HT Staff

Micrograph showing

multiple myeloma

Combining a calcineurin inhibitor and a histone deacetylase (HDAC) inhibitor could improve the treatment of multiple myeloma (MM), according to researchers.

The team found that MM cells express high levels of the protein phosphatase PPP3CA, a subunit of calcineurin.

And combining the calcineurin inhibitor FK506 with the HDAC inhibitor panobinostat suppressed MM cell growth in vitro and decreased tumor growth in mouse models of MM.

Yoichi Imai, MD, PhD, of Tokyo Women’s Medical University in Japan, and colleagues conducted this research and reported the results in JCI Insight.

First, the team observed increased PPP3CA expression in MM cell lines and MM cells isolated from patients with advanced disease.

Then, the researchers found that panobinostat reduced PPP3CA expression in MM cell lines. And further investigation revealed that the drug induced degradation of PPP3CA through HSP90 inhibition.

When the team knocked down PPP3CA in MM cells, they observed a reduction in cell growth. And when they overexpressed PPP3CA, they observed enhanced MM cell growth.

The researchers noted that FK506 inhibits the association between PPP3CA and calcineurin B. Unfortunately, FK506 alone did not suppress the growth of MM cells in vitro.

However, when FK506 was given with panobinostat or the HDAC inhibitor ACY-1215, the researchers observed a greater reduction in MM cell growth than with either HDAC inhibitor alone.

Panobinostat and FK506 reduced the growth of MM cells that were t(4;14)-positive (KMS-11, KMS-18, and KMS-26) and t(4;14)-negative (U266 and KMS-12PE) more effectively than panobinostat alone.

In mice with MM, those treated with FK506 alone had tumor sizes similar to control mice. However, mice treated with panobinostat saw a decrease in tumor size. And this effect was enhanced by the addition of FK506.

The researchers observed reduced PPP3CA expression, enhanced histone H3 acetylation, and cleavage of caspase-3 in samples from panobinostat-treated mice. And FK506 augmented panobinostat-induced apoptosis.

The team said these results suggest that FK506 enhances the antimyeloma effect of panobinostat through PPP3CA reduction, which supports the importance of calcineurin in the pathogenesis of MM.

Micrograph showing

multiple myeloma

Combining a calcineurin inhibitor and a histone deacetylase (HDAC) inhibitor could improve the treatment of multiple myeloma (MM), according to researchers.

The team found that MM cells express high levels of the protein phosphatase PPP3CA, a subunit of calcineurin.

And combining the calcineurin inhibitor FK506 with the HDAC inhibitor panobinostat suppressed MM cell growth in vitro and decreased tumor growth in mouse models of MM.

Yoichi Imai, MD, PhD, of Tokyo Women’s Medical University in Japan, and colleagues conducted this research and reported the results in JCI Insight.

First, the team observed increased PPP3CA expression in MM cell lines and MM cells isolated from patients with advanced disease.

Then, the researchers found that panobinostat reduced PPP3CA expression in MM cell lines. And further investigation revealed that the drug induced degradation of PPP3CA through HSP90 inhibition.

When the team knocked down PPP3CA in MM cells, they observed a reduction in cell growth. And when they overexpressed PPP3CA, they observed enhanced MM cell growth.

The researchers noted that FK506 inhibits the association between PPP3CA and calcineurin B. Unfortunately, FK506 alone did not suppress the growth of MM cells in vitro.

However, when FK506 was given with panobinostat or the HDAC inhibitor ACY-1215, the researchers observed a greater reduction in MM cell growth than with either HDAC inhibitor alone.

Panobinostat and FK506 reduced the growth of MM cells that were t(4;14)-positive (KMS-11, KMS-18, and KMS-26) and t(4;14)-negative (U266 and KMS-12PE) more effectively than panobinostat alone.

In mice with MM, those treated with FK506 alone had tumor sizes similar to control mice. However, mice treated with panobinostat saw a decrease in tumor size. And this effect was enhanced by the addition of FK506.

The researchers observed reduced PPP3CA expression, enhanced histone H3 acetylation, and cleavage of caspase-3 in samples from panobinostat-treated mice. And FK506 augmented panobinostat-induced apoptosis.

The team said these results suggest that FK506 enhances the antimyeloma effect of panobinostat through PPP3CA reduction, which supports the importance of calcineurin in the pathogenesis of MM.

Micrograph showing

multiple myeloma

Combining a calcineurin inhibitor and a histone deacetylase (HDAC) inhibitor could improve the treatment of multiple myeloma (MM), according to researchers.

The team found that MM cells express high levels of the protein phosphatase PPP3CA, a subunit of calcineurin.

And combining the calcineurin inhibitor FK506 with the HDAC inhibitor panobinostat suppressed MM cell growth in vitro and decreased tumor growth in mouse models of MM.

Yoichi Imai, MD, PhD, of Tokyo Women’s Medical University in Japan, and colleagues conducted this research and reported the results in JCI Insight.

First, the team observed increased PPP3CA expression in MM cell lines and MM cells isolated from patients with advanced disease.

Then, the researchers found that panobinostat reduced PPP3CA expression in MM cell lines. And further investigation revealed that the drug induced degradation of PPP3CA through HSP90 inhibition.

When the team knocked down PPP3CA in MM cells, they observed a reduction in cell growth. And when they overexpressed PPP3CA, they observed enhanced MM cell growth.

The researchers noted that FK506 inhibits the association between PPP3CA and calcineurin B. Unfortunately, FK506 alone did not suppress the growth of MM cells in vitro.

However, when FK506 was given with panobinostat or the HDAC inhibitor ACY-1215, the researchers observed a greater reduction in MM cell growth than with either HDAC inhibitor alone.

Panobinostat and FK506 reduced the growth of MM cells that were t(4;14)-positive (KMS-11, KMS-18, and KMS-26) and t(4;14)-negative (U266 and KMS-12PE) more effectively than panobinostat alone.

In mice with MM, those treated with FK506 alone had tumor sizes similar to control mice. However, mice treated with panobinostat saw a decrease in tumor size. And this effect was enhanced by the addition of FK506.

The researchers observed reduced PPP3CA expression, enhanced histone H3 acetylation, and cleavage of caspase-3 in samples from panobinostat-treated mice. And FK506 augmented panobinostat-induced apoptosis.

The team said these results suggest that FK506 enhances the antimyeloma effect of panobinostat through PPP3CA reduction, which supports the importance of calcineurin in the pathogenesis of MM.

Red blood cells

The investigational therapy roxadustat can effectively treat anemia in patients with chronic kidney disease (CKD) who are not on dialysis, according to a phase 2 study.

Roxadustat increased and maintained hemoglobin levels and decreased hepcidin levels in these patients, who had not received previous treatment with

erythropoiesis-stimulating agents and were treated with roxadustat regardless of their baseline iron repletion status.

In addition, researchers said there were no serious adverse events related to roxadustat.

Robert Provenzano, MD, of St. John Hospital and Medical Center in Detroit, Michigan, and his colleagues reported these results in the Clinical Journal of the American Society of Nephrology.

The study was sponsored by FibroGen, Inc., the company developing roxadustat in collaboration with AstraZeneca.

Roxadustat (FG-4592) is an oral, small-molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase activity. HIF is a transcription factor that induces the natural physiological response to conditions of low oxygen, “turning on” erythropoiesis and other protective pathways.

In this randomized, phase 2 study of roxadustat, 145 patients with anemia (hemoglobin < 10.5 g/dL at baseline) and non-dialysis CKD were randomized into 1 of 6 cohorts of approximately 24 patients.

The cohorts had varying roxadustat starting doses (tiered weight and fixed amounts) and frequencies (2 and 3 times weekly), followed by hemoglobin maintenance with roxadustat 1 to 3 times weekly. The treatment duration was 16 or 24 weeks.

Results

Of the 143 patients evaluable for efficacy, 92% achieved a hemoglobin response—defined as a hemoglobin increase of > 1.0 g/dL from baseline and a hemoglobin of > 11.0 g/dL by the end of treatment (up to 16 weeks of treatment in 47 patients, and up to 24 weeks of treatment in 96 patients).

Generally, patients in all cohorts who received higher starting doses of roxadustat demonstrated earlier achievement of the hemoglobin response.

Roxadustat increased hemoglobin independently of the patients’ baseline iron repletion and inflammatory status, as measured by baseline C–reactive protein levels. Intravenous iron was not permitted throughout the study period, and 52.4% of patients were iron-replete at baseline.

Over 16 weeks of treatment, roxadustat decreased hepcidin levels by 16.9% (P=0.004), maintained reticulocyte hemoglobin content, and increased hemoglobin by a mean (±SD) of 1.83 (±0.09) g/dL (P<0.001).

After 8 weeks of roxadustat, total cholesterol levels decreased by a mean (±SD) of 26 (±30) mg/dL (P<0.001).

“In this study, anemia correction was achieved under a range of treatment options, including tiered-weight as well as fixed-starting-dose strategies,” Dr Provenzano said. “Correction of anemia and maintenance of hemoglobin response were seen at different dose frequencies—2 or 3 times weekly for achievement of hemoglobin response; 1, 2, or 3 times weekly for maintenance.”

“Secondary analyses showing decreases in hepcidin and increased iron utilization, as well as reductions in total cholesterol levels, suggest roxadustat consistently affects these parameters.”

Treatment-emergent adverse events were reported in 80% of all patients.

The most common events that occurred in more than 5% of patients were nausea (9.7%), diarrhea (8.3%), constipation (6.2%), vomiting (5.5%), peripheral edema (12.4%), urinary tract infection (9.7%), nasopharyngitis (9.0%), sinusitis (5.5%), dizziness (6.2%), headache (5.5%), and hypertension (7.6%).

