Lymphoma & Plasma Cell Disorders

The European Commission has granted orphan drug designation to IPH4102 for the treatment of cutaneous T-cell lymphoma (CTCL).

IPH4102 is a cytotoxic anti-KIR3DL2 monoclonal antibody (mAb) that targets CTCL cells.

Orphan status provides Innate Pharma, the company developing IPH4102, with benefits such as tax incentives, market exclusivity for 10 years, possibilities for additional research funding, and additional guidance from the European Medicines Agency during clinical development.

Preclinical results with IPH4102 were presented in a poster at the 2014 T-cell Lymphoma Forum. The research was conducted by investigators from Innate Pharma and INSERM at Hôpital Saint Louis in Paris.

The researchers generated 3 mAbs that bind selectively to KIR3DL2 and evaluated their efficacy against KIR3DL2-expressing tumors and Sézary cell lines.

IPH4102 was among the 3 mAbs and emerged as the most promising drug candidate.

Experiments revealed that anti-KIR3DL2 mAbs can kill KIR3DL2+ cell lines through allo-antibody-dependent cell cytotoxicity, even at low tumor antigen density.

The mAbs also improved survival in KIR3DL2+ xenograft models. Survival in mAb-treated mice ranged from 30.5 days to 54.5 days, compared to 19 days in controls.

Finally, the mAbs mediated killing of primary Sézary cells with autologous natural killer cells nearly as efficiently as alemtuzumab.

The investigators said these results suggest anti-KIR3DL2 mAbs are a feasible treatment option for CTCL patients. They plan to prove this hypothesis with a phase 1 trial of IPH4102, which is expected to begin in 2015.

The European Commission has granted orphan drug designation to IPH4102 for the treatment of cutaneous T-cell lymphoma (CTCL).

IPH4102 is a cytotoxic anti-KIR3DL2 monoclonal antibody (mAb) that targets CTCL cells.

Orphan status provides Innate Pharma, the company developing IPH4102, with benefits such as tax incentives, market exclusivity for 10 years, possibilities for additional research funding, and additional guidance from the European Medicines Agency during clinical development.

Preclinical results with IPH4102 were presented in a poster at the 2014 T-cell Lymphoma Forum. The research was conducted by investigators from Innate Pharma and INSERM at Hôpital Saint Louis in Paris.

The researchers generated 3 mAbs that bind selectively to KIR3DL2 and evaluated their efficacy against KIR3DL2-expressing tumors and Sézary cell lines.

IPH4102 was among the 3 mAbs and emerged as the most promising drug candidate.

Experiments revealed that anti-KIR3DL2 mAbs can kill KIR3DL2+ cell lines through allo-antibody-dependent cell cytotoxicity, even at low tumor antigen density.

The mAbs also improved survival in KIR3DL2+ xenograft models. Survival in mAb-treated mice ranged from 30.5 days to 54.5 days, compared to 19 days in controls.

Finally, the mAbs mediated killing of primary Sézary cells with autologous natural killer cells nearly as efficiently as alemtuzumab.

The investigators said these results suggest anti-KIR3DL2 mAbs are a feasible treatment option for CTCL patients. They plan to prove this hypothesis with a phase 1 trial of IPH4102, which is expected to begin in 2015.

The European Commission has granted orphan drug designation to IPH4102 for the treatment of cutaneous T-cell lymphoma (CTCL).

IPH4102 is a cytotoxic anti-KIR3DL2 monoclonal antibody (mAb) that targets CTCL cells.

Orphan status provides Innate Pharma, the company developing IPH4102, with benefits such as tax incentives, market exclusivity for 10 years, possibilities for additional research funding, and additional guidance from the European Medicines Agency during clinical development.

Preclinical results with IPH4102 were presented in a poster at the 2014 T-cell Lymphoma Forum. The research was conducted by investigators from Innate Pharma and INSERM at Hôpital Saint Louis in Paris.

The researchers generated 3 mAbs that bind selectively to KIR3DL2 and evaluated their efficacy against KIR3DL2-expressing tumors and Sézary cell lines.

IPH4102 was among the 3 mAbs and emerged as the most promising drug candidate.

Experiments revealed that anti-KIR3DL2 mAbs can kill KIR3DL2+ cell lines through allo-antibody-dependent cell cytotoxicity, even at low tumor antigen density.

The mAbs also improved survival in KIR3DL2+ xenograft models. Survival in mAb-treated mice ranged from 30.5 days to 54.5 days, compared to 19 days in controls.

Finally, the mAbs mediated killing of primary Sézary cells with autologous natural killer cells nearly as efficiently as alemtuzumab.

The investigators said these results suggest anti-KIR3DL2 mAbs are a feasible treatment option for CTCL patients. They plan to prove this hypothesis with a phase 1 trial of IPH4102, which is expected to begin in 2015.

Doctor consults with patient

Credit: NIH

Results of a large study suggest major depression is common—but largely untreated—among cancer patients in Scotland.

