Leukemia, Myelodysplasia, Transplantation

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.”

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.”

HSCs for transplant

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.

HSCs for transplant

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.

HSCs for transplant

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.

Monoclonal antibodies

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.”

Monoclonal antibodies

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.”

Monoclonal antibodies

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.”

MYC-expressing cancer cells

Credit: Juha Klefstrom

New research indicates that an unexpected partnership between the MYC oncogene and a non-coding RNA called PVT1 could be the key to understanding how MYC fuels cancers.

The researchers knew that MYC amplifications cause cancer, but MYC does not amplify alone. It often pairs with adjacent chromosomal regions.

“We wanted to know if the neighboring genes played a role,” said study author Anindya Bagchi, PhD, of the University of Minnesota in Minneapolis.

“We took a chance and were surprised to find this unexpected and counter-intuitive partnership between MYC and its neighbor, PVT1. Not only do these genes amplify together, PVT1 helps boost the MYC protein’s ability to carry out its dangerous activities in the cell.”

The researchers reported this finding in Nature.

Dr Bagchi and his team focused on a region of the genome, 8q24, which contains the MYC gene and is commonly expressed in cancer. The team separated MYC from the neighboring region containing the non-coding RNA PVT1.

Using chromosome engineering, the researchers developed mouse strains in 3 separate iterations: MYC only, the rest of the region containing PVT1 but without MYC, and the pairing of MYC with the regional genes.

The expected outcome, if MYC was the sole driver of the cancer, was tumor growth on the MYC line as well as the paired line. However, the researchers found growth only on the paired line. This suggests MYC is not acting alone and needs help from adjacent genes.

“The discovery of this partnership gives us a stronger understanding of how MYC amplification is fueled,” said David Largaespada, PhD, also of the University of Minnesota.

“When cancer promotes a cell to make more MYC, it also increases the PVT1 in the cell, which, in turn, boosts the amount of MYC. It’s a cycle, and now we’ve identified it, we can look for ways to uncouple this dangerous partnership.”

Testing this theory of uncoupling, the researchers looked closely at several breast and colorectal cancers that are driven by MYC. For example, in colorectal cancer lab models, where a mutation in the beta-catenin gene drives MYC to cancerous levels, eliminating PVT1 from these cells made the tumors nearly disappear.

“Finding the cooperation between MYC and PVT1 could be a game changer,” said Yuen-Yi Tseng, a graduate student at the University of Minnesota.

“We used to think MYC amplification is the major issue but ignored that other co-amplified genes, such as PVT1, can be significant. In this study, we show that PVT1 can be a key regulator of MYC protein, which can shift the paradigm in our understanding of MYC-amplified cancers.”

MYC has been notoriously elusive as a drug target. By uncoupling MYC and PVT1, the researchers suspect they could disable the cancer growth and limit MYC to precancerous levels. This would make PVT1 an ideal drug target to potentially control a major cancer gene.

“This is a thrilling discovery, but there are more questions that follow,” Dr Bagchi said. “Two major areas present themselves now for research. Will breaking the nexus between MYC and PVT1 perform the same in any MYC-driven cancer, even those not driven by this specific genetic location?”

“And how is PVT1 stabilizing or boosting MYC within the cells? This relationship will be a key to developing any drugs to target this mechanism.”

MYC-expressing cancer cells

Credit: Juha Klefstrom

New research indicates that an unexpected partnership between the MYC oncogene and a non-coding RNA called PVT1 could be the key to understanding how MYC fuels cancers.

The researchers knew that MYC amplifications cause cancer, but MYC does not amplify alone. It often pairs with adjacent chromosomal regions.

“We wanted to know if the neighboring genes played a role,” said study author Anindya Bagchi, PhD, of the University of Minnesota in Minneapolis.

“We took a chance and were surprised to find this unexpected and counter-intuitive partnership between MYC and its neighbor, PVT1. Not only do these genes amplify together, PVT1 helps boost the MYC protein’s ability to carry out its dangerous activities in the cell.”

The researchers reported this finding in Nature.

Dr Bagchi and his team focused on a region of the genome, 8q24, which contains the MYC gene and is commonly expressed in cancer. The team separated MYC from the neighboring region containing the non-coding RNA PVT1.

Using chromosome engineering, the researchers developed mouse strains in 3 separate iterations: MYC only, the rest of the region containing PVT1 but without MYC, and the pairing of MYC with the regional genes.

The expected outcome, if MYC was the sole driver of the cancer, was tumor growth on the MYC line as well as the paired line. However, the researchers found growth only on the paired line. This suggests MYC is not acting alone and needs help from adjacent genes.

“The discovery of this partnership gives us a stronger understanding of how MYC amplification is fueled,” said David Largaespada, PhD, also of the University of Minnesota.

“When cancer promotes a cell to make more MYC, it also increases the PVT1 in the cell, which, in turn, boosts the amount of MYC. It’s a cycle, and now we’ve identified it, we can look for ways to uncouple this dangerous partnership.”