Red blood cells

The investigational therapy roxadustat can effectively treat anemia in patients with chronic kidney disease (CKD) who are not on dialysis, according to a phase 2 study.

Roxadustat increased and maintained hemoglobin levels and decreased hepcidin levels in these patients, who had not received previous treatment with

erythropoiesis-stimulating agents and were treated with roxadustat regardless of their baseline iron repletion status.

In addition, researchers said there were no serious adverse events related to roxadustat.

Robert Provenzano, MD, of St. John Hospital and Medical Center in Detroit, Michigan, and his colleagues reported these results in the Clinical Journal of the American Society of Nephrology.

The study was sponsored by FibroGen, Inc., the company developing roxadustat in collaboration with AstraZeneca.

Roxadustat (FG-4592) is an oral, small-molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase activity. HIF is a transcription factor that induces the natural physiological response to conditions of low oxygen, “turning on” erythropoiesis and other protective pathways.

In this randomized, phase 2 study of roxadustat, 145 patients with anemia (hemoglobin < 10.5 g/dL at baseline) and non-dialysis CKD were randomized into 1 of 6 cohorts of approximately 24 patients.

The cohorts had varying roxadustat starting doses (tiered weight and fixed amounts) and frequencies (2 and 3 times weekly), followed by hemoglobin maintenance with roxadustat 1 to 3 times weekly. The treatment duration was 16 or 24 weeks.

Results

Of the 143 patients evaluable for efficacy, 92% achieved a hemoglobin response—defined as a hemoglobin increase of > 1.0 g/dL from baseline and a hemoglobin of > 11.0 g/dL by the end of treatment (up to 16 weeks of treatment in 47 patients, and up to 24 weeks of treatment in 96 patients).

Generally, patients in all cohorts who received higher starting doses of roxadustat demonstrated earlier achievement of the hemoglobin response.

Roxadustat increased hemoglobin independently of the patients’ baseline iron repletion and inflammatory status, as measured by baseline C–reactive protein levels. Intravenous iron was not permitted throughout the study period, and 52.4% of patients were iron-replete at baseline.

Over 16 weeks of treatment, roxadustat decreased hepcidin levels by 16.9% (P=0.004), maintained reticulocyte hemoglobin content, and increased hemoglobin by a mean (±SD) of 1.83 (±0.09) g/dL (P<0.001).

After 8 weeks of roxadustat, total cholesterol levels decreased by a mean (±SD) of 26 (±30) mg/dL (P<0.001).

“In this study, anemia correction was achieved under a range of treatment options, including tiered-weight as well as fixed-starting-dose strategies,” Dr Provenzano said. “Correction of anemia and maintenance of hemoglobin response were seen at different dose frequencies—2 or 3 times weekly for achievement of hemoglobin response; 1, 2, or 3 times weekly for maintenance.”

“Secondary analyses showing decreases in hepcidin and increased iron utilization, as well as reductions in total cholesterol levels, suggest roxadustat consistently affects these parameters.”

Treatment-emergent adverse events were reported in 80% of all patients.

The most common events that occurred in more than 5% of patients were nausea (9.7%), diarrhea (8.3%), constipation (6.2%), vomiting (5.5%), peripheral edema (12.4%), urinary tract infection (9.7%), nasopharyngitis (9.0%), sinusitis (5.5%), dizziness (6.2%), headache (5.5%), and hypertension (7.6%).

Red blood cells

The investigational therapy roxadustat can effectively treat anemia in patients with chronic kidney disease (CKD) who are not on dialysis, according to a phase 2 study.

Roxadustat increased and maintained hemoglobin levels and decreased hepcidin levels in these patients, who had not received previous treatment with

erythropoiesis-stimulating agents and were treated with roxadustat regardless of their baseline iron repletion status.

In addition, researchers said there were no serious adverse events related to roxadustat.

Robert Provenzano, MD, of St. John Hospital and Medical Center in Detroit, Michigan, and his colleagues reported these results in the Clinical Journal of the American Society of Nephrology.

The study was sponsored by FibroGen, Inc., the company developing roxadustat in collaboration with AstraZeneca.

Roxadustat (FG-4592) is an oral, small-molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase activity. HIF is a transcription factor that induces the natural physiological response to conditions of low oxygen, “turning on” erythropoiesis and other protective pathways.

In this randomized, phase 2 study of roxadustat, 145 patients with anemia (hemoglobin < 10.5 g/dL at baseline) and non-dialysis CKD were randomized into 1 of 6 cohorts of approximately 24 patients.

The cohorts had varying roxadustat starting doses (tiered weight and fixed amounts) and frequencies (2 and 3 times weekly), followed by hemoglobin maintenance with roxadustat 1 to 3 times weekly. The treatment duration was 16 or 24 weeks.

Results

Of the 143 patients evaluable for efficacy, 92% achieved a hemoglobin response—defined as a hemoglobin increase of > 1.0 g/dL from baseline and a hemoglobin of > 11.0 g/dL by the end of treatment (up to 16 weeks of treatment in 47 patients, and up to 24 weeks of treatment in 96 patients).

Generally, patients in all cohorts who received higher starting doses of roxadustat demonstrated earlier achievement of the hemoglobin response.

Roxadustat increased hemoglobin independently of the patients’ baseline iron repletion and inflammatory status, as measured by baseline C–reactive protein levels. Intravenous iron was not permitted throughout the study period, and 52.4% of patients were iron-replete at baseline.

Over 16 weeks of treatment, roxadustat decreased hepcidin levels by 16.9% (P=0.004), maintained reticulocyte hemoglobin content, and increased hemoglobin by a mean (±SD) of 1.83 (±0.09) g/dL (P<0.001).

After 8 weeks of roxadustat, total cholesterol levels decreased by a mean (±SD) of 26 (±30) mg/dL (P<0.001).

“In this study, anemia correction was achieved under a range of treatment options, including tiered-weight as well as fixed-starting-dose strategies,” Dr Provenzano said. “Correction of anemia and maintenance of hemoglobin response were seen at different dose frequencies—2 or 3 times weekly for achievement of hemoglobin response; 1, 2, or 3 times weekly for maintenance.”

“Secondary analyses showing decreases in hepcidin and increased iron utilization, as well as reductions in total cholesterol levels, suggest roxadustat consistently affects these parameters.”

Treatment-emergent adverse events were reported in 80% of all patients.

The most common events that occurred in more than 5% of patients were nausea (9.7%), diarrhea (8.3%), constipation (6.2%), vomiting (5.5%), peripheral edema (12.4%), urinary tract infection (9.7%), nasopharyngitis (9.0%), sinusitis (5.5%), dizziness (6.2%), headache (5.5%), and hypertension (7.6%).

Researcher in the lab

Photo by Daniel Sone

The National Institutes of Health (NIH) has suspended production in 2 of its facilities—a National Cancer Institute (NCI) laboratory engaged in the production of cell therapies and a National Institute of Mental Health facility producing positron emission tomography (PET) materials.

Last year, an inspection by the US Food and Drug Administration revealed problems with facilities, equipment, procedures, and training in the NIH Clinical Center Pharmaceutical Development Section (PDS), which is responsible for managing investigational drugs.

So the NIH closed the sterile production unit of the PDS and hired 2 companies specializing in quality assurance for manufacturing and compounding—Working Buildings and Clinical IQ—to evaluate all NIH facilities producing sterile or infused products for administration to research participants.

This review is still underway, and preliminary findings have identified facilities not in compliance with quality and safety standards, and not suitable for the production of sterile or infused products.

As a result, the NIH suspended production in the aforementioned facilities manufacturing cell therapy and PET materials.

The NIH said there is no evidence that any patients have been harmed, but a rigorous clinical review will be conducted. And the NIH will not enroll new patients in affected trials until the issues are resolved.

The NCI facility produces cell therapies in cooperation with Kite Pharma, Inc. The company and the NCI are advancing multiple clinical trials under Cooperative Research and Development Agreements for the treatment of hematologic malignancies and solid tumors.

Patients currently enrolled in ongoing NCI trials of cell therapy will continue to receive treatment, but no new patients will be enrolled until the review is complete.

And Kite Pharma said its 4 trials of the chimeric antigen receptor T-cell therapy KTE-C19 will continue. This includes:

ZUMA-1—KTE-C19 in patients with refractory, aggressive non-Hodgkin lymphoma

ZUMA-2—KTE-C19 in patients with relapsed/refractory mantle cell lymphoma

ZUMA-3—KTE-C19 in adults with relapsed/refractory B-precursor acute lymphoblastic leukemia

ZUMA-4—KTE-C19 in pediatric and adolescent patients with relapsed/refractory B-precursor acute lymphoblastic leukemia.

The company stressed that the review of the NCI’s manufacturing facilities is not related to KTE-C19 or Kite’s manufacturing capabilities.

Researcher in the lab

Photo by Daniel Sone

The National Institutes of Health (NIH) has suspended production in 2 of its facilities—a National Cancer Institute (NCI) laboratory engaged in the production of cell therapies and a National Institute of Mental Health facility producing positron emission tomography (PET) materials.

Last year, an inspection by the US Food and Drug Administration revealed problems with facilities, equipment, procedures, and training in the NIH Clinical Center Pharmaceutical Development Section (PDS), which is responsible for managing investigational drugs.

So the NIH closed the sterile production unit of the PDS and hired 2 companies specializing in quality assurance for manufacturing and compounding—Working Buildings and Clinical IQ—to evaluate all NIH facilities producing sterile or infused products for administration to research participants.

This review is still underway, and preliminary findings have identified facilities not in compliance with quality and safety standards, and not suitable for the production of sterile or infused products.

As a result, the NIH suspended production in the aforementioned facilities manufacturing cell therapy and PET materials.

The NIH said there is no evidence that any patients have been harmed, but a rigorous clinical review will be conducted. And the NIH will not enroll new patients in affected trials until the issues are resolved.