And 2 additional studies of Scottish patients showed that a program specifically designed for individuals with cancer can treat depression and improve quality of life more effectively than current methods of care.

These studies appear in The Lancet, The Lancet Oncology, and The Lancet Psychiatry.

In The Lancet Psychiatry, researchers recounted their analysis of data from 21,151 patients treated at cancer clinics in Scotland. The team found that major depression was substantially more common in cancer patients than in the general population.

Major depression was most common in patients with lung cancer (13%) and lowest in those with genitourinary cancer (6%). Moreover, nearly three-quarters (73%) of depressed cancer patients were not receiving treatment.

To address the problem of inadequate treatment, researchers initiated the SMaRT Oncology-2 trial. They reported the results in The Lancet.

The team evaluated a new treatment program called “Depression Care for People with Cancer” (DCPC). DCPC is delivered by specially trained cancer nurses and psychiatrists, working in collaboration with the patient’s cancer team and general practitioner, and is given as part of cancer care. It is a systematic treatment program that includes both antidepressants and psychological therapy.

The trial included 500 adults with major depression and a cancer with a good prognosis (predicted survival of more than 12 months).

Patients were randomized to receive either DCPC or “usual care,” which was provided by a patient’s general practitioner and might have included prescribing antidepressants or referring the patient to mental health services for assessment or psychological treatment.

Results showed that DCPC was more effective than usual care in reducing depression. At 6 months, 62% of patients who received DCPC responded to treatment (experiencing at least a 50% reduction in the severity of their depression), compared with 17% of those who received the usual care (P<0.0001). This benefit was sustained at 12 months.

In addition, DCPC improved anxiety, pain, fatigue, functioning, and overall quality of life (all P<0.05). The researchers also noted that the cost of providing DCPC was modest (£613 per patient).

“The huge benefit that DCPC delivers for patients with cancer and depression shows what we can achieve for patients if we take as much care with the treatment of their depression as we do with the treatment of their cancer,” said study author Michael Sharpe, MD, of the University of Oxford in the UK.

To see if patients with a poor-prognosis cancer could also benefit from DCPC, researchers initiated the SMaRT Oncology-3 trial. They reported the results in The Lancet Oncology.

The team tested a version of DCPC adapted for cancer patients with a poor prognosis. The trial included 142 patients with lung cancer and major depression.

Patients who received the modified version of DCPC had a significantly greater improvement in depression than those who received the usual care during 32 weeks of follow-up (P=0.0003). DCPC also improved patients’ anxiety (P=0.046), functioning (P=0.0019), and quality of life (P=0.018).

“Patients with lung cancer often have a poor prognosis,” said study author Jane Walker, MBChB, PhD, of the University of Oxford and Sobell House Hospice in Oxford, UK.

“If they also have major depression, that can blight the time they have left to live. This trial shows that we can effectively treat depression in patients with poor-prognosis cancers, like lung cancer, and really improve patients’ lives.”

Doctor consults with patient

Credit: NIH

Results of a large study suggest major depression is common—but largely untreated—among cancer patients in Scotland.

And 2 additional studies of Scottish patients showed that a program specifically designed for individuals with cancer can treat depression and improve quality of life more effectively than current methods of care.

These studies appear in The Lancet, The Lancet Oncology, and The Lancet Psychiatry.

In The Lancet Psychiatry, researchers recounted their analysis of data from 21,151 patients treated at cancer clinics in Scotland. The team found that major depression was substantially more common in cancer patients than in the general population.

Major depression was most common in patients with lung cancer (13%) and lowest in those with genitourinary cancer (6%). Moreover, nearly three-quarters (73%) of depressed cancer patients were not receiving treatment.

To address the problem of inadequate treatment, researchers initiated the SMaRT Oncology-2 trial. They reported the results in The Lancet.

The team evaluated a new treatment program called “Depression Care for People with Cancer” (DCPC). DCPC is delivered by specially trained cancer nurses and psychiatrists, working in collaboration with the patient’s cancer team and general practitioner, and is given as part of cancer care. It is a systematic treatment program that includes both antidepressants and psychological therapy.

The trial included 500 adults with major depression and a cancer with a good prognosis (predicted survival of more than 12 months).

Patients were randomized to receive either DCPC or “usual care,” which was provided by a patient’s general practitioner and might have included prescribing antidepressants or referring the patient to mental health services for assessment or psychological treatment.

Results showed that DCPC was more effective than usual care in reducing depression. At 6 months, 62% of patients who received DCPC responded to treatment (experiencing at least a 50% reduction in the severity of their depression), compared with 17% of those who received the usual care (P<0.0001). This benefit was sustained at 12 months.

In addition, DCPC improved anxiety, pain, fatigue, functioning, and overall quality of life (all P<0.05). The researchers also noted that the cost of providing DCPC was modest (£613 per patient).

