User login
Switch may increase supply of HSCs from cord blood
Photo courtesy of NHS
Researchers have discovered a genetic switch that could increase the supply of hematopoietic stem cells (HSCs) derived from cord blood, according to a paper published in Cell Stem Cell.
However, experiments in mice suggest that flipping the switch may also spur the development of myeloproliferative disease.
The researchers explained that, when an HSC divides, it produces multipotent progenitor (MPP) cells immediately downstream that retain the ability to differentiate but have lost the ability to self-renew.
By analyzing murine and human models of hematopoiesis, the team discovered that a microRNA, miR-125a, controls self-renewal and is normally switched on in HSCs but turned off in MPPs.
“Our work shows that if we artificially throw the switch on in those downstream cells [MPPs], we can endow them with stemness, and they basically become stem cells and can be maintained over the long term,” said study author John Dick, PhD, of Princess Margaret Cancer Centre at University Health Network in Toronto, Ontario, Canada.
Specifically, Dr Dick and his colleagues found that overexpression of miR-125a induced stem cell potential in both human MPPs and an as-yet-unidentified population within the CD34+38+ committed progenitor compartment.
Overexpression of miR-125a had a similar effect in murine MPPs. When the researchers transplanted these MPPs into recipient mice, the cells exhibited increased self-renewal and generated high levels of multi-lineage reconstitution for up to 16 weeks after transplant.
Unfortunately, when the miR-125a-overexpressed MPPs were transplanted into secondary and tertiary recipient mice, the animals developed symptoms of a myeloproliferative disease.
The researchers said this result is in line with findings from previous studies and has been shown to be dependent upon sustained expression of miR-125a and dosage.
The current study suggested that the miR-125a-induced myeloproliferative disease occurs, in part, as a function of replicative stress.
The researchers therefore speculated that, with careful titration of miR-125a levels, it may be possible to reap the beneficial self-renewal effects of miR-125a without inducing myeloproliferative disease.
In fact, the team hopes that, in the future, approaches combining miR-125a-modified MPPs with existing small-molecule compounds will enable the expansion of cord blood units for transplant. 
Photo courtesy of NHS
Researchers have discovered a genetic switch that could increase the supply of hematopoietic stem cells (HSCs) derived from cord blood, according to a paper published in Cell Stem Cell.
However, experiments in mice suggest that flipping the switch may also spur the development of myeloproliferative disease.
The researchers explained that, when an HSC divides, it produces multipotent progenitor (MPP) cells immediately downstream that retain the ability to differentiate but have lost the ability to self-renew.
By analyzing murine and human models of hematopoiesis, the team discovered that a microRNA, miR-125a, controls self-renewal and is normally switched on in HSCs but turned off in MPPs.
“Our work shows that if we artificially throw the switch on in those downstream cells [MPPs], we can endow them with stemness, and they basically become stem cells and can be maintained over the long term,” said study author John Dick, PhD, of Princess Margaret Cancer Centre at University Health Network in Toronto, Ontario, Canada.
Specifically, Dr Dick and his colleagues found that overexpression of miR-125a induced stem cell potential in both human MPPs and an as-yet-unidentified population within the CD34+38+ committed progenitor compartment.
Overexpression of miR-125a had a similar effect in murine MPPs. When the researchers transplanted these MPPs into recipient mice, the cells exhibited increased self-renewal and generated high levels of multi-lineage reconstitution for up to 16 weeks after transplant.
Unfortunately, when the miR-125a-overexpressed MPPs were transplanted into secondary and tertiary recipient mice, the animals developed symptoms of a myeloproliferative disease.
The researchers said this result is in line with findings from previous studies and has been shown to be dependent upon sustained expression of miR-125a and dosage.
The current study suggested that the miR-125a-induced myeloproliferative disease occurs, in part, as a function of replicative stress.
The researchers therefore speculated that, with careful titration of miR-125a levels, it may be possible to reap the beneficial self-renewal effects of miR-125a without inducing myeloproliferative disease.
In fact, the team hopes that, in the future, approaches combining miR-125a-modified MPPs with existing small-molecule compounds will enable the expansion of cord blood units for transplant.
Photo courtesy of NHS
Researchers have discovered a genetic switch that could increase the supply of hematopoietic stem cells (HSCs) derived from cord blood, according to a paper published in Cell Stem Cell.
However, experiments in mice suggest that flipping the switch may also spur the development of myeloproliferative disease.
The researchers explained that, when an HSC divides, it produces multipotent progenitor (MPP) cells immediately downstream that retain the ability to differentiate but have lost the ability to self-renew.
By analyzing murine and human models of hematopoiesis, the team discovered that a microRNA, miR-125a, controls self-renewal and is normally switched on in HSCs but turned off in MPPs.
“Our work shows that if we artificially throw the switch on in those downstream cells [MPPs], we can endow them with stemness, and they basically become stem cells and can be maintained over the long term,” said study author John Dick, PhD, of Princess Margaret Cancer Centre at University Health Network in Toronto, Ontario, Canada.
Specifically, Dr Dick and his colleagues found that overexpression of miR-125a induced stem cell potential in both human MPPs and an as-yet-unidentified population within the CD34+38+ committed progenitor compartment.
Overexpression of miR-125a had a similar effect in murine MPPs. When the researchers transplanted these MPPs into recipient mice, the cells exhibited increased self-renewal and generated high levels of multi-lineage reconstitution for up to 16 weeks after transplant.
Unfortunately, when the miR-125a-overexpressed MPPs were transplanted into secondary and tertiary recipient mice, the animals developed symptoms of a myeloproliferative disease.
The researchers said this result is in line with findings from previous studies and has been shown to be dependent upon sustained expression of miR-125a and dosage.
The current study suggested that the miR-125a-induced myeloproliferative disease occurs, in part, as a function of replicative stress.
The researchers therefore speculated that, with careful titration of miR-125a levels, it may be possible to reap the beneficial self-renewal effects of miR-125a without inducing myeloproliferative disease.
In fact, the team hopes that, in the future, approaches combining miR-125a-modified MPPs with existing small-molecule compounds will enable the expansion of cord blood units for transplant.
Cancer patients and docs disagree about prognosis
patient and her father
Photo by Rhoda Baer
In a survey of advanced cancer patients and their oncologists, differing opinions about prognosis were common.
And the vast majority of patients didn’t know their doctors held different opinions about how long the patients might live.
Results of the survey were published in JAMA Oncology.
“We’ve discovered 2 important things happening between oncologists and patients with advanced cancer,” said study author Ronald M. Epstein, MD, of the University of Rochester Medical Center in Rochester, New York.
“First, some patients might know the doctor’s prognosis estimate, but the patient chooses to disagree, often because they believe other sources. And, second, some patients think that their doctor agrees with their opinion about prognosis but, in fact, the doctor doesn’t.”
Dr Epstein and his colleagues surveyed 236 patients with stage 3 or 4 cancer. According to medical evidence, fewer than 5% of these patients would be expected to live for 5 years.
The 38 oncologists who treated these patients were also surveyed. The doctors were asked,“What do you believe are the chances that this patient will live for 2 years or more?” And the patients were asked, “What do you believe are the chances that you will live for 2 years or more?”
Additional survey questions gauged whether patients knew their prognosis opinions differed from their doctors and to what extent treatment options were discussed in the context of life expectancy.
Among the 236 patients, 68% rated their survival prognosis differently than their oncologists, and 89% of these patients did not realize their opinions differed from their oncologists. In nearly all cases (96%), the patients were more optimistic than their doctors.
“Of course, it’s only possible for doctors to provide a ball-park estimate about life expectancy, and some people do beat the odds,” Dr Epstein noted. “But when a patient with very advanced cancer says that he has a 90% to 100% chance of being alive in 2 years and his oncologist believes that chance is more like 10%, there’s a problem.”
The challenge, according to Dr Epstein and his colleagues, is that talking about a cancer prognosis is not a straightforward exchange of information. It occurs in the context of fear, confusion, and uncertainty.
The researchers said prognosis should be addressed in several conversations about personal values and treatment goals. When doctor-patient communication is poor, it can result in mutual regret about end-of-life circumstances.
For example, nearly all of the patients surveyed said they wanted to be involved in treatment decisions. And 70% said they preferred supportive care at the end of their lives as opposed to aggressive therapy. However, as the researchers pointed out, making an informed decision requires knowing when death is approaching.
“When people think they’ll live a very long time with cancer, despite evidence to the contrary, they may end up taking more aggressive chemotherapy and agreeing to be placed on ventilators or dialysis, paradoxically reducing their quality of life, keeping them from enjoying time with family, and sometimes even shortening their lives,” Dr Epstein said. “So it’s very important for doctors and patients to be on the same page.”
patient and her father
Photo by Rhoda Baer
In a survey of advanced cancer patients and their oncologists, differing opinions about prognosis were common.