The NCI facility produces cell therapies in cooperation with Kite Pharma, Inc. The company and the NCI are advancing multiple clinical trials under Cooperative Research and Development Agreements for the treatment of hematologic malignancies and solid tumors.

Patients currently enrolled in ongoing NCI trials of cell therapy will continue to receive treatment, but no new patients will be enrolled until the review is complete.

And Kite Pharma said its 4 trials of the chimeric antigen receptor T-cell therapy KTE-C19 will continue. This includes:

ZUMA-1—KTE-C19 in patients with refractory, aggressive non-Hodgkin lymphoma

ZUMA-2—KTE-C19 in patients with relapsed/refractory mantle cell lymphoma

ZUMA-3—KTE-C19 in adults with relapsed/refractory B-precursor acute lymphoblastic leukemia

ZUMA-4—KTE-C19 in pediatric and adolescent patients with relapsed/refractory B-precursor acute lymphoblastic leukemia.

The company stressed that the review of the NCI’s manufacturing facilities is not related to KTE-C19 or Kite’s manufacturing capabilities.

Researcher in the lab

Photo by Daniel Sone

The National Institutes of Health (NIH) has suspended production in 2 of its facilities—a National Cancer Institute (NCI) laboratory engaged in the production of cell therapies and a National Institute of Mental Health facility producing positron emission tomography (PET) materials.

Last year, an inspection by the US Food and Drug Administration revealed problems with facilities, equipment, procedures, and training in the NIH Clinical Center Pharmaceutical Development Section (PDS), which is responsible for managing investigational drugs.

So the NIH closed the sterile production unit of the PDS and hired 2 companies specializing in quality assurance for manufacturing and compounding—Working Buildings and Clinical IQ—to evaluate all NIH facilities producing sterile or infused products for administration to research participants.

This review is still underway, and preliminary findings have identified facilities not in compliance with quality and safety standards, and not suitable for the production of sterile or infused products.

As a result, the NIH suspended production in the aforementioned facilities manufacturing cell therapy and PET materials.

The NIH said there is no evidence that any patients have been harmed, but a rigorous clinical review will be conducted. And the NIH will not enroll new patients in affected trials until the issues are resolved.

The NCI facility produces cell therapies in cooperation with Kite Pharma, Inc. The company and the NCI are advancing multiple clinical trials under Cooperative Research and Development Agreements for the treatment of hematologic malignancies and solid tumors.

Patients currently enrolled in ongoing NCI trials of cell therapy will continue to receive treatment, but no new patients will be enrolled until the review is complete.

And Kite Pharma said its 4 trials of the chimeric antigen receptor T-cell therapy KTE-C19 will continue. This includes:

ZUMA-1—KTE-C19 in patients with refractory, aggressive non-Hodgkin lymphoma

ZUMA-2—KTE-C19 in patients with relapsed/refractory mantle cell lymphoma

ZUMA-3—KTE-C19 in adults with relapsed/refractory B-precursor acute lymphoblastic leukemia

ZUMA-4—KTE-C19 in pediatric and adolescent patients with relapsed/refractory B-precursor acute lymphoblastic leukemia.

The company stressed that the review of the NCI’s manufacturing facilities is not related to KTE-C19 or Kite’s manufacturing capabilities.

Blood sample collection

Photo by Juan D. Alfonso

The US Department of Health and Human Services (HHS) is providing financial support for a clinical trial of the cobas® Zika test, which is designed to screen blood donations for Zika virus.

The US Food and Drug Administration (FDA) recently authorized the use of this test, under an investigational new drug application protocol, for screening donated blood in areas with active, mosquito-borne transmission of Zika virus.

This means the cobas® Zika test can be used by US blood screening laboratories, but the laboratories will need to be enrolled in and contracted into the clinical trial as specified and agreed with the FDA’s Center for Biologics Evaluation and Research.

Now, the HHS has announced that the Biomedical Advanced Research and Development Authority (BARDA) is supporting the trial, which will evaluate the sensitivity and specificity of the test in its actual use.

The trial is necessary for Roche, the company developing the cobas® Zika test, to apply for FDA approval for commercial marketing.

“BARDA staff has worked closely with our partners at FDA and the Office of the Assistant Secretary of Health to ensure the continuity and safety of the US blood supply,” said Richard Hatchett, BARDA’s acting director.

“Today’s award to Roche is an important step towards securing the safety of the blood supply in Puerto Rico and in the rest of the United States.”

Under the 1-year, $354,500 contract, Roche will study blood samples to confirm whether the test accurately and reliably detects and identifies Zika virus, even when present in very low concentrations in donor blood.

Blood sample collection

Photo by Juan D. Alfonso

The US Department of Health and Human Services (HHS) is providing financial support for a clinical trial of the cobas® Zika test, which is designed to screen blood donations for Zika virus.

The US Food and Drug Administration (FDA) recently authorized the use of this test, under an investigational new drug application protocol, for screening donated blood in areas with active, mosquito-borne transmission of Zika virus.

This means the cobas® Zika test can be used by US blood screening laboratories, but the laboratories will need to be enrolled in and contracted into the clinical trial as specified and agreed with the FDA’s Center for Biologics Evaluation and Research.

Now, the HHS has announced that the Biomedical Advanced Research and Development Authority (BARDA) is supporting the trial, which will evaluate the sensitivity and specificity of the test in its actual use.

The trial is necessary for Roche, the company developing the cobas® Zika test, to apply for FDA approval for commercial marketing.

“BARDA staff has worked closely with our partners at FDA and the Office of the Assistant Secretary of Health to ensure the continuity and safety of the US blood supply,” said Richard Hatchett, BARDA’s acting director.

“Today’s award to Roche is an important step towards securing the safety of the blood supply in Puerto Rico and in the rest of the United States.”

Under the 1-year, $354,500 contract, Roche will study blood samples to confirm whether the test accurately and reliably detects and identifies Zika virus, even when present in very low concentrations in donor blood.

Blood sample collection

Photo by Juan D. Alfonso

The US Department of Health and Human Services (HHS) is providing financial support for a clinical trial of the cobas® Zika test, which is designed to screen blood donations for Zika virus.

The US Food and Drug Administration (FDA) recently authorized the use of this test, under an investigational new drug application protocol, for screening donated blood in areas with active, mosquito-borne transmission of Zika virus.

This means the cobas® Zika test can be used by US blood screening laboratories, but the laboratories will need to be enrolled in and contracted into the clinical trial as specified and agreed with the FDA’s Center for Biologics Evaluation and Research.

Now, the HHS has announced that the Biomedical Advanced Research and Development Authority (BARDA) is supporting the trial, which will evaluate the sensitivity and specificity of the test in its actual use.

The trial is necessary for Roche, the company developing the cobas® Zika test, to apply for FDA approval for commercial marketing.

“BARDA staff has worked closely with our partners at FDA and the Office of the Assistant Secretary of Health to ensure the continuity and safety of the US blood supply,” said Richard Hatchett, BARDA’s acting director.

“Today’s award to Roche is an important step towards securing the safety of the blood supply in Puerto Rico and in the rest of the United States.”

Under the 1-year, $354,500 contract, Roche will study blood samples to confirm whether the test accurately and reliably detects and identifies Zika virus, even when present in very low concentrations in donor blood.

Blood in bags and vials

Photo by Daniel Gay

A pathogen-reduction system can safely minimize the risk of malaria transmitted via blood transfusion, according to a randomized trial.

The Mirasol pathogen-reduction technology system uses ultraviolet light energy and riboflavin to reduce the pathogen load and inactivate white blood cells in blood products.

In the current study, the system significantly reduced the transmission of malaria-causing Plasmodium parasites in patients receiving whole blood.

“This is the first study to look at the potential of pathogen-reduction technology in a real-world treatment setting and finds that, although the risk of malaria transmission is not completely eliminated, the risk is severely reduced,” said Jean-Pierre Allain, MD, of the University of Cambridge in the UK.

Dr Allain and his colleagues described this research in The Lancet. The work was funded by TerumoBCT Inc., the company developing the Mirasol system.

The trial included 223 adult patients from the Komfo Anokye Teaching Hospital in Kumasi, Ghana, who required a blood transfusion because of severe anemia or hemorrhage and were expected to remain in the hospital for at least 3 consecutive days after the initial transfusion.

The patients were randomized via computer to receive a transfusion with pathogen-reduced whole blood (treated) or whole blood that was prepared and transfused by standard local practice (untreated). Patients, healthcare providers, and data collectors were blinded to the treatment allocation.

The researchers analyzed blood samples for all of the recipients on the day of the transfusion and 1, 3, 7, and 28 days later. By studying the sequences of Plasmodium genes present in the blood, the team was able to tell whether the patients were likely to be carrying the donor parasite after the transfusion.

In all, 214 patients completed the protocol as planned—107 who received treated blood and 107 who received untreated blood.

A total of 65 patients were not previously carrying a Plasmodium parasite but received parasitemic blood. Twenty-eight of these patients received treated blood, and 37 received untreated blood.

The incidence of transfusion-transmitted malaria was significantly lower for the group that received the treated blood. Twenty-two percent of patients (8/37) who received untreated blood later tested positive for the malaria parasite, compared with 4% (1/28) of patients who received treated blood (P=0.039).

The researchers noted that coagulation parameters, platelet counts, and hemostatic status were similar whether patients received treated or untreated blood.

The Mirasol system did not appear to affect the coagulation properties of the blood, and patients who received the treated blood had slightly fewer allergic reactions than those who received the untreated blood (5% vs 8%).

The percentage of patients reporting at least 1 treatment-emergent adverse event (TEAE) was similar between the groups—43% in the treated-blood group and 39% in the untreated-blood group.

