The Scripps Research Institute. “It would make gene therapy accessible to a lot more patients.”
She said the team’s next steps are to carry out preclinical studies using rapamycin with stem cells in other animal models and then test the method in humans. The researchers are also working to delineate the dual pathways of rapamycin’s mechanism of action in HSCs.
Credit: Chad McNeeley
Scientists say they’ve overcome a major hurdle to developing gene therapies for blood disorders.
They found the drug rapamycin could help them bypass the natural defenses of hematopoietic stem cells (HSCs) and deliver therapeutic doses of disease-fighting genes, without compromising HSC function.
The team believes this discovery could lead to more effective and affordable long-term treatments for disorders such as leukemia and sickle cell anemia.
Bruce Torbett, PhD, of The Scripps Research Institute in La Jolla, California, and his colleagues reported their findings in Blood.
Past research showed that HIV vectors can deliver genes to HSCs. However, when scientists extract HSCs from the body for gene therapy, HIV vectors are usually able to deliver genes to about 30% to 40% of the cells.
For leukemia, leukodystrophy, or genetic diseases where treatment requires a reasonable number of healthy cells derived from stem cells, this number may be too low for therapeutic purposes.
This limitation prompted Dr Torbett and his colleagues to test whether rapamycin could improve delivery of a gene to HSCs. Rapamycin was selected based on its ability to control virus entry and slow cell growth.
The researchers began by isolating stem cells from cord blood samples. They exposed the HSCs to rapamycin and HIV vectors engineered to deliver a gene for a green florescent protein. This fluorescence provided a visual marker that helped the team track gene delivery.
They saw a big difference in both mouse and human stem cells treated with rapamycin, where therapeutic genes were inserted into up to 80% of cells. This property had never been connected to rapamycin before.
The researchers also found that rapamycin can keep HSCs from differentiating as quickly when taken out of the body for gene therapy.
“We wanted to make sure the conditions we will use preserve stem cells, so if we transplant them back into our animal models, they act just like the original stem cells,” Dr Torbett said. “We showed that, in 2 sets of animal models, stem cells remain and produce gene-modified cells.”
The scientists hope these methods could someday be useful in the clinic.
“Our methods could reduce costs and the amount of preparation that goes into modifying blood stem cells using viral vector gene therapy,” said Cathy Wang, also of The Scripps Research Institute. “It would make gene therapy accessible to a lot more patients.”
She said the team’s next steps are to carry out preclinical studies using rapamycin with stem cells in other animal models and then test the method in humans. The researchers are also working to delineate the dual pathways of rapamycin’s mechanism of action in HSCs.
Technology lowers stress among pediatric patients
Credit: Logan Tuttle
A new study suggests videoconferencing with family and friends can lower stress for pediatric patients who are hospitalized for an extended period.
UC Davis Children’s Hospital provides these patients with laptops, webcams, and secure Internet connections for videoconferencing.
And anecdotal accounts have suggested the service, called Family-Link, benefits patients. But researchers wanted more concrete evidence that Family-Link can reduce anxiety.
To that end, James Marcin, MD, and his colleagues studied 367 children who were hospitalized at UC Davis for at least 4 days.
Two hundred and thirty-two patients took advantage of the videoconferencing service, and 135 did not. The researchers used the Parent-Guardian Stress Survey to assess the children’s anxiety levels, both at admission and discharge.
The survey included 4 question groups centered on each child’s behavior and emotions, staff communication, sights and sounds, and the child’s appearance. Parents/guardians were asked whether the child exhibited a variety of behaviors, such as being demanding, frightened, angry, or confused.
The survey also included questions about the impact of monitoring equipment on stress levels and the staff’s ability to communicate important details about the child’s care.
Overall, children who used Family-Link experienced a greater reduction in stress than children who did not use the service.
The researchers were surprised to find this effect was even more pronounced for children who lived closer to the hospital and had shorter hospitalizations. This group experienced a 37% stress reduction when using Family-Link.
“This study shows that we have another tool to help children during their hospital stays,” said Nikki Yang, first author on the study. “The improvement in stress scores shows that Family-Link is really helping many children and might possibly be improving outcomes.”
Yang and her colleagues reported these findings in Pediatrics.
Credit: Logan Tuttle
A new study suggests videoconferencing with family and friends can lower stress for pediatric patients who are hospitalized for an extended period.
UC Davis Children’s Hospital provides these patients with laptops, webcams, and secure Internet connections for videoconferencing.