“The huge benefit that DCPC delivers for patients with cancer and depression shows what we can achieve for patients if we take as much care with the treatment of their depression as we do with the treatment of their cancer,” said study author Michael Sharpe, MD, of the University of Oxford in the UK.

To see if patients with a poor-prognosis cancer could also benefit from DCPC, researchers initiated the SMaRT Oncology-3 trial. They reported the results in The Lancet Oncology.

The team tested a version of DCPC adapted for cancer patients with a poor prognosis. The trial included 142 patients with lung cancer and major depression.

Patients who received the modified version of DCPC had a significantly greater improvement in depression than those who received the usual care during 32 weeks of follow-up (P=0.0003). DCPC also improved patients’ anxiety (P=0.046), functioning (P=0.0019), and quality of life (P=0.018).

“Patients with lung cancer often have a poor prognosis,” said study author Jane Walker, MBChB, PhD, of the University of Oxford and Sobell House Hospice in Oxford, UK.

“If they also have major depression, that can blight the time they have left to live. This trial shows that we can effectively treat depression in patients with poor-prognosis cancers, like lung cancer, and really improve patients’ lives.”

Doctor consults with patient

Credit: NIH

Results of a large study suggest major depression is common—but largely untreated—among cancer patients in Scotland.

And 2 additional studies of Scottish patients showed that a program specifically designed for individuals with cancer can treat depression and improve quality of life more effectively than current methods of care.

These studies appear in The Lancet, The Lancet Oncology, and The Lancet Psychiatry.

In The Lancet Psychiatry, researchers recounted their analysis of data from 21,151 patients treated at cancer clinics in Scotland. The team found that major depression was substantially more common in cancer patients than in the general population.

Major depression was most common in patients with lung cancer (13%) and lowest in those with genitourinary cancer (6%). Moreover, nearly three-quarters (73%) of depressed cancer patients were not receiving treatment.

To address the problem of inadequate treatment, researchers initiated the SMaRT Oncology-2 trial. They reported the results in The Lancet.

The team evaluated a new treatment program called “Depression Care for People with Cancer” (DCPC). DCPC is delivered by specially trained cancer nurses and psychiatrists, working in collaboration with the patient’s cancer team and general practitioner, and is given as part of cancer care. It is a systematic treatment program that includes both antidepressants and psychological therapy.

The trial included 500 adults with major depression and a cancer with a good prognosis (predicted survival of more than 12 months).

Patients were randomized to receive either DCPC or “usual care,” which was provided by a patient’s general practitioner and might have included prescribing antidepressants or referring the patient to mental health services for assessment or psychological treatment.

Results showed that DCPC was more effective than usual care in reducing depression. At 6 months, 62% of patients who received DCPC responded to treatment (experiencing at least a 50% reduction in the severity of their depression), compared with 17% of those who received the usual care (P<0.0001). This benefit was sustained at 12 months.

In addition, DCPC improved anxiety, pain, fatigue, functioning, and overall quality of life (all P<0.05). The researchers also noted that the cost of providing DCPC was modest (£613 per patient).

“The huge benefit that DCPC delivers for patients with cancer and depression shows what we can achieve for patients if we take as much care with the treatment of their depression as we do with the treatment of their cancer,” said study author Michael Sharpe, MD, of the University of Oxford in the UK.

To see if patients with a poor-prognosis cancer could also benefit from DCPC, researchers initiated the SMaRT Oncology-3 trial. They reported the results in The Lancet Oncology.

The team tested a version of DCPC adapted for cancer patients with a poor prognosis. The trial included 142 patients with lung cancer and major depression.

Patients who received the modified version of DCPC had a significantly greater improvement in depression than those who received the usual care during 32 weeks of follow-up (P=0.0003). DCPC also improved patients’ anxiety (P=0.046), functioning (P=0.0019), and quality of life (P=0.018).

“Patients with lung cancer often have a poor prognosis,” said study author Jane Walker, MBChB, PhD, of the University of Oxford and Sobell House Hospice in Oxford, UK.

“If they also have major depression, that can blight the time they have left to live. This trial shows that we can effectively treat depression in patients with poor-prognosis cancers, like lung cancer, and really improve patients’ lives.”

Drug release in a cancer cell

Credit: PNAS

A new type of nanoparticle (NP) could aid the diagnosis and treatment of cancers, according to research published in Nature Communications.

Built on an easy-to-make polymer, these particles can be used as contrast agents to light up tumors for MRI and PET scans or to deliver chemotherapy and other treatments to cancer cells.

Furthermore, in vivo experiments showed the particles are biocompatible and elicit minimal side effects.

“These are amazingly useful particles,” said study author Yuanpei Li, PhD, of the UC Davis Comprehensive Cancer Center in Sacramento, California.

“As a contrast agent, they make tumors easier to see on MRI and other scans. We can also use them as vehicles to deliver chemotherapy directly to tumors, apply light to make the nanoparticles release singlet oxygen (photodynamic therapy), or use a laser to heat them (photothermal therapy)—all proven ways to destroy tumors.”