And the vast majority of patients didn’t know their doctors held different opinions about how long the patients might live.
Results of the survey were published in JAMA Oncology.
“We’ve discovered 2 important things happening between oncologists and patients with advanced cancer,” said study author Ronald M. Epstein, MD, of the University of Rochester Medical Center in Rochester, New York.
“First, some patients might know the doctor’s prognosis estimate, but the patient chooses to disagree, often because they believe other sources. And, second, some patients think that their doctor agrees with their opinion about prognosis but, in fact, the doctor doesn’t.”
Dr Epstein and his colleagues surveyed 236 patients with stage 3 or 4 cancer. According to medical evidence, fewer than 5% of these patients would be expected to live for 5 years.
The 38 oncologists who treated these patients were also surveyed. The doctors were asked,“What do you believe are the chances that this patient will live for 2 years or more?” And the patients were asked, “What do you believe are the chances that you will live for 2 years or more?”
Additional survey questions gauged whether patients knew their prognosis opinions differed from their doctors and to what extent treatment options were discussed in the context of life expectancy.
Among the 236 patients, 68% rated their survival prognosis differently than their oncologists, and 89% of these patients did not realize their opinions differed from their oncologists. In nearly all cases (96%), the patients were more optimistic than their doctors.
“Of course, it’s only possible for doctors to provide a ball-park estimate about life expectancy, and some people do beat the odds,” Dr Epstein noted. “But when a patient with very advanced cancer says that he has a 90% to 100% chance of being alive in 2 years and his oncologist believes that chance is more like 10%, there’s a problem.”
The challenge, according to Dr Epstein and his colleagues, is that talking about a cancer prognosis is not a straightforward exchange of information. It occurs in the context of fear, confusion, and uncertainty.
The researchers said prognosis should be addressed in several conversations about personal values and treatment goals. When doctor-patient communication is poor, it can result in mutual regret about end-of-life circumstances.
For example, nearly all of the patients surveyed said they wanted to be involved in treatment decisions. And 70% said they preferred supportive care at the end of their lives as opposed to aggressive therapy. However, as the researchers pointed out, making an informed decision requires knowing when death is approaching.
“When people think they’ll live a very long time with cancer, despite evidence to the contrary, they may end up taking more aggressive chemotherapy and agreeing to be placed on ventilators or dialysis, paradoxically reducing their quality of life, keeping them from enjoying time with family, and sometimes even shortening their lives,” Dr Epstein said. “So it’s very important for doctors and patients to be on the same page.”
patient and her father
Photo by Rhoda Baer
In a survey of advanced cancer patients and their oncologists, differing opinions about prognosis were common.
And the vast majority of patients didn’t know their doctors held different opinions about how long the patients might live.
Results of the survey were published in JAMA Oncology.
“We’ve discovered 2 important things happening between oncologists and patients with advanced cancer,” said study author Ronald M. Epstein, MD, of the University of Rochester Medical Center in Rochester, New York.
“First, some patients might know the doctor’s prognosis estimate, but the patient chooses to disagree, often because they believe other sources. And, second, some patients think that their doctor agrees with their opinion about prognosis but, in fact, the doctor doesn’t.”
Dr Epstein and his colleagues surveyed 236 patients with stage 3 or 4 cancer. According to medical evidence, fewer than 5% of these patients would be expected to live for 5 years.
The 38 oncologists who treated these patients were also surveyed. The doctors were asked,“What do you believe are the chances that this patient will live for 2 years or more?” And the patients were asked, “What do you believe are the chances that you will live for 2 years or more?”
Additional survey questions gauged whether patients knew their prognosis opinions differed from their doctors and to what extent treatment options were discussed in the context of life expectancy.
Among the 236 patients, 68% rated their survival prognosis differently than their oncologists, and 89% of these patients did not realize their opinions differed from their oncologists. In nearly all cases (96%), the patients were more optimistic than their doctors.
“Of course, it’s only possible for doctors to provide a ball-park estimate about life expectancy, and some people do beat the odds,” Dr Epstein noted. “But when a patient with very advanced cancer says that he has a 90% to 100% chance of being alive in 2 years and his oncologist believes that chance is more like 10%, there’s a problem.”
The challenge, according to Dr Epstein and his colleagues, is that talking about a cancer prognosis is not a straightforward exchange of information. It occurs in the context of fear, confusion, and uncertainty.
The researchers said prognosis should be addressed in several conversations about personal values and treatment goals. When doctor-patient communication is poor, it can result in mutual regret about end-of-life circumstances.
For example, nearly all of the patients surveyed said they wanted to be involved in treatment decisions. And 70% said they preferred supportive care at the end of their lives as opposed to aggressive therapy. However, as the researchers pointed out, making an informed decision requires knowing when death is approaching.
“When people think they’ll live a very long time with cancer, despite evidence to the contrary, they may end up taking more aggressive chemotherapy and agreeing to be placed on ventilators or dialysis, paradoxically reducing their quality of life, keeping them from enjoying time with family, and sometimes even shortening their lives,” Dr Epstein said. “So it’s very important for doctors and patients to be on the same page.”
Weight loss lowers levels of cancer-associated proteins
A study of more than 400 women suggests that losing weight can reduce levels of cancer-promoting proteins in the blood.
Overweight or obese women who lost weight over a 12-month period—through diet alone or both diet and exercise—significantly lowered their levels of proteins that play a role in angiogenesis.
Researchers say this finding suggests that losing weight might help reduce the risk of developing certain cancers.
“We know that being overweight and having a sedentary lifestyle is associated with an increase in risk for developing certain types of cancer,” said Catherine Duggan, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.
“However, we don’t know exactly why. We wanted to investigate how levels of some biomarkers associated with angiogenesis were altered when overweight, sedentary, postmenopausal women enrolled in a research study lost weight and/or became physically active over the course of a year.”
Dr Duggan and her colleagues described this investigation in Cancer Research.
The team studied 439 women who were postmenopausal and overweight or obese but were otherwise healthy and ranged in age from 50 to 75.
The women were randomized to 1 of 4 study arms:
- A diet arm, in which women restricted their calorie intake to no more than 2000 kcal per day that included less than 30% of fat calories
- An aerobic exercise arm, in which women performed 45 minutes of moderate to vigorous exercise 5 days a week
- A combined diet and exercise arm
- A control arm.
The researchers collected blood samples at baseline and at 12 months, measuring levels of the angiogenesis-related proteins VEGF, PAI-1, and PEDF.
They also measured weight loss at 12 months and found that women in all 3 intervention arms had a significantly higher mean weight loss than women in the control arm.
The mean weight loss was 0.8% of body weight for women in the control arm, 2.4% for women in the exercise arm (P=0.03), 8.5% for women in the diet arm (P<0.001), and 10.8% for women in the diet and exercise arm (P<0.001).
Compared with women in the control arm, those in the diet-only arm and the diet and exercise arm had significantly lower levels of the angiogenesis-related proteins at 12 months. However, such effects were not apparent among women in the exercise-only arm.
Specifically, women in the diet and exercise arm had a significantly greater reduction in PAI-1 at 12 months than women in the control arm (-19.3% and +3.48%, respectively, P<0.0001).
Women in the diet-only arm and the diet and exercise arm had significantly greater reductions in PEDF than controls (-9.20%, -9.90%, and +0.18%, respectively, both P<0.0001).
And women in the diet-only arm (-8.25%, P=0.0005) and the diet and exercise arm (-9.98%, P<0.0001) had significantly greater reductions in VEGF than controls (-1.21%).
The researchers also observed a linear trend in the reductions. So the more weight loss the women experienced, the greater the reduction in angiogenesis-related protein levels.
“Our study shows that weight loss is a safe and effective method of improving the angiogenic profile in healthy individuals,” Dr Duggan said. “We were surprised by the magnitude of change in these biomarkers with weight loss.”
“While we can’t say for certain that reducing the circulating levels of angiogenic factors through weight loss would impact the growth of tumors, it is possible that they might be associated with a less favorable milieu for tumor growth and proliferation.”
Dr Duggan and her colleagues said limitations of this study include the fact that the researchers only measured 3 angiogenic factors and did not measure them in adipose or other tissues.
A study of more than 400 women suggests that losing weight can reduce levels of cancer-promoting proteins in the blood.
Overweight or obese women who lost weight over a 12-month period—through diet alone or both diet and exercise—significantly lowered their levels of proteins that play a role in angiogenesis.
Researchers say this finding suggests that losing weight might help reduce the risk of developing certain cancers.
“We know that being overweight and having a sedentary lifestyle is associated with an increase in risk for developing certain types of cancer,” said Catherine Duggan, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.
“However, we don’t know exactly why. We wanted to investigate how levels of some biomarkers associated with angiogenesis were altered when overweight, sedentary, postmenopausal women enrolled in a research study lost weight and/or became physically active over the course of a year.”