And anecdotal accounts have suggested the service, called Family-Link, benefits patients. But researchers wanted more concrete evidence that Family-Link can reduce anxiety.
To that end, James Marcin, MD, and his colleagues studied 367 children who were hospitalized at UC Davis for at least 4 days.
Two hundred and thirty-two patients took advantage of the videoconferencing service, and 135 did not. The researchers used the Parent-Guardian Stress Survey to assess the children’s anxiety levels, both at admission and discharge.
The survey included 4 question groups centered on each child’s behavior and emotions, staff communication, sights and sounds, and the child’s appearance. Parents/guardians were asked whether the child exhibited a variety of behaviors, such as being demanding, frightened, angry, or confused.
The survey also included questions about the impact of monitoring equipment on stress levels and the staff’s ability to communicate important details about the child’s care.
Overall, children who used Family-Link experienced a greater reduction in stress than children who did not use the service.
The researchers were surprised to find this effect was even more pronounced for children who lived closer to the hospital and had shorter hospitalizations. This group experienced a 37% stress reduction when using Family-Link.
“This study shows that we have another tool to help children during their hospital stays,” said Nikki Yang, first author on the study. “The improvement in stress scores shows that Family-Link is really helping many children and might possibly be improving outcomes.”
Yang and her colleagues reported these findings in Pediatrics.
Credit: Logan Tuttle
A new study suggests videoconferencing with family and friends can lower stress for pediatric patients who are hospitalized for an extended period.
UC Davis Children’s Hospital provides these patients with laptops, webcams, and secure Internet connections for videoconferencing.
And anecdotal accounts have suggested the service, called Family-Link, benefits patients. But researchers wanted more concrete evidence that Family-Link can reduce anxiety.
To that end, James Marcin, MD, and his colleagues studied 367 children who were hospitalized at UC Davis for at least 4 days.
Two hundred and thirty-two patients took advantage of the videoconferencing service, and 135 did not. The researchers used the Parent-Guardian Stress Survey to assess the children’s anxiety levels, both at admission and discharge.
The survey included 4 question groups centered on each child’s behavior and emotions, staff communication, sights and sounds, and the child’s appearance. Parents/guardians were asked whether the child exhibited a variety of behaviors, such as being demanding, frightened, angry, or confused.
The survey also included questions about the impact of monitoring equipment on stress levels and the staff’s ability to communicate important details about the child’s care.
Overall, children who used Family-Link experienced a greater reduction in stress than children who did not use the service.
The researchers were surprised to find this effect was even more pronounced for children who lived closer to the hospital and had shorter hospitalizations. This group experienced a 37% stress reduction when using Family-Link.
“This study shows that we have another tool to help children during their hospital stays,” said Nikki Yang, first author on the study. “The improvement in stress scores shows that Family-Link is really helping many children and might possibly be improving outcomes.”
Yang and her colleagues reported these findings in Pediatrics.
Ofatumumab falls short in CLL, DLBCL
Credit: Linda Bartlett
The anti-CD20 antibody ofatumumab (Arzerra) has failed to meet the primary endpoint in two phase 3 trials, according to the companies developing the drug.
Ofatumumab failed to improve progression-free survival (PFS) when compared to physicians’ choice in patients with bulky, fludarabine-refractory chronic lymphocytic leukemia (CLL).
Likewise, ofatumumab plus chemotherapy failed to improve PFS when compared to rituximab plus chemotherapy in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).
GlaxoSmithKline (GSK) and Genmab recently announced these headline results but said the full analyses of safety and efficacy data are underway and will be completed in the coming months.
However, based on these early results, the companies said they are unlikely to pursue regulatory filings for ofatumumab in either indication.
CLL trial
In the OMB114242 study, researchers enrolled 122 patients with bulky, fludarabine-refractory CLL. Patients were randomized to receive ofatumumab or physicians’ choice (2:1).
Patients randomized to ofatumumab received an initial dose of 300 mg, followed 1 week later by 2000 mg once weekly for 7 weeks, followed 4 weeks later by 1 infusion of 2000 mg every 4 weeks, for a total treatment duration of 6 to 12 months. Patients in the physicians’ choice arm received a treatment regimen chosen by a physician for up to 6 months.
The primary endpoint was PFS, and secondary objectives were to evaluate response, overall survival, safety, tolerability, and health-related quality of life.
The median PFS, as assessed by an independent review committee, was 5.36 months for ofatumumab and 3.61 months for physicians’ choice (hazard ratio 0.79, P=0.267).