Likewise, there were no significant differences between the groups in the incidence of serious TEAEs (12% vs 8%), life-threatening TEAEs (3% for both), hospital admission (5% vs 4%), or death (7% vs 5%). The researchers noted that none of the deaths were related to transfusion or pathogen-reduction technology.

The team said additional studies of this technology are needed in larger populations—in particular, at-risk populations such as young children and pregnant mothers.

Blood in bags and vials

Photo by Daniel Gay

A pathogen-reduction system can safely minimize the risk of malaria transmitted via blood transfusion, according to a randomized trial.

The Mirasol pathogen-reduction technology system uses ultraviolet light energy and riboflavin to reduce the pathogen load and inactivate white blood cells in blood products.

In the current study, the system significantly reduced the transmission of malaria-causing Plasmodium parasites in patients receiving whole blood.

“This is the first study to look at the potential of pathogen-reduction technology in a real-world treatment setting and finds that, although the risk of malaria transmission is not completely eliminated, the risk is severely reduced,” said Jean-Pierre Allain, MD, of the University of Cambridge in the UK.

Dr Allain and his colleagues described this research in The Lancet. The work was funded by TerumoBCT Inc., the company developing the Mirasol system.

The trial included 223 adult patients from the Komfo Anokye Teaching Hospital in Kumasi, Ghana, who required a blood transfusion because of severe anemia or hemorrhage and were expected to remain in the hospital for at least 3 consecutive days after the initial transfusion.

The patients were randomized via computer to receive a transfusion with pathogen-reduced whole blood (treated) or whole blood that was prepared and transfused by standard local practice (untreated). Patients, healthcare providers, and data collectors were blinded to the treatment allocation.

The researchers analyzed blood samples for all of the recipients on the day of the transfusion and 1, 3, 7, and 28 days later. By studying the sequences of Plasmodium genes present in the blood, the team was able to tell whether the patients were likely to be carrying the donor parasite after the transfusion.

In all, 214 patients completed the protocol as planned—107 who received treated blood and 107 who received untreated blood.

A total of 65 patients were not previously carrying a Plasmodium parasite but received parasitemic blood. Twenty-eight of these patients received treated blood, and 37 received untreated blood.

The incidence of transfusion-transmitted malaria was significantly lower for the group that received the treated blood. Twenty-two percent of patients (8/37) who received untreated blood later tested positive for the malaria parasite, compared with 4% (1/28) of patients who received treated blood (P=0.039).

The researchers noted that coagulation parameters, platelet counts, and hemostatic status were similar whether patients received treated or untreated blood.

The Mirasol system did not appear to affect the coagulation properties of the blood, and patients who received the treated blood had slightly fewer allergic reactions than those who received the untreated blood (5% vs 8%).

The percentage of patients reporting at least 1 treatment-emergent adverse event (TEAE) was similar between the groups—43% in the treated-blood group and 39% in the untreated-blood group.

Likewise, there were no significant differences between the groups in the incidence of serious TEAEs (12% vs 8%), life-threatening TEAEs (3% for both), hospital admission (5% vs 4%), or death (7% vs 5%). The researchers noted that none of the deaths were related to transfusion or pathogen-reduction technology.

The team said additional studies of this technology are needed in larger populations—in particular, at-risk populations such as young children and pregnant mothers.

Blood in bags and vials

Photo by Daniel Gay

A pathogen-reduction system can safely minimize the risk of malaria transmitted via blood transfusion, according to a randomized trial.

The Mirasol pathogen-reduction technology system uses ultraviolet light energy and riboflavin to reduce the pathogen load and inactivate white blood cells in blood products.

In the current study, the system significantly reduced the transmission of malaria-causing Plasmodium parasites in patients receiving whole blood.

“This is the first study to look at the potential of pathogen-reduction technology in a real-world treatment setting and finds that, although the risk of malaria transmission is not completely eliminated, the risk is severely reduced,” said Jean-Pierre Allain, MD, of the University of Cambridge in the UK.

Dr Allain and his colleagues described this research in The Lancet. The work was funded by TerumoBCT Inc., the company developing the Mirasol system.

The trial included 223 adult patients from the Komfo Anokye Teaching Hospital in Kumasi, Ghana, who required a blood transfusion because of severe anemia or hemorrhage and were expected to remain in the hospital for at least 3 consecutive days after the initial transfusion.

The patients were randomized via computer to receive a transfusion with pathogen-reduced whole blood (treated) or whole blood that was prepared and transfused by standard local practice (untreated). Patients, healthcare providers, and data collectors were blinded to the treatment allocation.

The researchers analyzed blood samples for all of the recipients on the day of the transfusion and 1, 3, 7, and 28 days later. By studying the sequences of Plasmodium genes present in the blood, the team was able to tell whether the patients were likely to be carrying the donor parasite after the transfusion.

In all, 214 patients completed the protocol as planned—107 who received treated blood and 107 who received untreated blood.

A total of 65 patients were not previously carrying a Plasmodium parasite but received parasitemic blood. Twenty-eight of these patients received treated blood, and 37 received untreated blood.

The incidence of transfusion-transmitted malaria was significantly lower for the group that received the treated blood. Twenty-two percent of patients (8/37) who received untreated blood later tested positive for the malaria parasite, compared with 4% (1/28) of patients who received treated blood (P=0.039).

The researchers noted that coagulation parameters, platelet counts, and hemostatic status were similar whether patients received treated or untreated blood.

The Mirasol system did not appear to affect the coagulation properties of the blood, and patients who received the treated blood had slightly fewer allergic reactions than those who received the untreated blood (5% vs 8%).

The percentage of patients reporting at least 1 treatment-emergent adverse event (TEAE) was similar between the groups—43% in the treated-blood group and 39% in the untreated-blood group.

Likewise, there were no significant differences between the groups in the incidence of serious TEAEs (12% vs 8%), life-threatening TEAEs (3% for both), hospital admission (5% vs 4%), or death (7% vs 5%). The researchers noted that none of the deaths were related to transfusion or pathogen-reduction technology.

The team said additional studies of this technology are needed in larger populations—in particular, at-risk populations such as young children and pregnant mothers.

Lab mouse

Researchers believe they may have discovered why medical interventions that succeed in mice don’t always translate to the clinic.

The team said the fact that lab mice are raised in pathogen-free environments may contribute to the differences in immune system development between lab mice and humans.

But co-housing lab mice with mice from pet stores can produce “dirty” mouse models that may better reflect the immune systems of adult humans.

David Masopust, PhD, of the University of Minnesota in Minneapolis, and his colleagues described these findings in a letter to Nature.

The researchers first explored immunological differences between lab mice and humans by analyzing cervical tissue specimens from adults of each species.

The team found that lab mice had fewer, less diverse, and less widely distributed memory T cells when compared with humans.

The immune systems of lab mice more closely resembled those of human infants, particularly with regard to the number and tissue distribution of memory T cells.

The researchers performed a similar analysis on tissues from lab mice and from mice found in barn or pet store environments.

The non-lab mice had immune systems more like those of adult humans, which suggests the variation in microbial environment—and not the species difference—could account for the immune system differences.

The researchers then set out to determine if the immune systems of lab mice with little exposure to environmental microbes could change when exposed to a different environment.

They co-housed lab mice with healthy mice raised in a pet store. After 8 weeks, analyses of the lab mice revealed patterns of T cells and other immune system components that more closely matched the pet store mice as well as adult humans.

The researchers said these findings suggest that “dirty” mice may model the human immune system more closely than typical lab mice and could be studied to learn more about the role of environment and genetics in the development of the human immune system.

Lab mouse

Researchers believe they may have discovered why medical interventions that succeed in mice don’t always translate to the clinic.

The team said the fact that lab mice are raised in pathogen-free environments may contribute to the differences in immune system development between lab mice and humans.

But co-housing lab mice with mice from pet stores can produce “dirty” mouse models that may better reflect the immune systems of adult humans.

David Masopust, PhD, of the University of Minnesota in Minneapolis, and his colleagues described these findings in a letter to Nature.

The researchers first explored immunological differences between lab mice and humans by analyzing cervical tissue specimens from adults of each species.

The team found that lab mice had fewer, less diverse, and less widely distributed memory T cells when compared with humans.

The immune systems of lab mice more closely resembled those of human infants, particularly with regard to the number and tissue distribution of memory T cells.

The researchers performed a similar analysis on tissues from lab mice and from mice found in barn or pet store environments.

The non-lab mice had immune systems more like those of adult humans, which suggests the variation in microbial environment—and not the species difference—could account for the immune system differences.

The researchers then set out to determine if the immune systems of lab mice with little exposure to environmental microbes could change when exposed to a different environment.

They co-housed lab mice with healthy mice raised in a pet store. After 8 weeks, analyses of the lab mice revealed patterns of T cells and other immune system components that more closely matched the pet store mice as well as adult humans.

The researchers said these findings suggest that “dirty” mice may model the human immune system more closely than typical lab mice and could be studied to learn more about the role of environment and genetics in the development of the human immune system.

Lab mouse

Researchers believe they may have discovered why medical interventions that succeed in mice don’t always translate to the clinic.

The team said the fact that lab mice are raised in pathogen-free environments may contribute to the differences in immune system development between lab mice and humans.

But co-housing lab mice with mice from pet stores can produce “dirty” mouse models that may better reflect the immune systems of adult humans.

David Masopust, PhD, of the University of Minnesota in Minneapolis, and his colleagues described these findings in a letter to Nature.

The researchers first explored immunological differences between lab mice and humans by analyzing cervical tissue specimens from adults of each species.

The team found that lab mice had fewer, less diverse, and less widely distributed memory T cells when compared with humans.

The immune systems of lab mice more closely resembled those of human infants, particularly with regard to the number and tissue distribution of memory T cells.

The researchers performed a similar analysis on tissues from lab mice and from mice found in barn or pet store environments.