Dr Duggan and her colleagues described this investigation in Cancer Research.
The team studied 439 women who were postmenopausal and overweight or obese but were otherwise healthy and ranged in age from 50 to 75.
The women were randomized to 1 of 4 study arms:
- A diet arm, in which women restricted their calorie intake to no more than 2000 kcal per day that included less than 30% of fat calories
- An aerobic exercise arm, in which women performed 45 minutes of moderate to vigorous exercise 5 days a week
- A combined diet and exercise arm
- A control arm.
The researchers collected blood samples at baseline and at 12 months, measuring levels of the angiogenesis-related proteins VEGF, PAI-1, and PEDF.
They also measured weight loss at 12 months and found that women in all 3 intervention arms had a significantly higher mean weight loss than women in the control arm.
The mean weight loss was 0.8% of body weight for women in the control arm, 2.4% for women in the exercise arm (P=0.03), 8.5% for women in the diet arm (P<0.001), and 10.8% for women in the diet and exercise arm (P<0.001).
Compared with women in the control arm, those in the diet-only arm and the diet and exercise arm had significantly lower levels of the angiogenesis-related proteins at 12 months. However, such effects were not apparent among women in the exercise-only arm.
Specifically, women in the diet and exercise arm had a significantly greater reduction in PAI-1 at 12 months than women in the control arm (-19.3% and +3.48%, respectively, P<0.0001).
Women in the diet-only arm and the diet and exercise arm had significantly greater reductions in PEDF than controls (-9.20%, -9.90%, and +0.18%, respectively, both P<0.0001).
And women in the diet-only arm (-8.25%, P=0.0005) and the diet and exercise arm (-9.98%, P<0.0001) had significantly greater reductions in VEGF than controls (-1.21%).
The researchers also observed a linear trend in the reductions. So the more weight loss the women experienced, the greater the reduction in angiogenesis-related protein levels.
“Our study shows that weight loss is a safe and effective method of improving the angiogenic profile in healthy individuals,” Dr Duggan said. “We were surprised by the magnitude of change in these biomarkers with weight loss.”
“While we can’t say for certain that reducing the circulating levels of angiogenic factors through weight loss would impact the growth of tumors, it is possible that they might be associated with a less favorable milieu for tumor growth and proliferation.”
Dr Duggan and her colleagues said limitations of this study include the fact that the researchers only measured 3 angiogenic factors and did not measure them in adipose or other tissues.
A study of more than 400 women suggests that losing weight can reduce levels of cancer-promoting proteins in the blood.
Overweight or obese women who lost weight over a 12-month period—through diet alone or both diet and exercise—significantly lowered their levels of proteins that play a role in angiogenesis.
Researchers say this finding suggests that losing weight might help reduce the risk of developing certain cancers.
“We know that being overweight and having a sedentary lifestyle is associated with an increase in risk for developing certain types of cancer,” said Catherine Duggan, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.
“However, we don’t know exactly why. We wanted to investigate how levels of some biomarkers associated with angiogenesis were altered when overweight, sedentary, postmenopausal women enrolled in a research study lost weight and/or became physically active over the course of a year.”
Dr Duggan and her colleagues described this investigation in Cancer Research.
The team studied 439 women who were postmenopausal and overweight or obese but were otherwise healthy and ranged in age from 50 to 75.
The women were randomized to 1 of 4 study arms:
- A diet arm, in which women restricted their calorie intake to no more than 2000 kcal per day that included less than 30% of fat calories
- An aerobic exercise arm, in which women performed 45 minutes of moderate to vigorous exercise 5 days a week
- A combined diet and exercise arm
- A control arm.
The researchers collected blood samples at baseline and at 12 months, measuring levels of the angiogenesis-related proteins VEGF, PAI-1, and PEDF.
They also measured weight loss at 12 months and found that women in all 3 intervention arms had a significantly higher mean weight loss than women in the control arm.
The mean weight loss was 0.8% of body weight for women in the control arm, 2.4% for women in the exercise arm (P=0.03), 8.5% for women in the diet arm (P<0.001), and 10.8% for women in the diet and exercise arm (P<0.001).
Compared with women in the control arm, those in the diet-only arm and the diet and exercise arm had significantly lower levels of the angiogenesis-related proteins at 12 months. However, such effects were not apparent among women in the exercise-only arm.
Specifically, women in the diet and exercise arm had a significantly greater reduction in PAI-1 at 12 months than women in the control arm (-19.3% and +3.48%, respectively, P<0.0001).
Women in the diet-only arm and the diet and exercise arm had significantly greater reductions in PEDF than controls (-9.20%, -9.90%, and +0.18%, respectively, both P<0.0001).
And women in the diet-only arm (-8.25%, P=0.0005) and the diet and exercise arm (-9.98%, P<0.0001) had significantly greater reductions in VEGF than controls (-1.21%).
The researchers also observed a linear trend in the reductions. So the more weight loss the women experienced, the greater the reduction in angiogenesis-related protein levels.
“Our study shows that weight loss is a safe and effective method of improving the angiogenic profile in healthy individuals,” Dr Duggan said. “We were surprised by the magnitude of change in these biomarkers with weight loss.”
“While we can’t say for certain that reducing the circulating levels of angiogenic factors through weight loss would impact the growth of tumors, it is possible that they might be associated with a less favorable milieu for tumor growth and proliferation.”
Dr Duggan and her colleagues said limitations of this study include the fact that the researchers only measured 3 angiogenic factors and did not measure them in adipose or other tissues.
Predicting outcomes in AML patients
Photo by Darren Baker
An international competition has produced models that can help predict outcomes in patients with acute myeloid leukemia (AML), according to researchers.
For the competition, known as the DREAM 9 challenge, 31 teams of computational researchers attempted to predict outcomes using data from hundreds of patients with AML.
DREAM, which stands for Dialogue for Reverse Engineering Assessment and Methods, is a platform for crowd-sourced studies that focus on developing computational tools to solve biomedical problems.
Essentially, it’s a competition that serves as a large, long-standing, international scientific collaboration.
“We used DREAM as a way to get general insight into making more accurate predictive models of clinical outcomes,” said Amina Qutub, PhD, of Rice University in Houston, Texas.
She and her colleagues described this effort in PLOS Computational Biology.
For the DREAM 9 challenge, each team was presented with training data from 191 AML patients, which included demographic information, such as age and gender, and more complex proteomic and phosphoprotein data that describes signaling protein pathways believed to play a role in AML.
The teams were also presented with a test set of 100 AML patients and were asked to predict response to therapy, remission duration, or overall survival for these patients.
The top-performing models—by Team EvoMed of Arizona State University and Team Chipmunks of the Ontario Institute for Cancer Research—were able to predict patient response to therapy with an accuracy of close to 80%.
Both of these models were impacted by the perturbation of PIK3CA and NPM1, which singles out these proteins as candidates for further study, according to researchers.
Another discovery resulting from this competition was that, overall, the 31 models were not as effective for predicting outcomes in patients classified as “resistant to therapy” than for responsive patients.
The median model prediction accuracy was 42% for resistant patients and 73% for responsive patients.
Photo by Darren Baker
An international competition has produced models that can help predict outcomes in patients with acute myeloid leukemia (AML), according to researchers.
For the competition, known as the DREAM 9 challenge, 31 teams of computational researchers attempted to predict outcomes using data from hundreds of patients with AML.
DREAM, which stands for Dialogue for Reverse Engineering Assessment and Methods, is a platform for crowd-sourced studies that focus on developing computational tools to solve biomedical problems.
Essentially, it’s a competition that serves as a large, long-standing, international scientific collaboration.
“We used DREAM as a way to get general insight into making more accurate predictive models of clinical outcomes,” said Amina Qutub, PhD, of Rice University in Houston, Texas.
She and her colleagues described this effort in PLOS Computational Biology.
For the DREAM 9 challenge, each team was presented with training data from 191 AML patients, which included demographic information, such as age and gender, and more complex proteomic and phosphoprotein data that describes signaling protein pathways believed to play a role in AML.
The teams were also presented with a test set of 100 AML patients and were asked to predict response to therapy, remission duration, or overall survival for these patients.
The top-performing models—by Team EvoMed of Arizona State University and Team Chipmunks of the Ontario Institute for Cancer Research—were able to predict patient response to therapy with an accuracy of close to 80%.
Both of these models were impacted by the perturbation of PIK3CA and NPM1, which singles out these proteins as candidates for further study, according to researchers.
Another discovery resulting from this competition was that, overall, the 31 models were not as effective for predicting outcomes in patients classified as “resistant to therapy” than for responsive patients.
The median model prediction accuracy was 42% for resistant patients and 73% for responsive patients.
Photo by Darren Baker
An international competition has produced models that can help predict outcomes in patients with acute myeloid leukemia (AML), according to researchers.