“It was our priority to share this result with the scientific community as soon it became available,” said Rafael Amado, MD, Head of Oncology R&D at GSK. “We will now work to further analyze the data and to better understand the totality of the efficacy and safety findings.”
This study was conducted to meet the requirements from the European Commission for the conditional approval of ofatumumab for the treatment of CLL in patients who are refractory to fludarabine and alemtuzumab. The current indications in the European Union and the United States do not include bulky, fludarabine-refractory CLL patients.
“Although ofatumumab performed broadly in line with previous data, today’s result is disappointing,” said Jan van de Winkel, PhD, Chief Executive Officer of Genmab. “Based on this result, we do not anticipate applying for a label expansion for ofatumumab in this specific refractory CLL population.”
DLBCL trial
The ORCHARRD study included 447 patients who were refractory to, or had relapsed following, first-line treatment with rituximab in combination with a chemotherapy regimen containing anthracycline or anthracenedione. Patients were also eligible for autologous stem cell transplant.
Patients were randomized 1:1 to receive 3 cycles of either ofatumumab or rituximab in combination with DHAP (dexamethasone, cytarabine, and cisplatin) salvage chemotherapy. After the third treatment cycle, patients who obtained a complete or partial response received high-dose chemotherapy followed by transplant.
The primary endpoint was PFS. But GSK and Genmab reported no statistically significant difference in PFS between the treatment arms.
There were no differences in adverse events (AEs) leading to treatment discontinuation, grade 3 or higher AEs, or severe AEs between the treatment arms. However, there were more dose interruptions and delays due to infusion reactions and increased serum creatinine in the ofatumumab-plus-chemotherapy arm, which require further analysis.
“We plan to submit detailed data from the ofatumumab ORCHARRD study in DLBCL for presentation at a medical conference later this year, which we hope will provide further clarity on today’s headline results,” Dr van de Winkel said. “Based on [these early] results, we are unlikely to move forward with a regulatory filing.”
Credit: Linda Bartlett
The anti-CD20 antibody ofatumumab (Arzerra) has failed to meet the primary endpoint in two phase 3 trials, according to the companies developing the drug.
Ofatumumab failed to improve progression-free survival (PFS) when compared to physicians’ choice in patients with bulky, fludarabine-refractory chronic lymphocytic leukemia (CLL).
Likewise, ofatumumab plus chemotherapy failed to improve PFS when compared to rituximab plus chemotherapy in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).
GlaxoSmithKline (GSK) and Genmab recently announced these headline results but said the full analyses of safety and efficacy data are underway and will be completed in the coming months.
However, based on these early results, the companies said they are unlikely to pursue regulatory filings for ofatumumab in either indication.
CLL trial
In the OMB114242 study, researchers enrolled 122 patients with bulky, fludarabine-refractory CLL. Patients were randomized to receive ofatumumab or physicians’ choice (2:1).
Patients randomized to ofatumumab received an initial dose of 300 mg, followed 1 week later by 2000 mg once weekly for 7 weeks, followed 4 weeks later by 1 infusion of 2000 mg every 4 weeks, for a total treatment duration of 6 to 12 months. Patients in the physicians’ choice arm received a treatment regimen chosen by a physician for up to 6 months.
The primary endpoint was PFS, and secondary objectives were to evaluate response, overall survival, safety, tolerability, and health-related quality of life.
The median PFS, as assessed by an independent review committee, was 5.36 months for ofatumumab and 3.61 months for physicians’ choice (hazard ratio 0.79, P=0.267).
“It was our priority to share this result with the scientific community as soon it became available,” said Rafael Amado, MD, Head of Oncology R&D at GSK. “We will now work to further analyze the data and to better understand the totality of the efficacy and safety findings.”
This study was conducted to meet the requirements from the European Commission for the conditional approval of ofatumumab for the treatment of CLL in patients who are refractory to fludarabine and alemtuzumab. The current indications in the European Union and the United States do not include bulky, fludarabine-refractory CLL patients.
“Although ofatumumab performed broadly in line with previous data, today’s result is disappointing,” said Jan van de Winkel, PhD, Chief Executive Officer of Genmab. “Based on this result, we do not anticipate applying for a label expansion for ofatumumab in this specific refractory CLL population.”
DLBCL trial
The ORCHARRD study included 447 patients who were refractory to, or had relapsed following, first-line treatment with rituximab in combination with a chemotherapy regimen containing anthracycline or anthracenedione. Patients were also eligible for autologous stem cell transplant.