Testing this theory of uncoupling, the researchers looked closely at several breast and colorectal cancers that are driven by MYC. For example, in colorectal cancer lab models, where a mutation in the beta-catenin gene drives MYC to cancerous levels, eliminating PVT1 from these cells made the tumors nearly disappear.

“Finding the cooperation between MYC and PVT1 could be a game changer,” said Yuen-Yi Tseng, a graduate student at the University of Minnesota.

“We used to think MYC amplification is the major issue but ignored that other co-amplified genes, such as PVT1, can be significant. In this study, we show that PVT1 can be a key regulator of MYC protein, which can shift the paradigm in our understanding of MYC-amplified cancers.”

MYC has been notoriously elusive as a drug target. By uncoupling MYC and PVT1, the researchers suspect they could disable the cancer growth and limit MYC to precancerous levels. This would make PVT1 an ideal drug target to potentially control a major cancer gene.

“This is a thrilling discovery, but there are more questions that follow,” Dr Bagchi said. “Two major areas present themselves now for research. Will breaking the nexus between MYC and PVT1 perform the same in any MYC-driven cancer, even those not driven by this specific genetic location?”

“And how is PVT1 stabilizing or boosting MYC within the cells? This relationship will be a key to developing any drugs to target this mechanism.”

MYC-expressing cancer cells

Credit: Juha Klefstrom

New research indicates that an unexpected partnership between the MYC oncogene and a non-coding RNA called PVT1 could be the key to understanding how MYC fuels cancers.

The researchers knew that MYC amplifications cause cancer, but MYC does not amplify alone. It often pairs with adjacent chromosomal regions.

“We wanted to know if the neighboring genes played a role,” said study author Anindya Bagchi, PhD, of the University of Minnesota in Minneapolis.

“We took a chance and were surprised to find this unexpected and counter-intuitive partnership between MYC and its neighbor, PVT1. Not only do these genes amplify together, PVT1 helps boost the MYC protein’s ability to carry out its dangerous activities in the cell.”

The researchers reported this finding in Nature.

Dr Bagchi and his team focused on a region of the genome, 8q24, which contains the MYC gene and is commonly expressed in cancer. The team separated MYC from the neighboring region containing the non-coding RNA PVT1.

Using chromosome engineering, the researchers developed mouse strains in 3 separate iterations: MYC only, the rest of the region containing PVT1 but without MYC, and the pairing of MYC with the regional genes.

The expected outcome, if MYC was the sole driver of the cancer, was tumor growth on the MYC line as well as the paired line. However, the researchers found growth only on the paired line. This suggests MYC is not acting alone and needs help from adjacent genes.

“The discovery of this partnership gives us a stronger understanding of how MYC amplification is fueled,” said David Largaespada, PhD, also of the University of Minnesota.

“When cancer promotes a cell to make more MYC, it also increases the PVT1 in the cell, which, in turn, boosts the amount of MYC. It’s a cycle, and now we’ve identified it, we can look for ways to uncouple this dangerous partnership.”

Testing this theory of uncoupling, the researchers looked closely at several breast and colorectal cancers that are driven by MYC. For example, in colorectal cancer lab models, where a mutation in the beta-catenin gene drives MYC to cancerous levels, eliminating PVT1 from these cells made the tumors nearly disappear.

“Finding the cooperation between MYC and PVT1 could be a game changer,” said Yuen-Yi Tseng, a graduate student at the University of Minnesota.

“We used to think MYC amplification is the major issue but ignored that other co-amplified genes, such as PVT1, can be significant. In this study, we show that PVT1 can be a key regulator of MYC protein, which can shift the paradigm in our understanding of MYC-amplified cancers.”

MYC has been notoriously elusive as a drug target. By uncoupling MYC and PVT1, the researchers suspect they could disable the cancer growth and limit MYC to precancerous levels. This would make PVT1 an ideal drug target to potentially control a major cancer gene.

“This is a thrilling discovery, but there are more questions that follow,” Dr Bagchi said. “Two major areas present themselves now for research. Will breaking the nexus between MYC and PVT1 perform the same in any MYC-driven cancer, even those not driven by this specific genetic location?”

“And how is PVT1 stabilizing or boosting MYC within the cells? This relationship will be a key to developing any drugs to target this mechanism.”

B-cell cancers constitute a large group of diseases with diverse clinical and pathological characteristics that arise from the B (bursal- or bone marrow-derived) lymphocytes of the immune system. B cells are involved in humoral immunity as part of the adaptive immune response. They display a unique B-cell receptor (BCR) on their surface which binds to a specific antigen. Antigen- binding activates the process of clonal expansion, during which the B cell reproduces to form an army of clones that secrete the same antibody. These antibodies then bind to the target antigen on foreign cells and initiate a range of immune responses that ultimately lead to the destruction of that cell.
 

Click on the PDF icon at the top of this introduction to read the full article.