These NPs are built on a porphyrin/cholic acid polymer. Porphyrins are common organic compounds, and cholic acid is produced by the liver.

To further stabilize the particles, the researchers added the amino acid cysteine (creating CNPs), which prevents them from prematurely releasing their therapeutic payload when exposed to blood proteins and other barriers.

Therapeutic applications

The researchers tested the CNPs, both in vitro and in vivo, for a wide range of tasks. On the therapeutic side, the particles effectively transported anticancer drugs, such as doxorubicin.

CNPs carrying doxorubicin provided excellent cancer control in animals, with minimal side effects.

Even when kept in the blood for many hours, CNPs only released small amounts of the drug. However, when exposed to light or agents such as glutathione, they readily released their payloads.

The researchers showed that, when exposed to a single wavelength of light, the CNPs could generate heat or produce singlet oxygen to destroy tumor cells.

Imaging applications

CNPs offer a number of advantages to enhance imaging, according to the researchers. The particles readily chelate imaging agents and can remain in the body for long periods.

In animal studies, CNPs largely accumulated in tumors, rather than in normal tissue. So they dramatically enhanced tumor contrast for MRI and may also be promising for PET-MRI scans, the researchers said.

“These particles can combine imaging and therapeutics,” Dr Li noted. “We could potentially use them to simultaneously deliver treatment and monitor treatment efficacy.”

The researchers are now conducting additional preclinical studies with the CNPs. If all goes well, they will proceed to human trials. In the meantime, the team is excited about these capabilities.

“This is the first nanoparticle to perform so many different jobs,” Dr Li said. “From delivering chemo, photodynamic, and photothermal therapies, to enhancing diagnostic imaging, it’s the complete package.”

Drug release in a cancer cell

Credit: PNAS

A new type of nanoparticle (NP) could aid the diagnosis and treatment of cancers, according to research published in Nature Communications.

Built on an easy-to-make polymer, these particles can be used as contrast agents to light up tumors for MRI and PET scans or to deliver chemotherapy and other treatments to cancer cells.

Furthermore, in vivo experiments showed the particles are biocompatible and elicit minimal side effects.

“These are amazingly useful particles,” said study author Yuanpei Li, PhD, of the UC Davis Comprehensive Cancer Center in Sacramento, California.

“As a contrast agent, they make tumors easier to see on MRI and other scans. We can also use them as vehicles to deliver chemotherapy directly to tumors, apply light to make the nanoparticles release singlet oxygen (photodynamic therapy), or use a laser to heat them (photothermal therapy)—all proven ways to destroy tumors.”

These NPs are built on a porphyrin/cholic acid polymer. Porphyrins are common organic compounds, and cholic acid is produced by the liver.

To further stabilize the particles, the researchers added the amino acid cysteine (creating CNPs), which prevents them from prematurely releasing their therapeutic payload when exposed to blood proteins and other barriers.

Therapeutic applications

The researchers tested the CNPs, both in vitro and in vivo, for a wide range of tasks. On the therapeutic side, the particles effectively transported anticancer drugs, such as doxorubicin.

CNPs carrying doxorubicin provided excellent cancer control in animals, with minimal side effects.

Even when kept in the blood for many hours, CNPs only released small amounts of the drug. However, when exposed to light or agents such as glutathione, they readily released their payloads.

The researchers showed that, when exposed to a single wavelength of light, the CNPs could generate heat or produce singlet oxygen to destroy tumor cells.

Imaging applications

CNPs offer a number of advantages to enhance imaging, according to the researchers. The particles readily chelate imaging agents and can remain in the body for long periods.

In animal studies, CNPs largely accumulated in tumors, rather than in normal tissue. So they dramatically enhanced tumor contrast for MRI and may also be promising for PET-MRI scans, the researchers said.

“These particles can combine imaging and therapeutics,” Dr Li noted. “We could potentially use them to simultaneously deliver treatment and monitor treatment efficacy.”

The researchers are now conducting additional preclinical studies with the CNPs. If all goes well, they will proceed to human trials. In the meantime, the team is excited about these capabilities.

“This is the first nanoparticle to perform so many different jobs,” Dr Li said. “From delivering chemo, photodynamic, and photothermal therapies, to enhancing diagnostic imaging, it’s the complete package.”

Drug release in a cancer cell

Credit: PNAS

A new type of nanoparticle (NP) could aid the diagnosis and treatment of cancers, according to research published in Nature Communications.

Built on an easy-to-make polymer, these particles can be used as contrast agents to light up tumors for MRI and PET scans or to deliver chemotherapy and other treatments to cancer cells.

Furthermore, in vivo experiments showed the particles are biocompatible and elicit minimal side effects.

“These are amazingly useful particles,” said study author Yuanpei Li, PhD, of the UC Davis Comprehensive Cancer Center in Sacramento, California.