Patients were randomized 1:1 to receive 3 cycles of either ofatumumab or rituximab in combination with DHAP (dexamethasone, cytarabine, and cisplatin) salvage chemotherapy. After the third treatment cycle, patients who obtained a complete or partial response received high-dose chemotherapy followed by transplant.
The primary endpoint was PFS. But GSK and Genmab reported no statistically significant difference in PFS between the treatment arms.
There were no differences in adverse events (AEs) leading to treatment discontinuation, grade 3 or higher AEs, or severe AEs between the treatment arms. However, there were more dose interruptions and delays due to infusion reactions and increased serum creatinine in the ofatumumab-plus-chemotherapy arm, which require further analysis.
“We plan to submit detailed data from the ofatumumab ORCHARRD study in DLBCL for presentation at a medical conference later this year, which we hope will provide further clarity on today’s headline results,” Dr van de Winkel said. “Based on [these early] results, we are unlikely to move forward with a regulatory filing.”
Credit: Linda Bartlett
The anti-CD20 antibody ofatumumab (Arzerra) has failed to meet the primary endpoint in two phase 3 trials, according to the companies developing the drug.
Ofatumumab failed to improve progression-free survival (PFS) when compared to physicians’ choice in patients with bulky, fludarabine-refractory chronic lymphocytic leukemia (CLL).
Likewise, ofatumumab plus chemotherapy failed to improve PFS when compared to rituximab plus chemotherapy in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).
GlaxoSmithKline (GSK) and Genmab recently announced these headline results but said the full analyses of safety and efficacy data are underway and will be completed in the coming months.
However, based on these early results, the companies said they are unlikely to pursue regulatory filings for ofatumumab in either indication.
CLL trial
In the OMB114242 study, researchers enrolled 122 patients with bulky, fludarabine-refractory CLL. Patients were randomized to receive ofatumumab or physicians’ choice (2:1).
Patients randomized to ofatumumab received an initial dose of 300 mg, followed 1 week later by 2000 mg once weekly for 7 weeks, followed 4 weeks later by 1 infusion of 2000 mg every 4 weeks, for a total treatment duration of 6 to 12 months. Patients in the physicians’ choice arm received a treatment regimen chosen by a physician for up to 6 months.
The primary endpoint was PFS, and secondary objectives were to evaluate response, overall survival, safety, tolerability, and health-related quality of life.
The median PFS, as assessed by an independent review committee, was 5.36 months for ofatumumab and 3.61 months for physicians’ choice (hazard ratio 0.79, P=0.267).
“It was our priority to share this result with the scientific community as soon it became available,” said Rafael Amado, MD, Head of Oncology R&D at GSK. “We will now work to further analyze the data and to better understand the totality of the efficacy and safety findings.”
This study was conducted to meet the requirements from the European Commission for the conditional approval of ofatumumab for the treatment of CLL in patients who are refractory to fludarabine and alemtuzumab. The current indications in the European Union and the United States do not include bulky, fludarabine-refractory CLL patients.
“Although ofatumumab performed broadly in line with previous data, today’s result is disappointing,” said Jan van de Winkel, PhD, Chief Executive Officer of Genmab. “Based on this result, we do not anticipate applying for a label expansion for ofatumumab in this specific refractory CLL population.”
DLBCL trial
The ORCHARRD study included 447 patients who were refractory to, or had relapsed following, first-line treatment with rituximab in combination with a chemotherapy regimen containing anthracycline or anthracenedione. Patients were also eligible for autologous stem cell transplant.
Patients were randomized 1:1 to receive 3 cycles of either ofatumumab or rituximab in combination with DHAP (dexamethasone, cytarabine, and cisplatin) salvage chemotherapy. After the third treatment cycle, patients who obtained a complete or partial response received high-dose chemotherapy followed by transplant.
The primary endpoint was PFS. But GSK and Genmab reported no statistically significant difference in PFS between the treatment arms.
There were no differences in adverse events (AEs) leading to treatment discontinuation, grade 3 or higher AEs, or severe AEs between the treatment arms. However, there were more dose interruptions and delays due to infusion reactions and increased serum creatinine in the ofatumumab-plus-chemotherapy arm, which require further analysis.
“We plan to submit detailed data from the ofatumumab ORCHARRD study in DLBCL for presentation at a medical conference later this year, which we hope will provide further clarity on today’s headline results,” Dr van de Winkel said. “Based on [these early] results, we are unlikely to move forward with a regulatory filing.”