The non-lab mice had immune systems more like those of adult humans, which suggests the variation in microbial environment—and not the species difference—could account for the immune system differences.

The researchers then set out to determine if the immune systems of lab mice with little exposure to environmental microbes could change when exposed to a different environment.

They co-housed lab mice with healthy mice raised in a pet store. After 8 weeks, analyses of the lab mice revealed patterns of T cells and other immune system components that more closely matched the pet store mice as well as adult humans.

The researchers said these findings suggest that “dirty” mice may model the human immune system more closely than typical lab mice and could be studied to learn more about the role of environment and genetics in the development of the human immune system.

Red blood cells

Preliminary data from a phase 1/2 study suggest an investigational gene therapy can increase factor VIII (FVIII) levels in patients with severe hemophilia A.

The therapy, BMN 270, is a recombinant adeno-associated virus (AAV) vector coding for FVIII.

To date, 8 patients have received a single dose of BMN 270, and most have experienced an increase in FVIII levels and a decrease in the severity of their disease.

At last observation, patients receiving the highest dose of BMN 270 experienced increasing FVIII activity levels ranging between 4% and 60% (as a percentage calculated based on the numbers of International Units (IU) per milliliter of whole blood).

These results were recently announced by BioMarin Pharmaceutical Inc., the company developing BMN 270.

“If BMN 270 allows hemophilia A patients to maintain around 5% of normal levels of FVIII, it could have a real and meaningful clinical benefit by reducing the need for FVIII infusions and spontaneous bleeds,” said study investigator John Pasi, PhD, of Barts and the London School of Medicine and Dentistry in the UK.

“I am looking forward to further assessing the data over the 16 weeks and beyond in this ongoing study.”

This dose-escalation study was designed to evaluate the safety and efficacy of BMN 270 gene therapy in up to 12 patients with severe hemophilia A.

The primary endpoints are to assess the safety of a single intravenous administration of a recombinant AAV vector coding for FVIII and determine the change from baseline of FVIII expression level at 16 weeks after infusion.

Secondary endpoints include assessing the impact of BMN 270 on the frequency of FVIII replacement therapy, the number of bleeding episodes requiring treatment, and any potential immune responses. Researchers plan to monitor patients for safety and durability of effect for 5 years.

Results

A total of 8 patients with severe hemophilia A have received a single dose of BMN 270—one at 6 x 10¹² vg/kg, one at 2 x 10¹³ vg/kg, and six at 6 x 10¹³ vg/kg.

At 20 weeks after administration, the patient who received the lowest dose of BMN 270 had a FVIII activity level of less than 1% and still had severe hemophilia.

At 16 weeks, the patient who received the middle dose of BMN 270 had a FVIII activity level of 2% and moderate hemophilia.

One patient in the highest dose group also had moderate hemophilia and a FVIII activity level of 4% at 7 weeks.

Three patients in the high-dose group had mild hemophilia and FVIII activity levels of 8%, 10%, and 21% at 7, 5, and 6 weeks, respectively.

And 2 patients in the high-dose group had normal levels of FVIII activity—57% at 16 weeks and 60% at 8 weeks.

Liver function

The researchers have monitored liver function tests closely during the trial. The first 3 patients did not receive prophylactic corticosteroids, and 2 of these patients experienced elevated alanine aminotransferase (ALT) levels.

Patient 3, the first patient treated at the highest dose level, experienced a mild ALT elevation at week 4, which prompted administration of a course of corticosteroids. ALT levels in this patient continued to rise modestly during the corticosteroid therapy, which was completed at week 14.

Two weeks later, Patient 3 began a new corticosteroid regimen when ALT levels became minimally abnormal for the first time. The expression of FVIII continued to increase during this ALT elevation and is currently at 57%.

In addition, Patient 1, who was treated at the lowest dose of BMN 270, experienced a rise in ALT level to 128 IU/L at 28 weeks after dosing.

After the third patient, all patients were started on prophylactic corticosteroid therapy. To date, no additional patients have experienced abnormal ALT levels.

BioMarin said it plans to discuss these findings with UK regulatory authorities prior to dosing the remaining patients.

“We are encouraged by this early data on BMN 270 and the trend we are seeing in increasing FVIII levels over time,” said Hank Fuchs, MD, chief medical officer at BioMarin.

“BMN 270 could have the potential to reduce and possibly eliminate the need for infusions of FVIII.”

BMN 270 has received orphan drug designation from the European Commission and US Food and Drug Administration. Phase 3 design preparation and high-volume manufacturing plans are underway.

Red blood cells

Preliminary data from a phase 1/2 study suggest an investigational gene therapy can increase factor VIII (FVIII) levels in patients with severe hemophilia A.

The therapy, BMN 270, is a recombinant adeno-associated virus (AAV) vector coding for FVIII.

To date, 8 patients have received a single dose of BMN 270, and most have experienced an increase in FVIII levels and a decrease in the severity of their disease.

At last observation, patients receiving the highest dose of BMN 270 experienced increasing FVIII activity levels ranging between 4% and 60% (as a percentage calculated based on the numbers of International Units (IU) per milliliter of whole blood).

These results were recently announced by BioMarin Pharmaceutical Inc., the company developing BMN 270.

“If BMN 270 allows hemophilia A patients to maintain around 5% of normal levels of FVIII, it could have a real and meaningful clinical benefit by reducing the need for FVIII infusions and spontaneous bleeds,” said study investigator John Pasi, PhD, of Barts and the London School of Medicine and Dentistry in the UK.

“I am looking forward to further assessing the data over the 16 weeks and beyond in this ongoing study.”

This dose-escalation study was designed to evaluate the safety and efficacy of BMN 270 gene therapy in up to 12 patients with severe hemophilia A.

The primary endpoints are to assess the safety of a single intravenous administration of a recombinant AAV vector coding for FVIII and determine the change from baseline of FVIII expression level at 16 weeks after infusion.

Secondary endpoints include assessing the impact of BMN 270 on the frequency of FVIII replacement therapy, the number of bleeding episodes requiring treatment, and any potential immune responses. Researchers plan to monitor patients for safety and durability of effect for 5 years.

Results

A total of 8 patients with severe hemophilia A have received a single dose of BMN 270—one at 6 x 10¹² vg/kg, one at 2 x 10¹³ vg/kg, and six at 6 x 10¹³ vg/kg.

At 20 weeks after administration, the patient who received the lowest dose of BMN 270 had a FVIII activity level of less than 1% and still had severe hemophilia.

At 16 weeks, the patient who received the middle dose of BMN 270 had a FVIII activity level of 2% and moderate hemophilia.

One patient in the highest dose group also had moderate hemophilia and a FVIII activity level of 4% at 7 weeks.

Three patients in the high-dose group had mild hemophilia and FVIII activity levels of 8%, 10%, and 21% at 7, 5, and 6 weeks, respectively.

And 2 patients in the high-dose group had normal levels of FVIII activity—57% at 16 weeks and 60% at 8 weeks.

Liver function

The researchers have monitored liver function tests closely during the trial. The first 3 patients did not receive prophylactic corticosteroids, and 2 of these patients experienced elevated alanine aminotransferase (ALT) levels.

Patient 3, the first patient treated at the highest dose level, experienced a mild ALT elevation at week 4, which prompted administration of a course of corticosteroids. ALT levels in this patient continued to rise modestly during the corticosteroid therapy, which was completed at week 14.

Two weeks later, Patient 3 began a new corticosteroid regimen when ALT levels became minimally abnormal for the first time. The expression of FVIII continued to increase during this ALT elevation and is currently at 57%.

In addition, Patient 1, who was treated at the lowest dose of BMN 270, experienced a rise in ALT level to 128 IU/L at 28 weeks after dosing.

After the third patient, all patients were started on prophylactic corticosteroid therapy. To date, no additional patients have experienced abnormal ALT levels.

BioMarin said it plans to discuss these findings with UK regulatory authorities prior to dosing the remaining patients.

“We are encouraged by this early data on BMN 270 and the trend we are seeing in increasing FVIII levels over time,” said Hank Fuchs, MD, chief medical officer at BioMarin.

“BMN 270 could have the potential to reduce and possibly eliminate the need for infusions of FVIII.”

BMN 270 has received orphan drug designation from the European Commission and US Food and Drug Administration. Phase 3 design preparation and high-volume manufacturing plans are underway.

Red blood cells

Preliminary data from a phase 1/2 study suggest an investigational gene therapy can increase factor VIII (FVIII) levels in patients with severe hemophilia A.

The therapy, BMN 270, is a recombinant adeno-associated virus (AAV) vector coding for FVIII.

To date, 8 patients have received a single dose of BMN 270, and most have experienced an increase in FVIII levels and a decrease in the severity of their disease.

At last observation, patients receiving the highest dose of BMN 270 experienced increasing FVIII activity levels ranging between 4% and 60% (as a percentage calculated based on the numbers of International Units (IU) per milliliter of whole blood).

These results were recently announced by BioMarin Pharmaceutical Inc., the company developing BMN 270.

“If BMN 270 allows hemophilia A patients to maintain around 5% of normal levels of FVIII, it could have a real and meaningful clinical benefit by reducing the need for FVIII infusions and spontaneous bleeds,” said study investigator John Pasi, PhD, of Barts and the London School of Medicine and Dentistry in the UK.

“I am looking forward to further assessing the data over the 16 weeks and beyond in this ongoing study.”

This dose-escalation study was designed to evaluate the safety and efficacy of BMN 270 gene therapy in up to 12 patients with severe hemophilia A.

The primary endpoints are to assess the safety of a single intravenous administration of a recombinant AAV vector coding for FVIII and determine the change from baseline of FVIII expression level at 16 weeks after infusion.

Secondary endpoints include assessing the impact of BMN 270 on the frequency of FVIII replacement therapy, the number of bleeding episodes requiring treatment, and any potential immune responses. Researchers plan to monitor patients for safety and durability of effect for 5 years.