B-cell cancers constitute a large group of diseases with diverse clinical and pathological characteristics that arise from the B (bursal- or bone marrow-derived) lymphocytes of the immune system. B cells are involved in humoral immunity as part of the adaptive immune response. They display a unique B-cell receptor (BCR) on their surface which binds to a specific antigen. Antigen- binding activates the process of clonal expansion, during which the B cell reproduces to form an army of clones that secrete the same antibody. These antibodies then bind to the target antigen on foreign cells and initiate a range of immune responses that ultimately lead to the destruction of that cell.
 

Click on the PDF icon at the top of this introduction to read the full article.

B-cell cancers constitute a large group of diseases with diverse clinical and pathological characteristics that arise from the B (bursal- or bone marrow-derived) lymphocytes of the immune system. B cells are involved in humoral immunity as part of the adaptive immune response. They display a unique B-cell receptor (BCR) on their surface which binds to a specific antigen. Antigen- binding activates the process of clonal expansion, during which the B cell reproduces to form an army of clones that secrete the same antibody. These antibodies then bind to the target antigen on foreign cells and initiate a range of immune responses that ultimately lead to the destruction of that cell.
 

Click on the PDF icon at the top of this introduction to read the full article.

Leukemia patient

Credit: Bill Branson

Children recently diagnosed with standard-risk acute lymphoblastic leukemia (ALL) are likely to have few long-term complications into adulthood, investigators have reported in The Lancet Oncology.

The team said this is because current therapies are less harsh than their predecessors.

Newer protocols have eliminated radiation and restricted the use of chemotherapeutics that may cause subsequent malignancies and other chronic health conditions.

Previous research had only assessed the very long-term outcomes of children treated with older protocols, leaving physicians to piece together information from this outdated data and anecdotal evidence.

“This is one of the first studies to show that, in addition to their excellent probability of survival, long-term survivors of standard-risk childhood ALL are at low risk for complications of their therapy once they enter adulthood,” said study author Paul Nathan, MD, of The Hospital for Sick Children in Toronto, Canada.

He and his colleagues used longitudinal data from the Childhood Cancer Survivor Study, a North American study of 5-year survivors of childhood cancer diagnosed between 1970 and 1986.

The team analyzed 556 patients from this study who were older than 1 year of age and younger than 10 at the time of diagnosis and who had received treatment consistent with current therapies for standard-risk ALL.

Patients were followed from 5 years following diagnosis to a median of 18 years. The survivor group was compared with a group of their siblings who had not had cancer, as well as the general population.

Twenty-eight patients in the survivor group died. Sixteen of these deaths were from causes other than relapse.

Survivors were at a slightly increased risk of death due to non-relapse causes, when compared to controls. However, no individual cause was increased.

Six survivors developed another malignancy. The risk for most chronic health disorders did not differ between survivors and siblings. But survivors appeared to have a moderately increased risk for osteoporosis or osteopenia, short stature, and cataracts.

Survivors and their siblings had similar socioeconomic outcomes, including education, rates of marriage, independent living, and household income.

While these results suggest the prognosis is favorable, Dr Nathan noted that ALL survivors should receive ongoing care from a knowledgeable primary-care practitioner.

“Among kids with standard-risk ALL, we expect most to survive,” Dr Nathan said. “Now we can say with more certainty that they will probably do well in the long-term as well. This information will be very useful for oncologists counselling newly diagnosed patients and their families and will be quite reassuring to parents.”

Leukemia patient

Credit: Bill Branson

Children recently diagnosed with standard-risk acute lymphoblastic leukemia (ALL) are likely to have few long-term complications into adulthood, investigators have reported in The Lancet Oncology.

The team said this is because current therapies are less harsh than their predecessors.

Newer protocols have eliminated radiation and restricted the use of chemotherapeutics that may cause subsequent malignancies and other chronic health conditions.

Previous research had only assessed the very long-term outcomes of children treated with older protocols, leaving physicians to piece together information from this outdated data and anecdotal evidence.

“This is one of the first studies to show that, in addition to their excellent probability of survival, long-term survivors of standard-risk childhood ALL are at low risk for complications of their therapy once they enter adulthood,” said study author Paul Nathan, MD, of The Hospital for Sick Children in Toronto, Canada.

He and his colleagues used longitudinal data from the Childhood Cancer Survivor Study, a North American study of 5-year survivors of childhood cancer diagnosed between 1970 and 1986.

The team analyzed 556 patients from this study who were older than 1 year of age and younger than 10 at the time of diagnosis and who had received treatment consistent with current therapies for standard-risk ALL.

Patients were followed from 5 years following diagnosis to a median of 18 years. The survivor group was compared with a group of their siblings who had not had cancer, as well as the general population.

Twenty-eight patients in the survivor group died. Sixteen of these deaths were from causes other than relapse.

Survivors were at a slightly increased risk of death due to non-relapse causes, when compared to controls. However, no individual cause was increased.

Six survivors developed another malignancy. The risk for most chronic health disorders did not differ between survivors and siblings. But survivors appeared to have a moderately increased risk for osteoporosis or osteopenia, short stature, and cataracts.