For the competition, known as the DREAM 9 challenge, 31 teams of computational researchers attempted to predict outcomes using data from hundreds of patients with AML.
DREAM, which stands for Dialogue for Reverse Engineering Assessment and Methods, is a platform for crowd-sourced studies that focus on developing computational tools to solve biomedical problems.
Essentially, it’s a competition that serves as a large, long-standing, international scientific collaboration.
“We used DREAM as a way to get general insight into making more accurate predictive models of clinical outcomes,” said Amina Qutub, PhD, of Rice University in Houston, Texas.
She and her colleagues described this effort in PLOS Computational Biology.
For the DREAM 9 challenge, each team was presented with training data from 191 AML patients, which included demographic information, such as age and gender, and more complex proteomic and phosphoprotein data that describes signaling protein pathways believed to play a role in AML.
The teams were also presented with a test set of 100 AML patients and were asked to predict response to therapy, remission duration, or overall survival for these patients.
The top-performing models—by Team EvoMed of Arizona State University and Team Chipmunks of the Ontario Institute for Cancer Research—were able to predict patient response to therapy with an accuracy of close to 80%.
Both of these models were impacted by the perturbation of PIK3CA and NPM1, which singles out these proteins as candidates for further study, according to researchers.
Another discovery resulting from this competition was that, overall, the 31 models were not as effective for predicting outcomes in patients classified as “resistant to therapy” than for responsive patients.
The median model prediction accuracy was 42% for resistant patients and 73% for responsive patients.
FDA lifts hold on phase 2 JCAR015 trial
Image from NIAID
The US Food and Drug Administration (FDA) has removed the clinical hold on the phase 2 ROCKET trial, a study of the chimeric antigen receptor (CAR) T-cell therapy JCAR015 in adults with relapsed or refractory B-cell acute lymphoblastic leukemia.
The trial will continue with a revised protocol, under which patients will receive only cyclophosphamide as conditioning.
The ROCKET trial was placed on hold after 3 patients died of cerebral edema.
Juno Therapeutics, the company developing JCAR015, believes the deaths were likely a result of adding fludarabine to the conditioning regimen.
Patients initially received conditioning with cyclophosphamide alone, but investigators decided to add fludarabine in hopes of increasing efficacy. Adding fludarabine to conditioning had been shown to increase the efficacy of 2 other CAR T-cell therapies, JCAR014 and JCAR017, in phase 1/2 trials.
However, in the ROCKET trial, the addition of fludarabine was associated with an increase in the incidence of severe neurotoxicity and the 3 deaths from cerebral edema.
Although other factors may have contributed to the deaths, Juno said fludarabine was the most likely culprit. So the company asked the FDA if it could continue the ROCKET trial using conditioning with cyclophosphamide alone.
In response, the FDA requested that Juno submit a revised patient informed consent form, revised investigator brochure, revised trial protocol, and a copy of a presentation the company made to the FDA.
The FDA said it would review these documents within 30 days of receiving them, but the review only took a few days. The agency agreed to lift the clinical hold and allow the trial to proceed with the revised protocol.
ROCKET is not the first trial of JCAR015 to be placed on clinical hold. The phase 1 trial of the therapy was placed on hold in 2014, after 2 patients died of cytokine release syndrome.
That hold was lifted following changes to enrollment criteria and dosing. Results from this trial were presented at ASCO 2015 and ASCO 2016.
Image from NIAID
The US Food and Drug Administration (FDA) has removed the clinical hold on the phase 2 ROCKET trial, a study of the chimeric antigen receptor (CAR) T-cell therapy JCAR015 in adults with relapsed or refractory B-cell acute lymphoblastic leukemia.
The trial will continue with a revised protocol, under which patients will receive only cyclophosphamide as conditioning.
The ROCKET trial was placed on hold after 3 patients died of cerebral edema.
Juno Therapeutics, the company developing JCAR015, believes the deaths were likely a result of adding fludarabine to the conditioning regimen.
Patients initially received conditioning with cyclophosphamide alone, but investigators decided to add fludarabine in hopes of increasing efficacy. Adding fludarabine to conditioning had been shown to increase the efficacy of 2 other CAR T-cell therapies, JCAR014 and JCAR017, in phase 1/2 trials.
However, in the ROCKET trial, the addition of fludarabine was associated with an increase in the incidence of severe neurotoxicity and the 3 deaths from cerebral edema.
Although other factors may have contributed to the deaths, Juno said fludarabine was the most likely culprit. So the company asked the FDA if it could continue the ROCKET trial using conditioning with cyclophosphamide alone.
In response, the FDA requested that Juno submit a revised patient informed consent form, revised investigator brochure, revised trial protocol, and a copy of a presentation the company made to the FDA.
The FDA said it would review these documents within 30 days of receiving them, but the review only took a few days. The agency agreed to lift the clinical hold and allow the trial to proceed with the revised protocol.
ROCKET is not the first trial of JCAR015 to be placed on clinical hold. The phase 1 trial of the therapy was placed on hold in 2014, after 2 patients died of cytokine release syndrome.
That hold was lifted following changes to enrollment criteria and dosing. Results from this trial were presented at ASCO 2015 and ASCO 2016.
Image from NIAID
The US Food and Drug Administration (FDA) has removed the clinical hold on the phase 2 ROCKET trial, a study of the chimeric antigen receptor (CAR) T-cell therapy JCAR015 in adults with relapsed or refractory B-cell acute lymphoblastic leukemia.
The trial will continue with a revised protocol, under which patients will receive only cyclophosphamide as conditioning.
The ROCKET trial was placed on hold after 3 patients died of cerebral edema.
Juno Therapeutics, the company developing JCAR015, believes the deaths were likely a result of adding fludarabine to the conditioning regimen.
Patients initially received conditioning with cyclophosphamide alone, but investigators decided to add fludarabine in hopes of increasing efficacy. Adding fludarabine to conditioning had been shown to increase the efficacy of 2 other CAR T-cell therapies, JCAR014 and JCAR017, in phase 1/2 trials.
However, in the ROCKET trial, the addition of fludarabine was associated with an increase in the incidence of severe neurotoxicity and the 3 deaths from cerebral edema.
Although other factors may have contributed to the deaths, Juno said fludarabine was the most likely culprit. So the company asked the FDA if it could continue the ROCKET trial using conditioning with cyclophosphamide alone.
In response, the FDA requested that Juno submit a revised patient informed consent form, revised investigator brochure, revised trial protocol, and a copy of a presentation the company made to the FDA.
The FDA said it would review these documents within 30 days of receiving them, but the review only took a few days. The agency agreed to lift the clinical hold and allow the trial to proceed with the revised protocol.
ROCKET is not the first trial of JCAR015 to be placed on clinical hold. The phase 1 trial of the therapy was placed on hold in 2014, after 2 patients died of cytokine release syndrome.
That hold was lifted following changes to enrollment criteria and dosing. Results from this trial were presented at ASCO 2015 and ASCO 2016.
Cell of origin impacts aggressiveness of AML
New research suggests the cell of origin controls the aggressiveness and outcome of acute myeloid leukemia (AML) driven by MLL-AF9.
Using a mouse model, investigators found that MLL-AF9 expression in long-term hematopoietic stem cells (HSCs) causes invasive, chemoresistant AML that expresses genes related to epithelial-mesenchymal transition (EMT).
The researchers also found these genes were associated with poor survival in humans with AML.
“The prognosis thus depends on the particular hematopoietic stem or precursor cells in which the genetic alteration occurs and what genes are expressed,” said Antoine Peters, PhD, of Friedrich Miescher Institute for Biomedical Research in Basel, Switzerland.
Dr Peters and his colleagues related these findings in Cancer Cell.
The investigators compared the results of MLL-AF9 expression in long-term HSCs and granulocyte-macrophage progenitors (GMPs) in vitro. They found that colonies derived from long-term HSCs exhibited a greater capacity to migrate and expressed genes known to be involved in cell migration and tissue invasion.
With in vivo experiments, the researchers found that long-term HSCs were more potent in inducing AML than GMPs. Twenty percent of long-term HSC-derived AMLs proved especially aggressive, exhibiting extensive tissue infiltration, resistance to chemotherapy, and the expression of EMT genes such as EVI1, ERG, and ZEB1.
The investigators then tested the function of EMT-related transcription factors in leukemic cell migration and invasion. And they found that knocking down ZEB1 significantly reduced leukemic blast invasion.
Next, the researchers classified mouse and human leukemias according to EVI1/Evi1 and ERG/Erg expression and compared transcriptional profiles between species.
This revealed 111 genes that were more highly expressed in EVI1highERGhigh AML and Evi1highErghigh iMLL-AF9 long-term-HSC-early AML. These genes were dubbed ‘‘cluster I.’’
The investigators also identified 40 genes that were more highly expressed in EVI1lowERGlow AML samples and in iMLL-AF9 GMP-derived AML. These were called ‘‘cluster II.’’