Results

A total of 8 patients with severe hemophilia A have received a single dose of BMN 270—one at 6 x 10¹² vg/kg, one at 2 x 10¹³ vg/kg, and six at 6 x 10¹³ vg/kg.

At 20 weeks after administration, the patient who received the lowest dose of BMN 270 had a FVIII activity level of less than 1% and still had severe hemophilia.

At 16 weeks, the patient who received the middle dose of BMN 270 had a FVIII activity level of 2% and moderate hemophilia.

One patient in the highest dose group also had moderate hemophilia and a FVIII activity level of 4% at 7 weeks.

Three patients in the high-dose group had mild hemophilia and FVIII activity levels of 8%, 10%, and 21% at 7, 5, and 6 weeks, respectively.

And 2 patients in the high-dose group had normal levels of FVIII activity—57% at 16 weeks and 60% at 8 weeks.

Liver function

The researchers have monitored liver function tests closely during the trial. The first 3 patients did not receive prophylactic corticosteroids, and 2 of these patients experienced elevated alanine aminotransferase (ALT) levels.

Patient 3, the first patient treated at the highest dose level, experienced a mild ALT elevation at week 4, which prompted administration of a course of corticosteroids. ALT levels in this patient continued to rise modestly during the corticosteroid therapy, which was completed at week 14.

Two weeks later, Patient 3 began a new corticosteroid regimen when ALT levels became minimally abnormal for the first time. The expression of FVIII continued to increase during this ALT elevation and is currently at 57%.

In addition, Patient 1, who was treated at the lowest dose of BMN 270, experienced a rise in ALT level to 128 IU/L at 28 weeks after dosing.

After the third patient, all patients were started on prophylactic corticosteroid therapy. To date, no additional patients have experienced abnormal ALT levels.

BioMarin said it plans to discuss these findings with UK regulatory authorities prior to dosing the remaining patients.

“We are encouraged by this early data on BMN 270 and the trend we are seeing in increasing FVIII levels over time,” said Hank Fuchs, MD, chief medical officer at BioMarin.

“BMN 270 could have the potential to reduce and possibly eliminate the need for infusions of FVIII.”

BMN 270 has received orphan drug designation from the European Commission and US Food and Drug Administration. Phase 3 design preparation and high-volume manufacturing plans are underway.

Lisa Diller, MD

Photo from Dana-Farber/

Boston Children’s Cancer

and Blood Disorders Center

Young adult survivors of childhood cancer tend to have inferior health-related quality of life (HRQOL) when compared to the general population, according to research published in the Journal of the National Cancer Institute.

Childhood cancer survivors (CCSs) ages 18 to 29 reported overall HRQOL similar to that of people from the general population who were in their 40s.

However, CCSs fared better if they did not have chronic health conditions.

“Our findings indicate survivors’ accelerated aging and also help us understand the health-related risks associated with having had cancer as a child,” said study author Lisa Diller, MD, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Harvard Medical School in Boston, Massachusetts.

“What’s encouraging is that the lower quality of life scores are associated with chronic disease after treatment, not with a history of pediatric cancer itself. If we can prevent treatment-related conditions by changes in the therapy we use for the cancer, then childhood cancer will become an acute, rather than a chronic, illness.”

Dr Diller and her colleagues used information from the Childhood Cancer Survivor Study to compare CCSs (n=7105) and their siblings (n=372) and information from the Medical Expenditures Panel Survey to make comparisons to the general population (n=12,803).

The researchers estimated health utility, a summary measure of quality of life, in these subjects using the Short Form-6D (SF-6D). A score of “1” indicated perfect health, and a score of “0” indicated death.

Results showed that CCSs had significantly lower SF-6D scores than the general population. The mean scores were 0.77 and 0.81, respectively (P<0.001).

But there were no clinically meaningful differences between the CCSs’ siblings and the general population. Their mean SF-6D scores were 0.80 and 0.81, respectively.

Young adult CCSs ages 18 to 29 had a mean score of 0.78, which was roughly equivalent to that reported for 40-to-49-year-old adults in the general population.

However, the presence or absence of chronic health conditions played a role in HRQOL. CCSs who reported no chronic conditions had SF-6D scores similar to the general population, with a mean score of 0.81.

But CCSs with chronic conditions had scores that matched the scores of chronically ill members of the general population. CCSs with 2 chronic conditions had a mean score of 0.77. Those with 3 or more disabling, severe, or life-threatening conditions had a mean score of 0.70.

“By enabling comparisons to the general population, our findings provide context to better understand how the cancer experience may influence the long-term well-being of survivors,” said study author Jennifer Yeh, PhD, of the Harvard T.H. Chan School of Public Health in Boston.

“This is another way to understand the health challenges survivors face and where to focus efforts to improve the long-term health and quality of life of survivors.”

Lisa Diller, MD

Photo from Dana-Farber/

Boston Children’s Cancer

and Blood Disorders Center

Young adult survivors of childhood cancer tend to have inferior health-related quality of life (HRQOL) when compared to the general population, according to research published in the Journal of the National Cancer Institute.

Childhood cancer survivors (CCSs) ages 18 to 29 reported overall HRQOL similar to that of people from the general population who were in their 40s.

However, CCSs fared better if they did not have chronic health conditions.

“Our findings indicate survivors’ accelerated aging and also help us understand the health-related risks associated with having had cancer as a child,” said study author Lisa Diller, MD, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Harvard Medical School in Boston, Massachusetts.

“What’s encouraging is that the lower quality of life scores are associated with chronic disease after treatment, not with a history of pediatric cancer itself. If we can prevent treatment-related conditions by changes in the therapy we use for the cancer, then childhood cancer will become an acute, rather than a chronic, illness.”

Dr Diller and her colleagues used information from the Childhood Cancer Survivor Study to compare CCSs (n=7105) and their siblings (n=372) and information from the Medical Expenditures Panel Survey to make comparisons to the general population (n=12,803).

The researchers estimated health utility, a summary measure of quality of life, in these subjects using the Short Form-6D (SF-6D). A score of “1” indicated perfect health, and a score of “0” indicated death.

Results showed that CCSs had significantly lower SF-6D scores than the general population. The mean scores were 0.77 and 0.81, respectively (P<0.001).

But there were no clinically meaningful differences between the CCSs’ siblings and the general population. Their mean SF-6D scores were 0.80 and 0.81, respectively.

Young adult CCSs ages 18 to 29 had a mean score of 0.78, which was roughly equivalent to that reported for 40-to-49-year-old adults in the general population.

However, the presence or absence of chronic health conditions played a role in HRQOL. CCSs who reported no chronic conditions had SF-6D scores similar to the general population, with a mean score of 0.81.

But CCSs with chronic conditions had scores that matched the scores of chronically ill members of the general population. CCSs with 2 chronic conditions had a mean score of 0.77. Those with 3 or more disabling, severe, or life-threatening conditions had a mean score of 0.70.

“By enabling comparisons to the general population, our findings provide context to better understand how the cancer experience may influence the long-term well-being of survivors,” said study author Jennifer Yeh, PhD, of the Harvard T.H. Chan School of Public Health in Boston.

“This is another way to understand the health challenges survivors face and where to focus efforts to improve the long-term health and quality of life of survivors.”

Lisa Diller, MD

Photo from Dana-Farber/

Boston Children’s Cancer

and Blood Disorders Center

Young adult survivors of childhood cancer tend to have inferior health-related quality of life (HRQOL) when compared to the general population, according to research published in the Journal of the National Cancer Institute.

Childhood cancer survivors (CCSs) ages 18 to 29 reported overall HRQOL similar to that of people from the general population who were in their 40s.

However, CCSs fared better if they did not have chronic health conditions.

“Our findings indicate survivors’ accelerated aging and also help us understand the health-related risks associated with having had cancer as a child,” said study author Lisa Diller, MD, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Harvard Medical School in Boston, Massachusetts.

“What’s encouraging is that the lower quality of life scores are associated with chronic disease after treatment, not with a history of pediatric cancer itself. If we can prevent treatment-related conditions by changes in the therapy we use for the cancer, then childhood cancer will become an acute, rather than a chronic, illness.”

Dr Diller and her colleagues used information from the Childhood Cancer Survivor Study to compare CCSs (n=7105) and their siblings (n=372) and information from the Medical Expenditures Panel Survey to make comparisons to the general population (n=12,803).

The researchers estimated health utility, a summary measure of quality of life, in these subjects using the Short Form-6D (SF-6D). A score of “1” indicated perfect health, and a score of “0” indicated death.

Results showed that CCSs had significantly lower SF-6D scores than the general population. The mean scores were 0.77 and 0.81, respectively (P<0.001).

But there were no clinically meaningful differences between the CCSs’ siblings and the general population. Their mean SF-6D scores were 0.80 and 0.81, respectively.

Young adult CCSs ages 18 to 29 had a mean score of 0.78, which was roughly equivalent to that reported for 40-to-49-year-old adults in the general population.

However, the presence or absence of chronic health conditions played a role in HRQOL. CCSs who reported no chronic conditions had SF-6D scores similar to the general population, with a mean score of 0.81.

But CCSs with chronic conditions had scores that matched the scores of chronically ill members of the general population. CCSs with 2 chronic conditions had a mean score of 0.77. Those with 3 or more disabling, severe, or life-threatening conditions had a mean score of 0.70.

“By enabling comparisons to the general population, our findings provide context to better understand how the cancer experience may influence the long-term well-being of survivors,” said study author Jennifer Yeh, PhD, of the Harvard T.H. Chan School of Public Health in Boston.

“This is another way to understand the health challenges survivors face and where to focus efforts to improve the long-term health and quality of life of survivors.”