“As a contrast agent, they make tumors easier to see on MRI and other scans. We can also use them as vehicles to deliver chemotherapy directly to tumors, apply light to make the nanoparticles release singlet oxygen (photodynamic therapy), or use a laser to heat them (photothermal therapy)—all proven ways to destroy tumors.”

These NPs are built on a porphyrin/cholic acid polymer. Porphyrins are common organic compounds, and cholic acid is produced by the liver.

To further stabilize the particles, the researchers added the amino acid cysteine (creating CNPs), which prevents them from prematurely releasing their therapeutic payload when exposed to blood proteins and other barriers.

Therapeutic applications

The researchers tested the CNPs, both in vitro and in vivo, for a wide range of tasks. On the therapeutic side, the particles effectively transported anticancer drugs, such as doxorubicin.

CNPs carrying doxorubicin provided excellent cancer control in animals, with minimal side effects.

Even when kept in the blood for many hours, CNPs only released small amounts of the drug. However, when exposed to light or agents such as glutathione, they readily released their payloads.

The researchers showed that, when exposed to a single wavelength of light, the CNPs could generate heat or produce singlet oxygen to destroy tumor cells.

Imaging applications

CNPs offer a number of advantages to enhance imaging, according to the researchers. The particles readily chelate imaging agents and can remain in the body for long periods.

In animal studies, CNPs largely accumulated in tumors, rather than in normal tissue. So they dramatically enhanced tumor contrast for MRI and may also be promising for PET-MRI scans, the researchers said.

“These particles can combine imaging and therapeutics,” Dr Li noted. “We could potentially use them to simultaneously deliver treatment and monitor treatment efficacy.”

The researchers are now conducting additional preclinical studies with the CNPs. If all goes well, they will proceed to human trials. In the meantime, the team is excited about these capabilities.

“This is the first nanoparticle to perform so many different jobs,” Dr Li said. “From delivering chemo, photodynamic, and photothermal therapies, to enhancing diagnostic imaging, it’s the complete package.”

An infusion of chimeric antigen receptor (CAR) T-cell therapy following chemotherapy can elicit responses in patients with non-Hodgkin lymphoma, a small study suggests.

However, patients also experienced significant acute toxicities, including fever, low blood pressure, focal neurological deficits, and delirium.

James N. Kochenderfer, MD, of the National Institutes of Health in Bethesda, Maryland, and his colleagues reported these results in the Journal of Clinical Oncology.

The trial was sponsored by the National Cancer Institute, but the CAR T-cell therapy being tested uses the same CAR construct as KTE-C19, which is being developed by Kite Pharma, Inc.

The study included 15 patients with advanced B-cell malignancies. The patients first received conditioning with cyclophosphamide and fludarabine.

A day later, they received a single infusion of the CAR T-cell therapy, which consists of T cells taken from each patient’s peripheral blood and modified to target CD19.

The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.

Response rates

Thirteen patients were evaluable for response. One patient was lost to follow-up because of noncompliance, and 1 died soon after treatment. The researchers said the cause of death was likely cardiac arrhythmia.

The overall response rate was 92%. Eight patients achieved a complete response (CR), and 4 had a partial response (PR).

Of the 7 patients with chemotherapy-refractory diffuse large B-cell lymphoma, 4 achieved a CR, 2 achieved a PR, and 1 had stable disease. Three of the CRs are ongoing, with the duration ranging from 9 months to 22 months.

Of the 4 patients with chronic lymphocytic leukemia, 3 had a CR, and 1 had a PR. All 3 CRs are ongoing, with the duration ranging from 14 months to 23 months.

Among the 2 patients with indolent lymphomas, 1 achieved a CR, and 1 had a PR. The duration of the ongoing CR is 11 months.

Toxicity

As seen in other studies, the CAR T-cell therapy was associated with fever, low blood pressure, focal neurological deficits, and delirium. Toxicities largely occurred in the first 2 weeks after infusion.

All but 2 patients experienced grade 3/4 adverse events. Four patients had grade 3/4 hypotension.

All patients had elevations in serum interferon gamma and/or IL-6 around the time of peak toxicity, but most did not develop elevations in serum tumor necrosis factor.

Neurologic toxicities included confusion and obtundation, which have been reported in previous studies. However, 3  patients developed unexpected neurologic abnormalities.

One of these patients developed aphasia on day 5 after CAR T-cell infusion. It occurred intermittently for 7 days before resolving. The patient also experienced right-sided facial paresis that lasted approximately 20 minutes on day 8 after infusion.

Another patient developed aphasia 5 days after CAR T-cell infusion, but this was followed by confusion and severe generalized myoclonus. All symptoms resolved by 11 days after the infusion, except for a mild tremor that resolved over the next month.

A third patient developed aphasia 5 days after CAR T-cell infusion. This was followed by confusion, hemifacial spasms, apraxia, and gait disturbances. These effects varied in severity but dramatically improved 20 days after the infusion, according to the researchers.