Survivors and their siblings had similar socioeconomic outcomes, including education, rates of marriage, independent living, and household income.

While these results suggest the prognosis is favorable, Dr Nathan noted that ALL survivors should receive ongoing care from a knowledgeable primary-care practitioner.

“Among kids with standard-risk ALL, we expect most to survive,” Dr Nathan said. “Now we can say with more certainty that they will probably do well in the long-term as well. This information will be very useful for oncologists counselling newly diagnosed patients and their families and will be quite reassuring to parents.”

Leukemia patient

Credit: Bill Branson

Children recently diagnosed with standard-risk acute lymphoblastic leukemia (ALL) are likely to have few long-term complications into adulthood, investigators have reported in The Lancet Oncology.

The team said this is because current therapies are less harsh than their predecessors.

Newer protocols have eliminated radiation and restricted the use of chemotherapeutics that may cause subsequent malignancies and other chronic health conditions.

Previous research had only assessed the very long-term outcomes of children treated with older protocols, leaving physicians to piece together information from this outdated data and anecdotal evidence.

“This is one of the first studies to show that, in addition to their excellent probability of survival, long-term survivors of standard-risk childhood ALL are at low risk for complications of their therapy once they enter adulthood,” said study author Paul Nathan, MD, of The Hospital for Sick Children in Toronto, Canada.

He and his colleagues used longitudinal data from the Childhood Cancer Survivor Study, a North American study of 5-year survivors of childhood cancer diagnosed between 1970 and 1986.

The team analyzed 556 patients from this study who were older than 1 year of age and younger than 10 at the time of diagnosis and who had received treatment consistent with current therapies for standard-risk ALL.

Patients were followed from 5 years following diagnosis to a median of 18 years. The survivor group was compared with a group of their siblings who had not had cancer, as well as the general population.

Twenty-eight patients in the survivor group died. Sixteen of these deaths were from causes other than relapse.

Survivors were at a slightly increased risk of death due to non-relapse causes, when compared to controls. However, no individual cause was increased.

Six survivors developed another malignancy. The risk for most chronic health disorders did not differ between survivors and siblings. But survivors appeared to have a moderately increased risk for osteoporosis or osteopenia, short stature, and cataracts.

Survivors and their siblings had similar socioeconomic outcomes, including education, rates of marriage, independent living, and household income.

While these results suggest the prognosis is favorable, Dr Nathan noted that ALL survivors should receive ongoing care from a knowledgeable primary-care practitioner.

“Among kids with standard-risk ALL, we expect most to survive,” Dr Nathan said. “Now we can say with more certainty that they will probably do well in the long-term as well. This information will be very useful for oncologists counselling newly diagnosed patients and their families and will be quite reassuring to parents.”

Hydrogels

Credit: Kathy Atkinson

Researchers have devised a novel way to deliver chemotherapy drugs “on demand,” according to a paper published in Proceedings of the National Academy of Sciences.

The team loaded a biocompatible hydrogel with a chemotherapy drug and used ultrasound to trigger the gel to release the drug.

Like many other injectable gels, this one gradually releases a low level of the drug by diffusion over time. But the new hydrogel differs from others in a key way.

Researchers previously applied ultrasound to gels to temporarily increase doses of drug, but that approach was a one-shot deal, as the ultrasound was used to destroy those gels.

In the current study, the researchers used ultrasound to temporarily disrupt the gel so that it released short, high-dose bursts of the drug. But when they stopped the ultrasound, the hydrogels self-healed.

By closing back up, they were ready to go for the next “on demand” drug burst, providing a way to administer drugs with a greater level of control than was possible before.

The researchers also demonstrated in lab cultures and in mouse models of breast cancer that the pulsed, ultrasound-triggered hydrogel approach to drug delivery was more effective at stopping the growth of tumor cells than traditional, sustained-release drug therapy.

“Our approach counters the whole idea of sustained drug release and offers a double whammy,” said study author David J. Mooney, PhD, of the Harvard School of Engineering and Applied Sciences in Boston.

“We have shown that we can use the hydrogels repeatedly and turn the drug pulses on and off at will, and that the drug bursts in concert with the baseline low-level drug delivery seems to be particularly effective in killing cancer cells.”

Self-healing hydrogel

Key to the researchers’ success in designing a hydrogel that self-heals was choosing the right kind of hydrogel with the right kind of drug and applying the right intensity of ultrasound.

“We were able to trigger our system with a level of ultrasound that was much lower than high-intensity focused ultrasound that is used clinically to heat and destroy tumors,” said study author Cathal Kearney, PhD, of the Royal College of Surgeons in Ireland. “The careful selection of materials and properties make it a reversible process.”

The team carried out the majority of their work for this study with a gel made out of alginate, a natural polysaccharide from algae that is held together with calcium ions.

In a series of tests, they found that, with the right level of ultrasound, the bonds break up and enable the gel to release its drug cargo. But as long as the gel is in the presence of more calcium, the bonds reform and the gel self-heals.

Drug testing

Once the researchers knew the gel would self-heal, they tested out a drug they suspected it would hold well: the chemotherapy drug mitoxantrone.