AML cells

NEW ORLEANS—A phase 4 study has revealed biomarkers that appear to predict the efficacy of treatment with histamine dihydrochloride (HDC) and interleukin-2 (IL-2) in patients with acute myeloid leukemia (AML).

Researchers found that patients who remained in complete remission after 1 cycle of HDC/IL-2 experienced a significant reduction in effector memory T cells (T_EM) and a concomitant increase in effector T cells (T_eff) during therapy.

This “T_EM to T_eff transition” was associated with favorable leukemia-free survival (LFS) and overall survival (OS), especially among patients older than 60.

Frida Ewald Sander, PhD, of University of Gothenburg in Sweden, and her colleagues presented this research at the 2016 AACR Annual Meeting (abstract CT116*).

The study was supported by The Swedish Research Council, The Swedish Cancer Society, The Swedish Society for Medical Research, Meda Pharma, and Immune Pharmaceuticals, which markets HDC as Ceplene®.

The combination of HDC and IL-2 is currently approved in more than 30 countries to prevent relapse in AML patients. In this phase 4 study (Re:MISSION), the researchers set out to assess the immunomodulatory properties of this treatment and correlate potential biomarkers with clinical outcomes.

The study included 84 non-transplanted AML patients (ages 18 to 79) in first complete remission. The patients received HDC (0.5 mg SC BID) and human recombinant IL-2 (1MIU SC BID) in 3-week cycles for 18 months. The patients were followed for at least 2 years from the start of immunotherapy to evaluate survival.

The researchers collected blood from the patients before they began HDC/IL-2 therapy and at the end of the first treatment cycle. From these samples, the team assessed the frequency of CD8+ T cells, including naïve T cells (CD45RA+CCR7+), central memory T cells (CD45RO+CCR7+), T_EM cells (CD45RO+CCR7-), and T_eff cells (CD45RA+CCR7-).

The researchers found that non-relapsing patients experienced a significant reduction in T_EM cells (P=0.001) and a significant increase in T_eff cells (P=0.007) during cycle 1. However, this effect was not observed in patients who did relapse.

Further analysis revealed that the reduction in T_EM cells was significantly associated with favorable LFS  and OS in the entire cohort (P=0.0007 and P=0.005, respectively) and among patients over 60 (P<0.0001 and P=0.002, respectively).

Likewise, the increase in T_eff cells was associated with favorable LFS and OS in the entire cohort (P=0.07 and P=0.04, respectively) and among patients over 60 (P=0.004 and P=0.0001, respectively).

The concomitant reduction of T_EM cells and induction of T_eff cells—the T_EM to T_eff transition—was associated with superior LFS and OS in the overall cohort (P=0.0002 and P=0.002, respectively) and in the over-60 population (P<0.0001 for LFS and OS).

The researchers said these predictors of outcome remained significant when they adjusted for potential confounders (age, risk group classification, number of induction courses required to achieve complete response, and number of consolidation courses).

Therefore, the team concluded that the altered distribution of cytotoxic T cells during treatment with HDC/IL-2 can prognosticate LFS and OS in AML patients, particularly those over 60.

“We believe that the new data may allow a personalized approach to selection of patients who are most likely to benefit from Ceplene/IL-2 treatment in AML—in particular, the older patient population, who have demonstrated almost 100% survival when positive for the T-cell transition biomarkers,” said Miri Ben-Ami, MD, executive vice president of oncology at Immune Pharmaceuticals.

“In addition, current research is revealing the potential synergy between immune checkpoint inhibitors and Ceplene, which could open the possibility of additional therapeutic indications for this combination.”

*Information in the abstract differs from that presented at the meeting.

AML cells

NEW ORLEANS—A phase 4 study has revealed biomarkers that appear to predict the efficacy of treatment with histamine dihydrochloride (HDC) and interleukin-2 (IL-2) in patients with acute myeloid leukemia (AML).

Researchers found that patients who remained in complete remission after 1 cycle of HDC/IL-2 experienced a significant reduction in effector memory T cells (T_EM) and a concomitant increase in effector T cells (T_eff) during therapy.

This “T_EM to T_eff transition” was associated with favorable leukemia-free survival (LFS) and overall survival (OS), especially among patients older than 60.

Frida Ewald Sander, PhD, of University of Gothenburg in Sweden, and her colleagues presented this research at the 2016 AACR Annual Meeting (abstract CT116*).

The study was supported by The Swedish Research Council, The Swedish Cancer Society, The Swedish Society for Medical Research, Meda Pharma, and Immune Pharmaceuticals, which markets HDC as Ceplene®.

The combination of HDC and IL-2 is currently approved in more than 30 countries to prevent relapse in AML patients. In this phase 4 study (Re:MISSION), the researchers set out to assess the immunomodulatory properties of this treatment and correlate potential biomarkers with clinical outcomes.

The study included 84 non-transplanted AML patients (ages 18 to 79) in first complete remission. The patients received HDC (0.5 mg SC BID) and human recombinant IL-2 (1MIU SC BID) in 3-week cycles for 18 months. The patients were followed for at least 2 years from the start of immunotherapy to evaluate survival.

The researchers collected blood from the patients before they began HDC/IL-2 therapy and at the end of the first treatment cycle. From these samples, the team assessed the frequency of CD8+ T cells, including naïve T cells (CD45RA+CCR7+), central memory T cells (CD45RO+CCR7+), T_EM cells (CD45RO+CCR7-), and T_eff cells (CD45RA+CCR7-).

The researchers found that non-relapsing patients experienced a significant reduction in T_EM cells (P=0.001) and a significant increase in T_eff cells (P=0.007) during cycle 1. However, this effect was not observed in patients who did relapse.

Further analysis revealed that the reduction in T_EM cells was significantly associated with favorable LFS  and OS in the entire cohort (P=0.0007 and P=0.005, respectively) and among patients over 60 (P<0.0001 and P=0.002, respectively).

Likewise, the increase in T_eff cells was associated with favorable LFS and OS in the entire cohort (P=0.07 and P=0.04, respectively) and among patients over 60 (P=0.004 and P=0.0001, respectively).

The concomitant reduction of T_EM cells and induction of T_eff cells—the T_EM to T_eff transition—was associated with superior LFS and OS in the overall cohort (P=0.0002 and P=0.002, respectively) and in the over-60 population (P<0.0001 for LFS and OS).

The researchers said these predictors of outcome remained significant when they adjusted for potential confounders (age, risk group classification, number of induction courses required to achieve complete response, and number of consolidation courses).

Therefore, the team concluded that the altered distribution of cytotoxic T cells during treatment with HDC/IL-2 can prognosticate LFS and OS in AML patients, particularly those over 60.

“We believe that the new data may allow a personalized approach to selection of patients who are most likely to benefit from Ceplene/IL-2 treatment in AML—in particular, the older patient population, who have demonstrated almost 100% survival when positive for the T-cell transition biomarkers,” said Miri Ben-Ami, MD, executive vice president of oncology at Immune Pharmaceuticals.

“In addition, current research is revealing the potential synergy between immune checkpoint inhibitors and Ceplene, which could open the possibility of additional therapeutic indications for this combination.”

*Information in the abstract differs from that presented at the meeting.

AML cells

NEW ORLEANS—A phase 4 study has revealed biomarkers that appear to predict the efficacy of treatment with histamine dihydrochloride (HDC) and interleukin-2 (IL-2) in patients with acute myeloid leukemia (AML).

Researchers found that patients who remained in complete remission after 1 cycle of HDC/IL-2 experienced a significant reduction in effector memory T cells (T_EM) and a concomitant increase in effector T cells (T_eff) during therapy.

This “T_EM to T_eff transition” was associated with favorable leukemia-free survival (LFS) and overall survival (OS), especially among patients older than 60.

Frida Ewald Sander, PhD, of University of Gothenburg in Sweden, and her colleagues presented this research at the 2016 AACR Annual Meeting (abstract CT116*).

The study was supported by The Swedish Research Council, The Swedish Cancer Society, The Swedish Society for Medical Research, Meda Pharma, and Immune Pharmaceuticals, which markets HDC as Ceplene®.

The combination of HDC and IL-2 is currently approved in more than 30 countries to prevent relapse in AML patients. In this phase 4 study (Re:MISSION), the researchers set out to assess the immunomodulatory properties of this treatment and correlate potential biomarkers with clinical outcomes.

The study included 84 non-transplanted AML patients (ages 18 to 79) in first complete remission. The patients received HDC (0.5 mg SC BID) and human recombinant IL-2 (1MIU SC BID) in 3-week cycles for 18 months. The patients were followed for at least 2 years from the start of immunotherapy to evaluate survival.

The researchers collected blood from the patients before they began HDC/IL-2 therapy and at the end of the first treatment cycle. From these samples, the team assessed the frequency of CD8+ T cells, including naïve T cells (CD45RA+CCR7+), central memory T cells (CD45RO+CCR7+), T_EM cells (CD45RO+CCR7-), and T_eff cells (CD45RA+CCR7-).

The researchers found that non-relapsing patients experienced a significant reduction in T_EM cells (P=0.001) and a significant increase in T_eff cells (P=0.007) during cycle 1. However, this effect was not observed in patients who did relapse.

Further analysis revealed that the reduction in T_EM cells was significantly associated with favorable LFS  and OS in the entire cohort (P=0.0007 and P=0.005, respectively) and among patients over 60 (P<0.0001 and P=0.002, respectively).

Likewise, the increase in T_eff cells was associated with favorable LFS and OS in the entire cohort (P=0.07 and P=0.04, respectively) and among patients over 60 (P=0.004 and P=0.0001, respectively).

The concomitant reduction of T_EM cells and induction of T_eff cells—the T_EM to T_eff transition—was associated with superior LFS and OS in the overall cohort (P=0.0002 and P=0.002, respectively) and in the over-60 population (P<0.0001 for LFS and OS).