An infusion of chimeric antigen receptor (CAR) T-cell therapy following chemotherapy can elicit responses in patients with non-Hodgkin lymphoma, a small study suggests.

However, patients also experienced significant acute toxicities, including fever, low blood pressure, focal neurological deficits, and delirium.

James N. Kochenderfer, MD, of the National Institutes of Health in Bethesda, Maryland, and his colleagues reported these results in the Journal of Clinical Oncology.

The trial was sponsored by the National Cancer Institute, but the CAR T-cell therapy being tested uses the same CAR construct as KTE-C19, which is being developed by Kite Pharma, Inc.

The study included 15 patients with advanced B-cell malignancies. The patients first received conditioning with cyclophosphamide and fludarabine.

A day later, they received a single infusion of the CAR T-cell therapy, which consists of T cells taken from each patient’s peripheral blood and modified to target CD19.

The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.

Response rates

Thirteen patients were evaluable for response. One patient was lost to follow-up because of noncompliance, and 1 died soon after treatment. The researchers said the cause of death was likely cardiac arrhythmia.

The overall response rate was 92%. Eight patients achieved a complete response (CR), and 4 had a partial response (PR).

Of the 7 patients with chemotherapy-refractory diffuse large B-cell lymphoma, 4 achieved a CR, 2 achieved a PR, and 1 had stable disease. Three of the CRs are ongoing, with the duration ranging from 9 months to 22 months.

Of the 4 patients with chronic lymphocytic leukemia, 3 had a CR, and 1 had a PR. All 3 CRs are ongoing, with the duration ranging from 14 months to 23 months.

Among the 2 patients with indolent lymphomas, 1 achieved a CR, and 1 had a PR. The duration of the ongoing CR is 11 months.

Toxicity

As seen in other studies, the CAR T-cell therapy was associated with fever, low blood pressure, focal neurological deficits, and delirium. Toxicities largely occurred in the first 2 weeks after infusion.

All but 2 patients experienced grade 3/4 adverse events. Four patients had grade 3/4 hypotension.

All patients had elevations in serum interferon gamma and/or IL-6 around the time of peak toxicity, but most did not develop elevations in serum tumor necrosis factor.

Neurologic toxicities included confusion and obtundation, which have been reported in previous studies. However, 3  patients developed unexpected neurologic abnormalities.

One of these patients developed aphasia on day 5 after CAR T-cell infusion. It occurred intermittently for 7 days before resolving. The patient also experienced right-sided facial paresis that lasted approximately 20 minutes on day 8 after infusion.

Another patient developed aphasia 5 days after CAR T-cell infusion, but this was followed by confusion and severe generalized myoclonus. All symptoms resolved by 11 days after the infusion, except for a mild tremor that resolved over the next month.

A third patient developed aphasia 5 days after CAR T-cell infusion. This was followed by confusion, hemifacial spasms, apraxia, and gait disturbances. These effects varied in severity but dramatically improved 20 days after the infusion, according to the researchers.

An infusion of chimeric antigen receptor (CAR) T-cell therapy following chemotherapy can elicit responses in patients with non-Hodgkin lymphoma, a small study suggests.

However, patients also experienced significant acute toxicities, including fever, low blood pressure, focal neurological deficits, and delirium.

James N. Kochenderfer, MD, of the National Institutes of Health in Bethesda, Maryland, and his colleagues reported these results in the Journal of Clinical Oncology.

The trial was sponsored by the National Cancer Institute, but the CAR T-cell therapy being tested uses the same CAR construct as KTE-C19, which is being developed by Kite Pharma, Inc.

The study included 15 patients with advanced B-cell malignancies. The patients first received conditioning with cyclophosphamide and fludarabine.

A day later, they received a single infusion of the CAR T-cell therapy, which consists of T cells taken from each patient’s peripheral blood and modified to target CD19.

The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.

Response rates

Thirteen patients were evaluable for response. One patient was lost to follow-up because of noncompliance, and 1 died soon after treatment. The researchers said the cause of death was likely cardiac arrhythmia.

The overall response rate was 92%. Eight patients achieved a complete response (CR), and 4 had a partial response (PR).

Of the 7 patients with chemotherapy-refractory diffuse large B-cell lymphoma, 4 achieved a CR, 2 achieved a PR, and 1 had stable disease. Three of the CRs are ongoing, with the duration ranging from 9 months to 22 months.

Of the 4 patients with chronic lymphocytic leukemia, 3 had a CR, and 1 had a PR. All 3 CRs are ongoing, with the duration ranging from 14 months to 23 months.

Among the 2 patients with indolent lymphomas, 1 achieved a CR, and 1 had a PR. The duration of the ongoing CR is 11 months.

Toxicity

As seen in other studies, the CAR T-cell therapy was associated with fever, low blood pressure, focal neurological deficits, and delirium. Toxicities largely occurred in the first 2 weeks after infusion.