Sure enough, the ultrasound triggered the gel to release the blue-colored drug, as indicated by the newly blue color of the surrounding medium. Just a single ultrasound dose was effective, and the gel reformed after it was disrupted, making multiple cycles possible.

Next, the team tested the treatment in mouse models of breast cancer. They injected the drug-laden gel close to the tumors.

Over the course of 6 months, the mice that received a low-level, sustained release of the drug with a daily concentrated pulse of ultrasound (2.5 minutes) fared significantly better than mice treated the same but without ultrasound.

In contrast to controls, the tumors in the ultrasound-treated mice did not grow substantially. And the mice survived for an additional 80 days.

Potential applications

The researchers believe their technique could help improve cancer treatment and other therapies requiring drugs to be delivered at the right place and the right time—from post-surgery pain medications to protein-based drugs that require daily injections.

It requires an initial injection of the hydrogel, but the approach could be a much less traumatic, minimally invasive, and more effective method of drug delivery than current methods, Dr Mooney said.

The researchers also found their hydrogel can release cargo other than drugs, including proteins and condensed plasmid DNA. This lays the groundwork for using these hydrogels for tissue regeneration and gene therapy.

Dr Mooney said he and his colleagues plan to explore these potential applications, as well as the possibility of unleashing 2 different drugs independently from the same hydrogel.

Hydrogels

Credit: Kathy Atkinson

Researchers have devised a novel way to deliver chemotherapy drugs “on demand,” according to a paper published in Proceedings of the National Academy of Sciences.

The team loaded a biocompatible hydrogel with a chemotherapy drug and used ultrasound to trigger the gel to release the drug.

Like many other injectable gels, this one gradually releases a low level of the drug by diffusion over time. But the new hydrogel differs from others in a key way.

Researchers previously applied ultrasound to gels to temporarily increase doses of drug, but that approach was a one-shot deal, as the ultrasound was used to destroy those gels.

In the current study, the researchers used ultrasound to temporarily disrupt the gel so that it released short, high-dose bursts of the drug. But when they stopped the ultrasound, the hydrogels self-healed.

By closing back up, they were ready to go for the next “on demand” drug burst, providing a way to administer drugs with a greater level of control than was possible before.

The researchers also demonstrated in lab cultures and in mouse models of breast cancer that the pulsed, ultrasound-triggered hydrogel approach to drug delivery was more effective at stopping the growth of tumor cells than traditional, sustained-release drug therapy.

“Our approach counters the whole idea of sustained drug release and offers a double whammy,” said study author David J. Mooney, PhD, of the Harvard School of Engineering and Applied Sciences in Boston.

“We have shown that we can use the hydrogels repeatedly and turn the drug pulses on and off at will, and that the drug bursts in concert with the baseline low-level drug delivery seems to be particularly effective in killing cancer cells.”

Self-healing hydrogel

Key to the researchers’ success in designing a hydrogel that self-heals was choosing the right kind of hydrogel with the right kind of drug and applying the right intensity of ultrasound.

“We were able to trigger our system with a level of ultrasound that was much lower than high-intensity focused ultrasound that is used clinically to heat and destroy tumors,” said study author Cathal Kearney, PhD, of the Royal College of Surgeons in Ireland. “The careful selection of materials and properties make it a reversible process.”

The team carried out the majority of their work for this study with a gel made out of alginate, a natural polysaccharide from algae that is held together with calcium ions.

In a series of tests, they found that, with the right level of ultrasound, the bonds break up and enable the gel to release its drug cargo. But as long as the gel is in the presence of more calcium, the bonds reform and the gel self-heals.

Drug testing

Once the researchers knew the gel would self-heal, they tested out a drug they suspected it would hold well: the chemotherapy drug mitoxantrone.

Sure enough, the ultrasound triggered the gel to release the blue-colored drug, as indicated by the newly blue color of the surrounding medium. Just a single ultrasound dose was effective, and the gel reformed after it was disrupted, making multiple cycles possible.

Next, the team tested the treatment in mouse models of breast cancer. They injected the drug-laden gel close to the tumors.

Over the course of 6 months, the mice that received a low-level, sustained release of the drug with a daily concentrated pulse of ultrasound (2.5 minutes) fared significantly better than mice treated the same but without ultrasound.

In contrast to controls, the tumors in the ultrasound-treated mice did not grow substantially. And the mice survived for an additional 80 days.

Potential applications

The researchers believe their technique could help improve cancer treatment and other therapies requiring drugs to be delivered at the right place and the right time—from post-surgery pain medications to protein-based drugs that require daily injections.

It requires an initial injection of the hydrogel, but the approach could be a much less traumatic, minimally invasive, and more effective method of drug delivery than current methods, Dr Mooney said.

The researchers also found their hydrogel can release cargo other than drugs, including proteins and condensed plasmid DNA. This lays the groundwork for using these hydrogels for tissue regeneration and gene therapy.