Finally, the team evaluated how the 2 gene clusters related to overall survival in patients with 11q23+ AML.
Patients with high expression of cluster I genes tended to have poor survival rates, while patients with high levels of cluster II genes had variable survival rates and a propensity for poor outcomes if they had co-expression of a “substantial fraction” of cluster I genes.
The researchers noted that many cluster I genes are implicated in cell migration, invasion, EMT, and inflammation.
“The expression of genes such as EVI1, ERG, or ZEB1 now allows us to classify patients into different groups according to prognosis and, if necessary, to adapt treatment,” said Jürg Schwaller, MD, of University Children’s Hospital and University of Basel in Switzerland.
“Our findings should also enable us to develop new, more personalized therapies for these patients.”
New research suggests the cell of origin controls the aggressiveness and outcome of acute myeloid leukemia (AML) driven by MLL-AF9.
Using a mouse model, investigators found that MLL-AF9 expression in long-term hematopoietic stem cells (HSCs) causes invasive, chemoresistant AML that expresses genes related to epithelial-mesenchymal transition (EMT).
The researchers also found these genes were associated with poor survival in humans with AML.
“The prognosis thus depends on the particular hematopoietic stem or precursor cells in which the genetic alteration occurs and what genes are expressed,” said Antoine Peters, PhD, of Friedrich Miescher Institute for Biomedical Research in Basel, Switzerland.
Dr Peters and his colleagues related these findings in Cancer Cell.
The investigators compared the results of MLL-AF9 expression in long-term HSCs and granulocyte-macrophage progenitors (GMPs) in vitro. They found that colonies derived from long-term HSCs exhibited a greater capacity to migrate and expressed genes known to be involved in cell migration and tissue invasion.
With in vivo experiments, the researchers found that long-term HSCs were more potent in inducing AML than GMPs. Twenty percent of long-term HSC-derived AMLs proved especially aggressive, exhibiting extensive tissue infiltration, resistance to chemotherapy, and the expression of EMT genes such as EVI1, ERG, and ZEB1.
The investigators then tested the function of EMT-related transcription factors in leukemic cell migration and invasion. And they found that knocking down ZEB1 significantly reduced leukemic blast invasion.
Next, the researchers classified mouse and human leukemias according to EVI1/Evi1 and ERG/Erg expression and compared transcriptional profiles between species.
This revealed 111 genes that were more highly expressed in EVI1highERGhigh AML and Evi1highErghigh iMLL-AF9 long-term-HSC-early AML. These genes were dubbed ‘‘cluster I.’’
The investigators also identified 40 genes that were more highly expressed in EVI1lowERGlow AML samples and in iMLL-AF9 GMP-derived AML. These were called ‘‘cluster II.’’
Finally, the team evaluated how the 2 gene clusters related to overall survival in patients with 11q23+ AML.
Patients with high expression of cluster I genes tended to have poor survival rates, while patients with high levels of cluster II genes had variable survival rates and a propensity for poor outcomes if they had co-expression of a “substantial fraction” of cluster I genes.
The researchers noted that many cluster I genes are implicated in cell migration, invasion, EMT, and inflammation.
“The expression of genes such as EVI1, ERG, or ZEB1 now allows us to classify patients into different groups according to prognosis and, if necessary, to adapt treatment,” said Jürg Schwaller, MD, of University Children’s Hospital and University of Basel in Switzerland.
“Our findings should also enable us to develop new, more personalized therapies for these patients.”
New research suggests the cell of origin controls the aggressiveness and outcome of acute myeloid leukemia (AML) driven by MLL-AF9.
Using a mouse model, investigators found that MLL-AF9 expression in long-term hematopoietic stem cells (HSCs) causes invasive, chemoresistant AML that expresses genes related to epithelial-mesenchymal transition (EMT).
The researchers also found these genes were associated with poor survival in humans with AML.
“The prognosis thus depends on the particular hematopoietic stem or precursor cells in which the genetic alteration occurs and what genes are expressed,” said Antoine Peters, PhD, of Friedrich Miescher Institute for Biomedical Research in Basel, Switzerland.
Dr Peters and his colleagues related these findings in Cancer Cell.
The investigators compared the results of MLL-AF9 expression in long-term HSCs and granulocyte-macrophage progenitors (GMPs) in vitro. They found that colonies derived from long-term HSCs exhibited a greater capacity to migrate and expressed genes known to be involved in cell migration and tissue invasion.
With in vivo experiments, the researchers found that long-term HSCs were more potent in inducing AML than GMPs. Twenty percent of long-term HSC-derived AMLs proved especially aggressive, exhibiting extensive tissue infiltration, resistance to chemotherapy, and the expression of EMT genes such as EVI1, ERG, and ZEB1.
The investigators then tested the function of EMT-related transcription factors in leukemic cell migration and invasion. And they found that knocking down ZEB1 significantly reduced leukemic blast invasion.
Next, the researchers classified mouse and human leukemias according to EVI1/Evi1 and ERG/Erg expression and compared transcriptional profiles between species.
This revealed 111 genes that were more highly expressed in EVI1highERGhigh AML and Evi1highErghigh iMLL-AF9 long-term-HSC-early AML. These genes were dubbed ‘‘cluster I.’’
The investigators also identified 40 genes that were more highly expressed in EVI1lowERGlow AML samples and in iMLL-AF9 GMP-derived AML. These were called ‘‘cluster II.’’
Finally, the team evaluated how the 2 gene clusters related to overall survival in patients with 11q23+ AML.
Patients with high expression of cluster I genes tended to have poor survival rates, while patients with high levels of cluster II genes had variable survival rates and a propensity for poor outcomes if they had co-expression of a “substantial fraction” of cluster I genes.
The researchers noted that many cluster I genes are implicated in cell migration, invasion, EMT, and inflammation.
“The expression of genes such as EVI1, ERG, or ZEB1 now allows us to classify patients into different groups according to prognosis and, if necessary, to adapt treatment,” said Jürg Schwaller, MD, of University Children’s Hospital and University of Basel in Switzerland.
“Our findings should also enable us to develop new, more personalized therapies for these patients.”
Study reveals increase in susceptibility to malaria
Photo by Gabrielle Tenenbaum
Progress in reducing the malaria burden in Africa may have had the paradoxical effect of increasing malaria transmission among older children in recent years, according to research published in PLOS Medicine.
Researchers analyzed data on children admitted to a hospital in Kenya over a 25-year period and found that malaria transmission decreased from 1998 to 2009 but began to rise after that, and older children accounted for most of this increase.
The researchers believe this may be a result of a decrease in acquired immunity among the older children.
Philip Bejon, PhD, of the University of Oxford in the UK, and his colleagues conducted this study. The team analyzed malaria screening data from pediatric emergency admissions to Kilifi County Hospital between 1990 and 2014 and linked it to data on residence and insecticide-treated bednet (ITN) use.
During the period studied, 69,104 children, ages 3 months to 13 years, had malaria screening data available.
The proportion of hospital admissions found positive for malaria decreased from a high of 56% in 1998 to a low of 7% in 2009, but then rose again to 24% in 2014.
The researchers said they were unable to determine the cause of the decline in malaria infections between 1998 and 2009, which pre-dated the dramatic scale-up in ITN distribution and use in the area.
However, they noted that the subsequent increases in malaria infections coincided with a shift in burden from younger to older children, and children who lived in areas with high usage of ITNs were less likely to present with malaria than children who lived in areas with low usage of ITNs.
The researchers said the upswing in malaria transmission among older children following a period of low malaria transmission may be due to decreased acquired immunity because these children were less likely to have been exposed to malaria early in life.
The team also noted that varying levels of access to care and ITN use may have introduced bias in this study, and these data were taken from a single geographic setting. However, they still believe the findings suggest malaria elimination will require continued—and increasing—vigilance.
Photo by Gabrielle Tenenbaum
Progress in reducing the malaria burden in Africa may have had the paradoxical effect of increasing malaria transmission among older children in recent years, according to research published in PLOS Medicine.
Researchers analyzed data on children admitted to a hospital in Kenya over a 25-year period and found that malaria transmission decreased from 1998 to 2009 but began to rise after that, and older children accounted for most of this increase.
The researchers believe this may be a result of a decrease in acquired immunity among the older children.
Philip Bejon, PhD, of the University of Oxford in the UK, and his colleagues conducted this study. The team analyzed malaria screening data from pediatric emergency admissions to Kilifi County Hospital between 1990 and 2014 and linked it to data on residence and insecticide-treated bednet (ITN) use.
During the period studied, 69,104 children, ages 3 months to 13 years, had malaria screening data available.
The proportion of hospital admissions found positive for malaria decreased from a high of 56% in 1998 to a low of 7% in 2009, but then rose again to 24% in 2014.