All but 2 patients experienced grade 3/4 adverse events. Four patients had grade 3/4 hypotension.

All patients had elevations in serum interferon gamma and/or IL-6 around the time of peak toxicity, but most did not develop elevations in serum tumor necrosis factor.

Neurologic toxicities included confusion and obtundation, which have been reported in previous studies. However, 3  patients developed unexpected neurologic abnormalities.

One of these patients developed aphasia on day 5 after CAR T-cell infusion. It occurred intermittently for 7 days before resolving. The patient also experienced right-sided facial paresis that lasted approximately 20 minutes on day 8 after infusion.

Another patient developed aphasia 5 days after CAR T-cell infusion, but this was followed by confusion and severe generalized myoclonus. All symptoms resolved by 11 days after the infusion, except for a mild tremor that resolved over the next month.

A third patient developed aphasia 5 days after CAR T-cell infusion. This was followed by confusion, hemifacial spasms, apraxia, and gait disturbances. These effects varied in severity but dramatically improved 20 days after the infusion, according to the researchers.

Doctor examines patient

Credit: NCI

The risk of premature menopause among survivors of Hodgkin lymphoma (HL) may vary greatly, according to a study of more than 2000 women.

The results suggest that ovarian radiotherapy and certain chemotherapeutic regimens increase a woman’s risk of premature menopause.

And the radiation dose, number of treatment cycles, and patient age at treatment all influence that risk.

The findings appear in the Journal of the National Cancer Institute.

Previous research suggested that women with HL who receive certain types of chemotherapy or radiotherapy are at an increased risk of early menopause, but there was insufficient information to provide patients with detailed advice.

To gain more insight, Anthony Swerdlow, DSc, of The Institute of Cancer Research in London, UK, and his colleagues studied 2127 women who were treated for HL in England or Wales between 1960 and 2004.

All of the women were younger than 36 at the time of treatment, and all had received chest radiotherapy, sometimes alongside other treatments.

Some 605 of the women underwent non-surgical menopause before the age of 40. The researchers said this was a large enough number for them to estimate accurate risks of menopause, depending on the type and dose of treatments patients received and the age they received them.

The team found that several treatments caused a sharp increase in premature menopause risk, and menopause was more like among women treated at older ages.

The risk of premature menopause increased more than 20-fold after ovarian radiotherapy, alkylating chemotherapy other than dacarbazine, or BEAM (bis-chloroethylnitrosourea, etoposide, cytarabine, melphalan) chemotherapy given prior to stem cell transplant.

However, there was no significant increase in risk after receiving adriamycin, bleomycin, vinblastine, dacarbazine (ABVD).

Within 5 years of treatment, menopause had occurred in 62.5% of patients who received ≥5 Gy of ovarian radiotherapy, 50.9% of patients who received BEAM, and 24.2% of patients who received ≥6 cycles of alkylating chemotherapy.

The cumulative risk of menopause by age 40 was 81.3% after ≥ 5 Gy of ovarian radiotherapy, 75.3% after BEAM, 49.1% after ≥ 6 cycles of alkylating chemotherapy, 3.0% after solely supradiaphragmatic radiotherapy, and 1.4% after ABVD.

“We hope our study will help women to understand better, in consultation with their doctors, their risks of future infertility following treatment for this malignancy,” Dr Swerdlow said.

“By looking in a much larger group of women than previous studies of this type, we were able to produce age- and treatment-specific risk estimates that we hope will be of practical use to individual women.”

Doctor examines patient

Credit: NCI

The risk of premature menopause among survivors of Hodgkin lymphoma (HL) may vary greatly, according to a study of more than 2000 women.

The results suggest that ovarian radiotherapy and certain chemotherapeutic regimens increase a woman’s risk of premature menopause.

And the radiation dose, number of treatment cycles, and patient age at treatment all influence that risk.

The findings appear in the Journal of the National Cancer Institute.

Previous research suggested that women with HL who receive certain types of chemotherapy or radiotherapy are at an increased risk of early menopause, but there was insufficient information to provide patients with detailed advice.

To gain more insight, Anthony Swerdlow, DSc, of The Institute of Cancer Research in London, UK, and his colleagues studied 2127 women who were treated for HL in England or Wales between 1960 and 2004.

All of the women were younger than 36 at the time of treatment, and all had received chest radiotherapy, sometimes alongside other treatments.

Some 605 of the women underwent non-surgical menopause before the age of 40. The researchers said this was a large enough number for them to estimate accurate risks of menopause, depending on the type and dose of treatments patients received and the age they received them.

The team found that several treatments caused a sharp increase in premature menopause risk, and menopause was more like among women treated at older ages.

The risk of premature menopause increased more than 20-fold after ovarian radiotherapy, alkylating chemotherapy other than dacarbazine, or BEAM (bis-chloroethylnitrosourea, etoposide, cytarabine, melphalan) chemotherapy given prior to stem cell transplant.