Dr Mooney said he and his colleagues plan to explore these potential applications, as well as the possibility of unleashing 2 different drugs independently from the same hydrogel.

Hydrogels

Credit: Kathy Atkinson

Researchers have devised a novel way to deliver chemotherapy drugs “on demand,” according to a paper published in Proceedings of the National Academy of Sciences.

The team loaded a biocompatible hydrogel with a chemotherapy drug and used ultrasound to trigger the gel to release the drug.

Like many other injectable gels, this one gradually releases a low level of the drug by diffusion over time. But the new hydrogel differs from others in a key way.

Researchers previously applied ultrasound to gels to temporarily increase doses of drug, but that approach was a one-shot deal, as the ultrasound was used to destroy those gels.

In the current study, the researchers used ultrasound to temporarily disrupt the gel so that it released short, high-dose bursts of the drug. But when they stopped the ultrasound, the hydrogels self-healed.

By closing back up, they were ready to go for the next “on demand” drug burst, providing a way to administer drugs with a greater level of control than was possible before.

The researchers also demonstrated in lab cultures and in mouse models of breast cancer that the pulsed, ultrasound-triggered hydrogel approach to drug delivery was more effective at stopping the growth of tumor cells than traditional, sustained-release drug therapy.

“Our approach counters the whole idea of sustained drug release and offers a double whammy,” said study author David J. Mooney, PhD, of the Harvard School of Engineering and Applied Sciences in Boston.

“We have shown that we can use the hydrogels repeatedly and turn the drug pulses on and off at will, and that the drug bursts in concert with the baseline low-level drug delivery seems to be particularly effective in killing cancer cells.”

Self-healing hydrogel

Key to the researchers’ success in designing a hydrogel that self-heals was choosing the right kind of hydrogel with the right kind of drug and applying the right intensity of ultrasound.

“We were able to trigger our system with a level of ultrasound that was much lower than high-intensity focused ultrasound that is used clinically to heat and destroy tumors,” said study author Cathal Kearney, PhD, of the Royal College of Surgeons in Ireland. “The careful selection of materials and properties make it a reversible process.”

The team carried out the majority of their work for this study with a gel made out of alginate, a natural polysaccharide from algae that is held together with calcium ions.

In a series of tests, they found that, with the right level of ultrasound, the bonds break up and enable the gel to release its drug cargo. But as long as the gel is in the presence of more calcium, the bonds reform and the gel self-heals.

Drug testing

Once the researchers knew the gel would self-heal, they tested out a drug they suspected it would hold well: the chemotherapy drug mitoxantrone.

Sure enough, the ultrasound triggered the gel to release the blue-colored drug, as indicated by the newly blue color of the surrounding medium. Just a single ultrasound dose was effective, and the gel reformed after it was disrupted, making multiple cycles possible.

Next, the team tested the treatment in mouse models of breast cancer. They injected the drug-laden gel close to the tumors.

Over the course of 6 months, the mice that received a low-level, sustained release of the drug with a daily concentrated pulse of ultrasound (2.5 minutes) fared significantly better than mice treated the same but without ultrasound.

In contrast to controls, the tumors in the ultrasound-treated mice did not grow substantially. And the mice survived for an additional 80 days.

Potential applications

The researchers believe their technique could help improve cancer treatment and other therapies requiring drugs to be delivered at the right place and the right time—from post-surgery pain medications to protein-based drugs that require daily injections.

It requires an initial injection of the hydrogel, but the approach could be a much less traumatic, minimally invasive, and more effective method of drug delivery than current methods, Dr Mooney said.

The researchers also found their hydrogel can release cargo other than drugs, including proteins and condensed plasmid DNA. This lays the groundwork for using these hydrogels for tissue regeneration and gene therapy.

Dr Mooney said he and his colleagues plan to explore these potential applications, as well as the possibility of unleashing 2 different drugs independently from the same hydrogel.

Hydrogels
Credit: Kathy Atkinson

Researchers have devised a novel way to deliver chemotherapy drugs “on demand,” according to a paper published in Proceedings of the National Academy of Sciences.

The team loaded a biocompatible hydrogel with a chemotherapy drug and used ultrasound to trigger the gel to release the drug.

Like many other injectable gels, this one gradually releases a low level of the drug by diffusion over time. But the new hydrogel differs from others in a key way.

Researchers previously applied ultrasound to gels to temporarily increase doses of drug, but that approach was a one-shot deal, as the ultrasound was used to destroy those gels.

In the current study, the researchers used ultrasound to temporarily disrupt the gel so that it released short, high-dose bursts of the drug. But when they stopped the ultrasound, the hydrogels self-healed.

By closing back up, they were ready to go for the next “on demand” drug burst, providing a way to administer drugs with a greater level of control than was possible before.

The researchers also demonstrated in lab cultures and in mouse models of breast cancer that the pulsed, ultrasound-triggered hydrogel approach to drug delivery was more effective at stopping the growth of tumor cells than traditional, sustained-release drug therapy.