The researchers said they were unable to determine the cause of the decline in malaria infections between 1998 and 2009, which pre-dated the dramatic scale-up in ITN distribution and use in the area.
However, they noted that the subsequent increases in malaria infections coincided with a shift in burden from younger to older children, and children who lived in areas with high usage of ITNs were less likely to present with malaria than children who lived in areas with low usage of ITNs.
The researchers said the upswing in malaria transmission among older children following a period of low malaria transmission may be due to decreased acquired immunity because these children were less likely to have been exposed to malaria early in life.
The team also noted that varying levels of access to care and ITN use may have introduced bias in this study, and these data were taken from a single geographic setting. However, they still believe the findings suggest malaria elimination will require continued—and increasing—vigilance.
Photo by Gabrielle Tenenbaum
Progress in reducing the malaria burden in Africa may have had the paradoxical effect of increasing malaria transmission among older children in recent years, according to research published in PLOS Medicine.
Researchers analyzed data on children admitted to a hospital in Kenya over a 25-year period and found that malaria transmission decreased from 1998 to 2009 but began to rise after that, and older children accounted for most of this increase.
The researchers believe this may be a result of a decrease in acquired immunity among the older children.
Philip Bejon, PhD, of the University of Oxford in the UK, and his colleagues conducted this study. The team analyzed malaria screening data from pediatric emergency admissions to Kilifi County Hospital between 1990 and 2014 and linked it to data on residence and insecticide-treated bednet (ITN) use.
During the period studied, 69,104 children, ages 3 months to 13 years, had malaria screening data available.
The proportion of hospital admissions found positive for malaria decreased from a high of 56% in 1998 to a low of 7% in 2009, but then rose again to 24% in 2014.
The researchers said they were unable to determine the cause of the decline in malaria infections between 1998 and 2009, which pre-dated the dramatic scale-up in ITN distribution and use in the area.
However, they noted that the subsequent increases in malaria infections coincided with a shift in burden from younger to older children, and children who lived in areas with high usage of ITNs were less likely to present with malaria than children who lived in areas with low usage of ITNs.
The researchers said the upswing in malaria transmission among older children following a period of low malaria transmission may be due to decreased acquired immunity because these children were less likely to have been exposed to malaria early in life.
The team also noted that varying levels of access to care and ITN use may have introduced bias in this study, and these data were taken from a single geographic setting. However, they still believe the findings suggest malaria elimination will require continued—and increasing—vigilance.
Immunotherapy may benefit relapsed HSCT recipients
Photo from Business Wire
Results of a phase 1 study suggest that repeated doses of the immunotherapy drug ipilimumab is a feasible treatment option for patients with hematologic diseases who relapse after allogeneic hematopoietic stem cell transplant (HSCT).
Seven of the 28 patients studied responded to the treatment, but immune-mediated toxic effects and graft-vs-host disease (GVHD) occurred as well.
These results were published in NEJM.
Ipilimumab, which is already approved to treat unresectable or metastatic melanoma, works by blocking the immune checkpoint CTLA-4. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation.
“We believe [,in the case of relapse after HSCT,] the donor immune cells are present but can’t recognize the tumor cells because of inhibitory signals that disguise them,” said study author Matthew Davids, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.
“By blocking the checkpoint, you allow the donor cells to see the cancer cells.”
Dr Davids and his colleagues tested this theory in 28 patients who had relapsed after allogeneic HSCT. The patients had acute myeloid leukemia (AML, n=12), Hodgkin lymphoma (n=7), non-Hodgkin lymphoma (n=4), myelodysplastic syndromes (MDS, n=2), multiple myeloma (n=1), myeloproliferative neoplasm (n=1), or acute lymphoblastic leukemia (n=1).
Patients had received a median of 3 prior treatment regimens, excluding HSCT (range, 1 to 14), and 20 patients (71%) had received treatment for relapse after transplant. Eight patients (29%) previously had grade 1/2 acute GVHD, and 16 (57%) previously had chronic GVHD.
The median time from transplant to initial treatment with ipilimumab was 675 days (range, 198 to 1830), and the median time from relapse to initial treatment with ipilimumab was 97 days (range, 0 to
1415).
Patients received induction therapy with ipilimumab at a dose of 3 mg/kg or 10 mg/kg every 3 weeks for a total of 4 doses. Those who had a clinical benefit received additional doses every 12 weeks for up to 60 weeks.
Safety
Five patients discontinued ipilimumab due to dose-limiting toxic effects. Four of these patients had GVHD, and 1 had severe immune-related adverse events.
Dose-limiting GVHD presented as chronic GVHD of the liver in 3 patients and acute GVHD of the gut in 1 patient.
Immune-related adverse events included death (n=1), pneumonitis (2 grade 2 events, 1 grade 4 event), colitis (1 grade 3 event), immune thrombocytopenia (1 grade 2 event), and diarrhea (1 grade 2 event).
Efficacy
There were no responses in patients who received ipilimumab at 3 mg/kg. Among the 22 patients who received ipilimumab at 10 mg/kg, 5 had a complete response, and 2 had a partial response.
Six other patients did not qualify as having responses but had a decrease in their tumor burden. Altogether, ipilimumab reduced tumor burden in 59% of patients.
The complete responses occurred in 4 patients with extramedullary AML and 1 patient with MDS developing into AML. Two of the AML patients remained in complete response at 12 and 15 months, and the patient with MDS remained in complete response at 16 months.
At a median follow-up of 15 months (range, 8 to 27), the median duration of response had not been reached. Responses were associated with in situ infiltration of cytotoxic CD8+ T cells, decreased activation of regulatory T cells, and expansion of subpopulations of effector T cells.
The 1-year overall survival rate was 49%.
The investigators said these encouraging results have set the stage for larger trials of checkpoint blockade in this patient population. Further research is planned to determine whether immunotherapy drugs could be given to high-risk patients to prevent relapse.
Photo from Business Wire
Results of a phase 1 study suggest that repeated doses of the immunotherapy drug ipilimumab is a feasible treatment option for patients with hematologic diseases who relapse after allogeneic hematopoietic stem cell transplant (HSCT).
Seven of the 28 patients studied responded to the treatment, but immune-mediated toxic effects and graft-vs-host disease (GVHD) occurred as well.
These results were published in NEJM.
Ipilimumab, which is already approved to treat unresectable or metastatic melanoma, works by blocking the immune checkpoint CTLA-4. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation.
“We believe [,in the case of relapse after HSCT,] the donor immune cells are present but can’t recognize the tumor cells because of inhibitory signals that disguise them,” said study author Matthew Davids, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.
“By blocking the checkpoint, you allow the donor cells to see the cancer cells.”
Dr Davids and his colleagues tested this theory in 28 patients who had relapsed after allogeneic HSCT. The patients had acute myeloid leukemia (AML, n=12), Hodgkin lymphoma (n=7), non-Hodgkin lymphoma (n=4), myelodysplastic syndromes (MDS, n=2), multiple myeloma (n=1), myeloproliferative neoplasm (n=1), or acute lymphoblastic leukemia (n=1).
Patients had received a median of 3 prior treatment regimens, excluding HSCT (range, 1 to 14), and 20 patients (71%) had received treatment for relapse after transplant. Eight patients (29%) previously had grade 1/2 acute GVHD, and 16 (57%) previously had chronic GVHD.
The median time from transplant to initial treatment with ipilimumab was 675 days (range, 198 to 1830), and the median time from relapse to initial treatment with ipilimumab was 97 days (range, 0 to
1415).
Patients received induction therapy with ipilimumab at a dose of 3 mg/kg or 10 mg/kg every 3 weeks for a total of 4 doses. Those who had a clinical benefit received additional doses every 12 weeks for up to 60 weeks.
Safety
Five patients discontinued ipilimumab due to dose-limiting toxic effects. Four of these patients had GVHD, and 1 had severe immune-related adverse events.
Dose-limiting GVHD presented as chronic GVHD of the liver in 3 patients and acute GVHD of the gut in 1 patient.
Immune-related adverse events included death (n=1), pneumonitis (2 grade 2 events, 1 grade 4 event), colitis (1 grade 3 event), immune thrombocytopenia (1 grade 2 event), and diarrhea (1 grade 2 event).
Efficacy
There were no responses in patients who received ipilimumab at 3 mg/kg. Among the 22 patients who received ipilimumab at 10 mg/kg, 5 had a complete response, and 2 had a partial response.
Six other patients did not qualify as having responses but had a decrease in their tumor burden. Altogether, ipilimumab reduced tumor burden in 59% of patients.
The complete responses occurred in 4 patients with extramedullary AML and 1 patient with MDS developing into AML. Two of the AML patients remained in complete response at 12 and 15 months, and the patient with MDS remained in complete response at 16 months.
At a median follow-up of 15 months (range, 8 to 27), the median duration of response had not been reached. Responses were associated with in situ infiltration of cytotoxic CD8+ T cells, decreased activation of regulatory T cells, and expansion of subpopulations of effector T cells.