The researchers said these predictors of outcome remained significant when they adjusted for potential confounders (age, risk group classification, number of induction courses required to achieve complete response, and number of consolidation courses).

Therefore, the team concluded that the altered distribution of cytotoxic T cells during treatment with HDC/IL-2 can prognosticate LFS and OS in AML patients, particularly those over 60.

“We believe that the new data may allow a personalized approach to selection of patients who are most likely to benefit from Ceplene/IL-2 treatment in AML—in particular, the older patient population, who have demonstrated almost 100% survival when positive for the T-cell transition biomarkers,” said Miri Ben-Ami, MD, executive vice president of oncology at Immune Pharmaceuticals.

“In addition, current research is revealing the potential synergy between immune checkpoint inhibitors and Ceplene, which could open the possibility of additional therapeutic indications for this combination.”

*Information in the abstract differs from that presented at the meeting.

Brian Sorrentino, MD

Photo courtesy of St. Jude

Children’s Research Hospital

Lentiviral gene therapy with reduced-intensity conditioning can provide long-term benefits for older patients with X-linked severe combined immunodeficiency (SCID-X1), according to a small study.

All 5 patients who received this therapy exhibited selective expansion of gene-marked B, T, and natural killer (NK) cells.

In 2 of the older patients, the treatment restored normal immune function, an effect that lasted 2 and 3 years, respectively.

“This study demonstrates that lentivirus gene therapy, when combined with busulfan conditioning, can rebuild the immune system and lead to broad immunity in young adults with this devastating disorder,” said Brian Sorrentino, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Dr Sorrentino and his colleagues described this research in Science Translational Medicine.

The researchers explained that SCID-X1 is a profound deficiency of T, B, and NK cell immunity caused by mutations in IL2RG encoding the common chain (γc) of several interleukin receptors. And gammaretroviral gene therapy given without conditioning can restore T-cell immunity in young children with SCID-X1 but fails in older patients.

With this in mind, the team developed a lentiviral vector γc transduced autologous hematopoietic stem cell (HSC) gene therapy and tested it with nonmyeloablative busulfan conditioning in 5 SCID-X1 patients.

The patients were 7 to 23 years old. They all had chronic viral infections and other health problems related to SCID-X1, despite having received 1 or more haploidentical HSC transplants.

More than 2 years after undergoing gene therapy, the first 2 patients (ages 22 and 23) were producing a greater percentage of T, B, and NK cells with the corrected gene. The therapy had also restored antibody production in response to vaccination.

Furthermore, the patients’ health improved as their chronic viral infections resolved, and they put on weight as their protein absorption improved. One patient’s disfiguring warts were eased, and both patients ended life-long immune globulin therapy.

However, one of these patients died from pre-existing lung damage more than 2 years after receiving gene therapy.

Like the 2 older patients, the 3 younger patients (ages 7, 10, and 15) began producing a greater percentage of T, B, and NK cells with the corrected gene after therapy. But the younger patients have only been followed for several months.

The researchers said the safety results in this study were reassuring. There were no adverse events associated with the gene therapy and no indication of possible precancer cell proliferation.

As expected, patients experienced busulfan-related neutropenia and thrombocytopenia but recovered without any intervention. And 3 patients developed febrile neutropenia that responded to empiric antimicrobial therapy.

“While additional clinical experience and follow-up is needed, these promising results suggest gene therapy should be considered as an early treatment for patients in order to minimize or prevent the life-threatening organ damage that occurs when bone marrow transplant therapy fails to provide a sufficient immune response,” Dr Sorrentino said.

To that end, St. Jude has opened a gene therapy trial using the same lentiviral vector and busulfan conditioning for newly identified infants with SCID-X1 who lack a genetically matched sibling HSC donor.

“Based on the safety and health benefits for older patients reported in this study, we hope this novel gene therapy will help improve immune functioning and transform the lives of younger patients with this devastating disease,” Dr Sorrentino said.

Brian Sorrentino, MD

Photo courtesy of St. Jude

Children’s Research Hospital

Lentiviral gene therapy with reduced-intensity conditioning can provide long-term benefits for older patients with X-linked severe combined immunodeficiency (SCID-X1), according to a small study.

All 5 patients who received this therapy exhibited selective expansion of gene-marked B, T, and natural killer (NK) cells.

In 2 of the older patients, the treatment restored normal immune function, an effect that lasted 2 and 3 years, respectively.

“This study demonstrates that lentivirus gene therapy, when combined with busulfan conditioning, can rebuild the immune system and lead to broad immunity in young adults with this devastating disorder,” said Brian Sorrentino, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Dr Sorrentino and his colleagues described this research in Science Translational Medicine.

The researchers explained that SCID-X1 is a profound deficiency of T, B, and NK cell immunity caused by mutations in IL2RG encoding the common chain (γc) of several interleukin receptors. And gammaretroviral gene therapy given without conditioning can restore T-cell immunity in young children with SCID-X1 but fails in older patients.

With this in mind, the team developed a lentiviral vector γc transduced autologous hematopoietic stem cell (HSC) gene therapy and tested it with nonmyeloablative busulfan conditioning in 5 SCID-X1 patients.

The patients were 7 to 23 years old. They all had chronic viral infections and other health problems related to SCID-X1, despite having received 1 or more haploidentical HSC transplants.

More than 2 years after undergoing gene therapy, the first 2 patients (ages 22 and 23) were producing a greater percentage of T, B, and NK cells with the corrected gene. The therapy had also restored antibody production in response to vaccination.

Furthermore, the patients’ health improved as their chronic viral infections resolved, and they put on weight as their protein absorption improved. One patient’s disfiguring warts were eased, and both patients ended life-long immune globulin therapy.

However, one of these patients died from pre-existing lung damage more than 2 years after receiving gene therapy.

Like the 2 older patients, the 3 younger patients (ages 7, 10, and 15) began producing a greater percentage of T, B, and NK cells with the corrected gene after therapy. But the younger patients have only been followed for several months.

The researchers said the safety results in this study were reassuring. There were no adverse events associated with the gene therapy and no indication of possible precancer cell proliferation.

As expected, patients experienced busulfan-related neutropenia and thrombocytopenia but recovered without any intervention. And 3 patients developed febrile neutropenia that responded to empiric antimicrobial therapy.

“While additional clinical experience and follow-up is needed, these promising results suggest gene therapy should be considered as an early treatment for patients in order to minimize or prevent the life-threatening organ damage that occurs when bone marrow transplant therapy fails to provide a sufficient immune response,” Dr Sorrentino said.

To that end, St. Jude has opened a gene therapy trial using the same lentiviral vector and busulfan conditioning for newly identified infants with SCID-X1 who lack a genetically matched sibling HSC donor.

“Based on the safety and health benefits for older patients reported in this study, we hope this novel gene therapy will help improve immune functioning and transform the lives of younger patients with this devastating disease,” Dr Sorrentino said.

Brian Sorrentino, MD

Photo courtesy of St. Jude

Children’s Research Hospital

Lentiviral gene therapy with reduced-intensity conditioning can provide long-term benefits for older patients with X-linked severe combined immunodeficiency (SCID-X1), according to a small study.

All 5 patients who received this therapy exhibited selective expansion of gene-marked B, T, and natural killer (NK) cells.

In 2 of the older patients, the treatment restored normal immune function, an effect that lasted 2 and 3 years, respectively.

“This study demonstrates that lentivirus gene therapy, when combined with busulfan conditioning, can rebuild the immune system and lead to broad immunity in young adults with this devastating disorder,” said Brian Sorrentino, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Dr Sorrentino and his colleagues described this research in Science Translational Medicine.

The researchers explained that SCID-X1 is a profound deficiency of T, B, and NK cell immunity caused by mutations in IL2RG encoding the common chain (γc) of several interleukin receptors. And gammaretroviral gene therapy given without conditioning can restore T-cell immunity in young children with SCID-X1 but fails in older patients.

With this in mind, the team developed a lentiviral vector γc transduced autologous hematopoietic stem cell (HSC) gene therapy and tested it with nonmyeloablative busulfan conditioning in 5 SCID-X1 patients.

The patients were 7 to 23 years old. They all had chronic viral infections and other health problems related to SCID-X1, despite having received 1 or more haploidentical HSC transplants.

More than 2 years after undergoing gene therapy, the first 2 patients (ages 22 and 23) were producing a greater percentage of T, B, and NK cells with the corrected gene. The therapy had also restored antibody production in response to vaccination.

Furthermore, the patients’ health improved as their chronic viral infections resolved, and they put on weight as their protein absorption improved. One patient’s disfiguring warts were eased, and both patients ended life-long immune globulin therapy.

However, one of these patients died from pre-existing lung damage more than 2 years after receiving gene therapy.

Like the 2 older patients, the 3 younger patients (ages 7, 10, and 15) began producing a greater percentage of T, B, and NK cells with the corrected gene after therapy. But the younger patients have only been followed for several months.

The researchers said the safety results in this study were reassuring. There were no adverse events associated with the gene therapy and no indication of possible precancer cell proliferation.

As expected, patients experienced busulfan-related neutropenia and thrombocytopenia but recovered without any intervention. And 3 patients developed febrile neutropenia that responded to empiric antimicrobial therapy.

“While additional clinical experience and follow-up is needed, these promising results suggest gene therapy should be considered as an early treatment for patients in order to minimize or prevent the life-threatening organ damage that occurs when bone marrow transplant therapy fails to provide a sufficient immune response,” Dr Sorrentino said.

To that end, St. Jude has opened a gene therapy trial using the same lentiviral vector and busulfan conditioning for newly identified infants with SCID-X1 who lack a genetically matched sibling HSC donor.

“Based on the safety and health benefits for older patients reported in this study, we hope this novel gene therapy will help improve immune functioning and transform the lives of younger patients with this devastating disease,” Dr Sorrentino said.