“Our approach counters the whole idea of sustained drug release and offers a double whammy,” said study author David J. Mooney, PhD, of the Harvard School of Engineering and Applied Sciences in Boston.

“We have shown that we can use the hydrogels repeatedly and turn the drug pulses on and off at will, and that the drug bursts in concert with the baseline low-level drug delivery seems to be particularly effective in killing cancer cells.”

Self-healing hydrogel

Key to the researchers’ success in designing a hydrogel that self-heals was choosing the right kind of hydrogel with the right kind of drug and applying the right intensity of ultrasound.

“We were able to trigger our system with a level of ultrasound that was much lower than high-intensity focused ultrasound that is used clinically to heat and destroy tumors,” said study author Cathal Kearney, PhD, of the Royal College of Surgeons in Ireland. “The careful selection of materials and properties make it a reversible process.” 

The team carried out the majority of their work for this study with a gel made out of alginate, a natural polysaccharide from algae that is held together with calcium ions.

In a series of tests, they found that, with the right level of ultrasound, the bonds break up and enable the gel to release its drug cargo. But as long as the gel is in the presence of more calcium, the bonds reform and the gel self-heals.

Drug testing

Once the researchers knew the gel would self-heal, they tested out a drug they suspected it would hold well: the chemotherapy drug mitoxantrone.

Sure enough, the ultrasound triggered the gel to release the blue-colored drug, as indicated by the newly blue color of the surrounding medium. Just a single ultrasound dose was effective, and the gel reformed after it was disrupted, making multiple cycles possible.

Next, the team tested the treatment in mouse models of breast cancer. They injected the drug-laden gel close to the tumors.

Over the course of 6 months, the mice that received a low-level, sustained release of the drug with a daily concentrated pulse of ultrasound (2.5 minutes) fared significantly better than mice treated the same but without ultrasound.

In contrast to controls, the tumors in the ultrasound-treated mice did not grow substantially. And the mice survived for an additional 80 days.

Potential applications

The researchers believe their technique could help improve cancer treatment and other therapies requiring drugs to be delivered at the right place and the right time—from post-surgery pain medications to protein-based drugs that require daily injections.

It requires an initial injection of the hydrogel, but the approach could be a much less traumatic, minimally invasive, and more effective method of drug delivery than current methods, Dr Mooney said.

The researchers also found their hydrogel can release cargo other than drugs, including proteins and condensed plasmid DNA. This lays the groundwork for using these hydrogels for tissue regeneration and gene therapy.

Dr Mooney said he and his colleagues plan to explore these potential applications, as well as the possibility of unleashing 2 different drugs independently from the same hydrogel.

Hydrogels
Credit: Kathy Atkinson

Researchers have devised a novel way to deliver chemotherapy drugs “on demand,” according to a paper published in Proceedings of the National Academy of Sciences.

The team loaded a biocompatible hydrogel with a chemotherapy drug and used ultrasound to trigger the gel to release the drug.

Like many other injectable gels, this one gradually releases a low level of the drug by diffusion over time. But the new hydrogel differs from others in a key way.

Researchers previously applied ultrasound to gels to temporarily increase doses of drug, but that approach was a one-shot deal, as the ultrasound was used to destroy those gels.

In the current study, the researchers used ultrasound to temporarily disrupt the gel so that it released short, high-dose bursts of the drug. But when they stopped the ultrasound, the hydrogels self-healed.

By closing back up, they were ready to go for the next “on demand” drug burst, providing a way to administer drugs with a greater level of control than was possible before.

The researchers also demonstrated in lab cultures and in mouse models of breast cancer that the pulsed, ultrasound-triggered hydrogel approach to drug delivery was more effective at stopping the growth of tumor cells than traditional, sustained-release drug therapy.

“Our approach counters the whole idea of sustained drug release and offers a double whammy,” said study author David J. Mooney, PhD, of the Harvard School of Engineering and Applied Sciences in Boston.

“We have shown that we can use the hydrogels repeatedly and turn the drug pulses on and off at will, and that the drug bursts in concert with the baseline low-level drug delivery seems to be particularly effective in killing cancer cells.”

Self-healing hydrogel

Key to the researchers’ success in designing a hydrogel that self-heals was choosing the right kind of hydrogel with the right kind of drug and applying the right intensity of ultrasound.

“We were able to trigger our system with a level of ultrasound that was much lower than high-intensity focused ultrasound that is used clinically to heat and destroy tumors,” said study author Cathal Kearney, PhD, of the Royal College of Surgeons in Ireland. “The careful selection of materials and properties make it a reversible process.” 

The team carried out the majority of their work for this study with a gel made out of alginate, a natural polysaccharide from algae that is held together with calcium ions.

In a series of tests, they found that, with the right level of ultrasound, the bonds break up and enable the gel to release its drug cargo. But as long as the gel is in the presence of more calcium, the bonds reform and the gel self-heals.

Drug testing

Once the researchers knew the gel would self-heal, they tested out a drug they suspected it would hold well: the chemotherapy drug mitoxantrone.