The 1-year overall survival rate was 49%.
The investigators said these encouraging results have set the stage for larger trials of checkpoint blockade in this patient population. Further research is planned to determine whether immunotherapy drugs could be given to high-risk patients to prevent relapse.
Photo from Business Wire
Results of a phase 1 study suggest that repeated doses of the immunotherapy drug ipilimumab is a feasible treatment option for patients with hematologic diseases who relapse after allogeneic hematopoietic stem cell transplant (HSCT).
Seven of the 28 patients studied responded to the treatment, but immune-mediated toxic effects and graft-vs-host disease (GVHD) occurred as well.
These results were published in NEJM.
Ipilimumab, which is already approved to treat unresectable or metastatic melanoma, works by blocking the immune checkpoint CTLA-4. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation.
“We believe [,in the case of relapse after HSCT,] the donor immune cells are present but can’t recognize the tumor cells because of inhibitory signals that disguise them,” said study author Matthew Davids, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.
“By blocking the checkpoint, you allow the donor cells to see the cancer cells.”
Dr Davids and his colleagues tested this theory in 28 patients who had relapsed after allogeneic HSCT. The patients had acute myeloid leukemia (AML, n=12), Hodgkin lymphoma (n=7), non-Hodgkin lymphoma (n=4), myelodysplastic syndromes (MDS, n=2), multiple myeloma (n=1), myeloproliferative neoplasm (n=1), or acute lymphoblastic leukemia (n=1).
Patients had received a median of 3 prior treatment regimens, excluding HSCT (range, 1 to 14), and 20 patients (71%) had received treatment for relapse after transplant. Eight patients (29%) previously had grade 1/2 acute GVHD, and 16 (57%) previously had chronic GVHD.
The median time from transplant to initial treatment with ipilimumab was 675 days (range, 198 to 1830), and the median time from relapse to initial treatment with ipilimumab was 97 days (range, 0 to
1415).
Patients received induction therapy with ipilimumab at a dose of 3 mg/kg or 10 mg/kg every 3 weeks for a total of 4 doses. Those who had a clinical benefit received additional doses every 12 weeks for up to 60 weeks.
Safety
Five patients discontinued ipilimumab due to dose-limiting toxic effects. Four of these patients had GVHD, and 1 had severe immune-related adverse events.
Dose-limiting GVHD presented as chronic GVHD of the liver in 3 patients and acute GVHD of the gut in 1 patient.
Immune-related adverse events included death (n=1), pneumonitis (2 grade 2 events, 1 grade 4 event), colitis (1 grade 3 event), immune thrombocytopenia (1 grade 2 event), and diarrhea (1 grade 2 event).
Efficacy
There were no responses in patients who received ipilimumab at 3 mg/kg. Among the 22 patients who received ipilimumab at 10 mg/kg, 5 had a complete response, and 2 had a partial response.
Six other patients did not qualify as having responses but had a decrease in their tumor burden. Altogether, ipilimumab reduced tumor burden in 59% of patients.
The complete responses occurred in 4 patients with extramedullary AML and 1 patient with MDS developing into AML. Two of the AML patients remained in complete response at 12 and 15 months, and the patient with MDS remained in complete response at 16 months.
At a median follow-up of 15 months (range, 8 to 27), the median duration of response had not been reached. Responses were associated with in situ infiltration of cytotoxic CD8+ T cells, decreased activation of regulatory T cells, and expansion of subpopulations of effector T cells.
The 1-year overall survival rate was 49%.
The investigators said these encouraging results have set the stage for larger trials of checkpoint blockade in this patient population. Further research is planned to determine whether immunotherapy drugs could be given to high-risk patients to prevent relapse.
Study links adipocytes and myeloma progression
A study published in Cancer Letters suggests that adipocytes contribute to the growth and progression of multiple myeloma (MM).
Researchers co-cultured MM cells with adipocytes derived from patients defined as normal weight, overweight, obese, or super obese.
This revealed a positive correlation between adipocytes and indicators of MM progression, which was most pronounced in cells from obese and super obese individuals.
“Once a person with cancer is out of the normal weight category, their BMI [body mass index] is contributing to multiple myeloma growth and progression,” said study author Katie DeCicco-Skinner, PhD, of American University in Washington, DC.
For this study, Dr DeCicco-Skinner and her colleagues obtained human adipose-derived stem cells from 29 patients who underwent liposuction and were defined as normal weight (BMI = 20–25 kg/m2), overweight (25–30 kg/m2), obese (30–35 kg/m2), or super obese (35–40 kg/m2).
Once the cells matured into adipocytes, they were co-cultured with the MM cell lines RPMI-8226 and NCI-H929.
The researchers found that adipocytes from overweight, obese, and super obese patients had increased levels of proteins linked to cancer, including PPAR-gamma, cytochrome C, interleukin-6, and leptin.
In addition, adipocyte-conditioned media from obese and super obese patients significantly increased MM cell adhesion.
And conditioned media from overweight, obese, and super obese patients increased angiogenic potential and expression of matrix metalloproteinase-2.
“We know multiple myeloma cells will anchor into bone marrow, and fat cells in the bone marrow will support the growth and spread of the cancer,” Dr DeCicco-Skinner said.
“In our study, as BMI increased, we started seeing an increase in the ability of multiple myeloma cells to adhere, which causes the cancer to better anchor. With angiogenesis, cancer cells cannot exist without their own blood supply. We also found the amount of blood vessels that developed was directly proportional to a patient’s BMI.”
Dr DeCicco-Skinner and her colleagues had assumed that cancer proliferation would benefit from a higher-than-normal BMI because of the epidemiological link between obesity and cancer. But the relationship between MM and the BMI of obese and super obese patients was drastic.
“We found that fat cells from obese or morbidly obese patients secreted a high amount of inflammatory proteins, which contributed to tumor progression,” Dr DeCicco-Skinner said.
These findings suggest a new approach for MM treatment, according to the researchers. They say physicians may want to consider tailoring drugs based on a patient’s BMI because a drug may not be as effective in obese or super obese patients.
“A patient may need to receive drugs to block inflammatory or other obesity-specific proteins, in addition to standard anticancer drugs they receive,” Dr DeCicco-Skinner said.
“Obesity increasingly plays a role in cancer cases, as the numbers of those who are obese rise. Improving our understanding of how fat cells and cancer cells communicate with each other, and how the communication changes during obesity, is critical.”
A study published in Cancer Letters suggests that adipocytes contribute to the growth and progression of multiple myeloma (MM).
Researchers co-cultured MM cells with adipocytes derived from patients defined as normal weight, overweight, obese, or super obese.
This revealed a positive correlation between adipocytes and indicators of MM progression, which was most pronounced in cells from obese and super obese individuals.
“Once a person with cancer is out of the normal weight category, their BMI [body mass index] is contributing to multiple myeloma growth and progression,” said study author Katie DeCicco-Skinner, PhD, of American University in Washington, DC.
For this study, Dr DeCicco-Skinner and her colleagues obtained human adipose-derived stem cells from 29 patients who underwent liposuction and were defined as normal weight (BMI = 20–25 kg/m2), overweight (25–30 kg/m2), obese (30–35 kg/m2), or super obese (35–40 kg/m2).
Once the cells matured into adipocytes, they were co-cultured with the MM cell lines RPMI-8226 and NCI-H929.
The researchers found that adipocytes from overweight, obese, and super obese patients had increased levels of proteins linked to cancer, including PPAR-gamma, cytochrome C, interleukin-6, and leptin.
In addition, adipocyte-conditioned media from obese and super obese patients significantly increased MM cell adhesion.
And conditioned media from overweight, obese, and super obese patients increased angiogenic potential and expression of matrix metalloproteinase-2.
“We know multiple myeloma cells will anchor into bone marrow, and fat cells in the bone marrow will support the growth and spread of the cancer,” Dr DeCicco-Skinner said.
“In our study, as BMI increased, we started seeing an increase in the ability of multiple myeloma cells to adhere, which causes the cancer to better anchor. With angiogenesis, cancer cells cannot exist without their own blood supply. We also found the amount of blood vessels that developed was directly proportional to a patient’s BMI.”
Dr DeCicco-Skinner and her colleagues had assumed that cancer proliferation would benefit from a higher-than-normal BMI because of the epidemiological link between obesity and cancer. But the relationship between MM and the BMI of obese and super obese patients was drastic.
“We found that fat cells from obese or morbidly obese patients secreted a high amount of inflammatory proteins, which contributed to tumor progression,” Dr DeCicco-Skinner said.
These findings suggest a new approach for MM treatment, according to the researchers. They say physicians may want to consider tailoring drugs based on a patient’s BMI because a drug may not be as effective in obese or super obese patients.
“A patient may need to receive drugs to block inflammatory or other obesity-specific proteins, in addition to standard anticancer drugs they receive,” Dr DeCicco-Skinner said.
“Obesity increasingly plays a role in cancer cases, as the numbers of those who are obese rise. Improving our understanding of how fat cells and cancer cells communicate with each other, and how the communication changes during obesity, is critical.”
A study published in Cancer Letters suggests that adipocytes contribute to the growth and progression of multiple myeloma (MM).
Researchers co-cultured MM cells with adipocytes derived from patients defined as normal weight, overweight, obese, or super obese.
This revealed a positive correlation between adipocytes and indicators of MM progression, which was most pronounced in cells from obese and super obese individuals.
“Once a person with cancer is out of the normal weight category, their BMI [body mass index] is contributing to multiple myeloma growth and progression,” said study author Katie DeCicco-Skinner, PhD, of American University in Washington, DC.
For this study, Dr DeCicco-Skinner and her colleagues obtained human adipose-derived stem cells from 29 patients who underwent liposuction and were defined as normal weight (BMI = 20–25 kg/m2), overweight (25–30 kg/m2), obese (30–35 kg/m2), or super obese (35–40 kg/m2).
Once the cells matured into adipocytes, they were co-cultured with the MM cell lines RPMI-8226 and NCI-H929.
The researchers found that adipocytes from overweight, obese, and super obese patients had increased levels of proteins linked to cancer, including PPAR-gamma, cytochrome C, interleukin-6, and leptin.
In addition, adipocyte-conditioned media from obese and super obese patients significantly increased MM cell adhesion.
And conditioned media from overweight, obese, and super obese patients increased angiogenic potential and expression of matrix metalloproteinase-2.
“We know multiple myeloma cells will anchor into bone marrow, and fat cells in the bone marrow will support the growth and spread of the cancer,” Dr DeCicco-Skinner said.
“In our study, as BMI increased, we started seeing an increase in the ability of multiple myeloma cells to adhere, which causes the cancer to better anchor. With angiogenesis, cancer cells cannot exist without their own blood supply. We also found the amount of blood vessels that developed was directly proportional to a patient’s BMI.”
Dr DeCicco-Skinner and her colleagues had assumed that cancer proliferation would benefit from a higher-than-normal BMI because of the epidemiological link between obesity and cancer. But the relationship between MM and the BMI of obese and super obese patients was drastic.
“We found that fat cells from obese or morbidly obese patients secreted a high amount of inflammatory proteins, which contributed to tumor progression,” Dr DeCicco-Skinner said.
These findings suggest a new approach for MM treatment, according to the researchers. They say physicians may want to consider tailoring drugs based on a patient’s BMI because a drug may not be as effective in obese or super obese patients.
“A patient may need to receive drugs to block inflammatory or other obesity-specific proteins, in addition to standard anticancer drugs they receive,” Dr DeCicco-Skinner said.
“Obesity increasingly plays a role in cancer cases, as the numbers of those who are obese rise. Improving our understanding of how fat cells and cancer cells communicate with each other, and how the communication changes during obesity, is critical.”
INR monitoring systems to be pulled from market
The Alere INRatio® and INRatio®2 PT/INR Monitoring Systems are being withdrawn from the US market because they may provide inaccurate international normalized ratio (INR) results.
These handheld blood coagulation systems, which consist of a small monitor and disposable test strips, are used to monitor patients taking warfarin.
The manufacturer of these systems, Alere Inc., said it is working with the US Food and Drug Administration (FDA) to determine the most appropriate timing for product discontinuation.
The company also said it will provide guidance on transitioning patients using the INRatio systems to an alternate solution to allow them to continue anticoagulation monitoring in the least disruptive manner possible.
Background on the withdrawal
In December 2014, Alere initiated a voluntary correction to inform users of the INRatio® and INRatio®2 PT/INR Monitoring Systems that patients with certain medical conditions should not be tested with the systems.
The company found that, in certain cases, the systems provided an INR result that was clinically significantly lower than a result obtained using a reference INR system (laboratory method).
In fact, there has been speculation that this issue may have affected the results of the ROCKET AF trial, a comparison of rivaroxaban and warfarin in which INRs were measured with the INRatio systems.
The FDA is currently investigating this possibility, although the European Medicines Agency has said the study’s overall results were not affected by the issue.
After Alere reported the issue with the INRatio systems to the FDA, the company began conducting its own investigation.
Over the past 2 years, Alere invested in the research and development of software enhancements to address the potential of the INRatio systems to deliver results that differ from laboratory INR measurement.
Alere said it is confident the software enhancements it developed and submitted to the FDA at the end of 2015 effectively address this issue.
However, the FDA said the company’s studies do not adequately demonstrate the effectiveness of the software modification. The agency therefore advised Alere to submit a proposed plan to voluntarily remove the INRatio systems from the market.
The company decided to follow this recommendation and plans to provide a timeline to discontinue the product line. Alere said it will provide further information on patient transition to patients and healthcare providers.
For more information regarding this product discontinuation, visit http://www.inr-care.com.
The Alere INRatio® and INRatio®2 PT/INR Monitoring Systems are being withdrawn from the US market because they may provide inaccurate international normalized ratio (INR) results.
These handheld blood coagulation systems, which consist of a small monitor and disposable test strips, are used to monitor patients taking warfarin.
The manufacturer of these systems, Alere Inc., said it is working with the US Food and Drug Administration (FDA) to determine the most appropriate timing for product discontinuation.
The company also said it will provide guidance on transitioning patients using the INRatio systems to an alternate solution to allow them to continue anticoagulation monitoring in the least disruptive manner possible.
Background on the withdrawal
In December 2014, Alere initiated a voluntary correction to inform users of the INRatio® and INRatio®2 PT/INR Monitoring Systems that patients with certain medical conditions should not be tested with the systems.
The company found that, in certain cases, the systems provided an INR result that was clinically significantly lower than a result obtained using a reference INR system (laboratory method).
In fact, there has been speculation that this issue may have affected the results of the ROCKET AF trial, a comparison of rivaroxaban and warfarin in which INRs were measured with the INRatio systems.
The FDA is currently investigating this possibility, although the European Medicines Agency has said the study’s overall results were not affected by the issue.
After Alere reported the issue with the INRatio systems to the FDA, the company began conducting its own investigation.
Over the past 2 years, Alere invested in the research and development of software enhancements to address the potential of the INRatio systems to deliver results that differ from laboratory INR measurement.
Alere said it is confident the software enhancements it developed and submitted to the FDA at the end of 2015 effectively address this issue.
However, the FDA said the company’s studies do not adequately demonstrate the effectiveness of the software modification. The agency therefore advised Alere to submit a proposed plan to voluntarily remove the INRatio systems from the market.
The company decided to follow this recommendation and plans to provide a timeline to discontinue the product line. Alere said it will provide further information on patient transition to patients and healthcare providers.
For more information regarding this product discontinuation, visit http://www.inr-care.com.
The Alere INRatio® and INRatio®2 PT/INR Monitoring Systems are being withdrawn from the US market because they may provide inaccurate international normalized ratio (INR) results.
These handheld blood coagulation systems, which consist of a small monitor and disposable test strips, are used to monitor patients taking warfarin.
The manufacturer of these systems, Alere Inc., said it is working with the US Food and Drug Administration (FDA) to determine the most appropriate timing for product discontinuation.
The company also said it will provide guidance on transitioning patients using the INRatio systems to an alternate solution to allow them to continue anticoagulation monitoring in the least disruptive manner possible.
Background on the withdrawal
In December 2014, Alere initiated a voluntary correction to inform users of the INRatio® and INRatio®2 PT/INR Monitoring Systems that patients with certain medical conditions should not be tested with the systems.
The company found that, in certain cases, the systems provided an INR result that was clinically significantly lower than a result obtained using a reference INR system (laboratory method).
In fact, there has been speculation that this issue may have affected the results of the ROCKET AF trial, a comparison of rivaroxaban and warfarin in which INRs were measured with the INRatio systems.
The FDA is currently investigating this possibility, although the European Medicines Agency has said the study’s overall results were not affected by the issue.
After Alere reported the issue with the INRatio systems to the FDA, the company began conducting its own investigation.
Over the past 2 years, Alere invested in the research and development of software enhancements to address the potential of the INRatio systems to deliver results that differ from laboratory INR measurement.
Alere said it is confident the software enhancements it developed and submitted to the FDA at the end of 2015 effectively address this issue.
However, the FDA said the company’s studies do not adequately demonstrate the effectiveness of the software modification. The agency therefore advised Alere to submit a proposed plan to voluntarily remove the INRatio systems from the market.
The company decided to follow this recommendation and plans to provide a timeline to discontinue the product line. Alere said it will provide further information on patient transition to patients and healthcare providers.
For more information regarding this product discontinuation, visit http://www.inr-care.com.