Sure enough, the ultrasound triggered the gel to release the blue-colored drug, as indicated by the newly blue color of the surrounding medium. Just a single ultrasound dose was effective, and the gel reformed after it was disrupted, making multiple cycles possible.

Next, the team tested the treatment in mouse models of breast cancer. They injected the drug-laden gel close to the tumors.

Over the course of 6 months, the mice that received a low-level, sustained release of the drug with a daily concentrated pulse of ultrasound (2.5 minutes) fared significantly better than mice treated the same but without ultrasound.

In contrast to controls, the tumors in the ultrasound-treated mice did not grow substantially. And the mice survived for an additional 80 days.

Potential applications

The researchers believe their technique could help improve cancer treatment and other therapies requiring drugs to be delivered at the right place and the right time—from post-surgery pain medications to protein-based drugs that require daily injections.

It requires an initial injection of the hydrogel, but the approach could be a much less traumatic, minimally invasive, and more effective method of drug delivery than current methods, Dr Mooney said.

The researchers also found their hydrogel can release cargo other than drugs, including proteins and condensed plasmid DNA. This lays the groundwork for using these hydrogels for tissue regeneration and gene therapy.

Dr Mooney said he and his colleagues plan to explore these potential applications, as well as the possibility of unleashing 2 different drugs independently from the same hydrogel.

Hydrogels
Credit: Kathy Atkinson

Researchers have devised a novel way to deliver chemotherapy drugs “on demand,” according to a paper published in Proceedings of the National Academy of Sciences.

The team loaded a biocompatible hydrogel with a chemotherapy drug and used ultrasound to trigger the gel to release the drug.

Like many other injectable gels, this one gradually releases a low level of the drug by diffusion over time. But the new hydrogel differs from others in a key way.

Researchers previously applied ultrasound to gels to temporarily increase doses of drug, but that approach was a one-shot deal, as the ultrasound was used to destroy those gels.

In the current study, the researchers used ultrasound to temporarily disrupt the gel so that it released short, high-dose bursts of the drug. But when they stopped the ultrasound, the hydrogels self-healed.

By closing back up, they were ready to go for the next “on demand” drug burst, providing a way to administer drugs with a greater level of control than was possible before.

The researchers also demonstrated in lab cultures and in mouse models of breast cancer that the pulsed, ultrasound-triggered hydrogel approach to drug delivery was more effective at stopping the growth of tumor cells than traditional, sustained-release drug therapy.

“Our approach counters the whole idea of sustained drug release and offers a double whammy,” said study author David J. Mooney, PhD, of the Harvard School of Engineering and Applied Sciences in Boston.

“We have shown that we can use the hydrogels repeatedly and turn the drug pulses on and off at will, and that the drug bursts in concert with the baseline low-level drug delivery seems to be particularly effective in killing cancer cells.”

Self-healing hydrogel

Key to the researchers’ success in designing a hydrogel that self-heals was choosing the right kind of hydrogel with the right kind of drug and applying the right intensity of ultrasound.

“We were able to trigger our system with a level of ultrasound that was much lower than high-intensity focused ultrasound that is used clinically to heat and destroy tumors,” said study author Cathal Kearney, PhD, of the Royal College of Surgeons in Ireland. “The careful selection of materials and properties make it a reversible process.” 

The team carried out the majority of their work for this study with a gel made out of alginate, a natural polysaccharide from algae that is held together with calcium ions.

In a series of tests, they found that, with the right level of ultrasound, the bonds break up and enable the gel to release its drug cargo. But as long as the gel is in the presence of more calcium, the bonds reform and the gel self-heals.

Drug testing

Once the researchers knew the gel would self-heal, they tested out a drug they suspected it would hold well: the chemotherapy drug mitoxantrone.

Sure enough, the ultrasound triggered the gel to release the blue-colored drug, as indicated by the newly blue color of the surrounding medium. Just a single ultrasound dose was effective, and the gel reformed after it was disrupted, making multiple cycles possible.

Next, the team tested the treatment in mouse models of breast cancer. They injected the drug-laden gel close to the tumors.

Over the course of 6 months, the mice that received a low-level, sustained release of the drug with a daily concentrated pulse of ultrasound (2.5 minutes) fared significantly better than mice treated the same but without ultrasound.

In contrast to controls, the tumors in the ultrasound-treated mice did not grow substantially. And the mice survived for an additional 80 days.

Potential applications

The researchers believe their technique could help improve cancer treatment and other therapies requiring drugs to be delivered at the right place and the right time—from post-surgery pain medications to protein-based drugs that require daily injections.

It requires an initial injection of the hydrogel, but the approach could be a much less traumatic, minimally invasive, and more effective method of drug delivery than current methods, Dr Mooney said.

The researchers also found their hydrogel can release cargo other than drugs, including proteins and condensed plasmid DNA. This lays the groundwork for using these hydrogels for tissue regeneration and gene therapy.

Dr Mooney said he and his colleagues plan to explore these potential applications, as well as the possibility of unleashing 2 different drugs independently from the same hydrogel.