However, there was no significant increase in risk after receiving adriamycin, bleomycin, vinblastine, dacarbazine (ABVD).

Within 5 years of treatment, menopause had occurred in 62.5% of patients who received ≥5 Gy of ovarian radiotherapy, 50.9% of patients who received BEAM, and 24.2% of patients who received ≥6 cycles of alkylating chemotherapy.

The cumulative risk of menopause by age 40 was 81.3% after ≥ 5 Gy of ovarian radiotherapy, 75.3% after BEAM, 49.1% after ≥ 6 cycles of alkylating chemotherapy, 3.0% after solely supradiaphragmatic radiotherapy, and 1.4% after ABVD.

“We hope our study will help women to understand better, in consultation with their doctors, their risks of future infertility following treatment for this malignancy,” Dr Swerdlow said.

“By looking in a much larger group of women than previous studies of this type, we were able to produce age- and treatment-specific risk estimates that we hope will be of practical use to individual women.”

Doctor examines patient

Credit: NCI

The risk of premature menopause among survivors of Hodgkin lymphoma (HL) may vary greatly, according to a study of more than 2000 women.

The results suggest that ovarian radiotherapy and certain chemotherapeutic regimens increase a woman’s risk of premature menopause.

And the radiation dose, number of treatment cycles, and patient age at treatment all influence that risk.

The findings appear in the Journal of the National Cancer Institute.

Previous research suggested that women with HL who receive certain types of chemotherapy or radiotherapy are at an increased risk of early menopause, but there was insufficient information to provide patients with detailed advice.

To gain more insight, Anthony Swerdlow, DSc, of The Institute of Cancer Research in London, UK, and his colleagues studied 2127 women who were treated for HL in England or Wales between 1960 and 2004.

All of the women were younger than 36 at the time of treatment, and all had received chest radiotherapy, sometimes alongside other treatments.

Some 605 of the women underwent non-surgical menopause before the age of 40. The researchers said this was a large enough number for them to estimate accurate risks of menopause, depending on the type and dose of treatments patients received and the age they received them.

The team found that several treatments caused a sharp increase in premature menopause risk, and menopause was more like among women treated at older ages.

The risk of premature menopause increased more than 20-fold after ovarian radiotherapy, alkylating chemotherapy other than dacarbazine, or BEAM (bis-chloroethylnitrosourea, etoposide, cytarabine, melphalan) chemotherapy given prior to stem cell transplant.

However, there was no significant increase in risk after receiving adriamycin, bleomycin, vinblastine, dacarbazine (ABVD).

Within 5 years of treatment, menopause had occurred in 62.5% of patients who received ≥5 Gy of ovarian radiotherapy, 50.9% of patients who received BEAM, and 24.2% of patients who received ≥6 cycles of alkylating chemotherapy.

The cumulative risk of menopause by age 40 was 81.3% after ≥ 5 Gy of ovarian radiotherapy, 75.3% after BEAM, 49.1% after ≥ 6 cycles of alkylating chemotherapy, 3.0% after solely supradiaphragmatic radiotherapy, and 1.4% after ABVD.

“We hope our study will help women to understand better, in consultation with their doctors, their risks of future infertility following treatment for this malignancy,” Dr Swerdlow said.

“By looking in a much larger group of women than previous studies of this type, we were able to produce age- and treatment-specific risk estimates that we hope will be of practical use to individual women.”

Doctor consults with cancer

patient and her father

Credit: Rhoda Baer

Guidelines developed almost 20 years ago can accurately predict infertility in girls with cancer, according to research published in The Lancet Oncology.

Researchers found the criteria in these guidelines can help healthcare professionals select which girls should be given the option of ovarian tissue cryopreservation.

The team noted that taking the initial samples of ovarian tissue involves a surgical technique that is still relatively experimental.

So it is crucial to accurately predict which patients are most likely to benefit from the procedure and when it can be safely performed.

The guidelines, known as the Edinburgh selection criteria, were instituted in 1996 to help healthcare professionals decide which girls should be given the option of cryopreservation, based on their age, type of cancer treatment, and their chance of cure.

Specifically, patients were required to meet the following criteria:

• Age younger than 35 years
• No previous chemotherapy or radiotherapy if 15 years or older at diagnosis, but mild, non-gonadotoxic chemotherapy was acceptable if a patient was younger than 15
• A realistic chance of surviving for 5 years
• A high risk of premature ovarian insufficiency (>50%)
• Informed consent (from parents and the patient, if possible)
• Negative serology results for HIV, syphilis, and hepatitis B
• Not pregnant and no existing children.

Testing the guidelines

To validate the selection criteria, W. Hamish B. Wallace, MD, of the Royal Hospital for Sick Children in Edinburgh, UK, and his colleagues analyzed 410 female cancer patients who were younger than 18 years at their time of diagnosis.

The patients were treated between January 1, 1996, and June 30, 2012, at the Edinburgh Children’s Cancer Centre, which serves the southeast region of Scotland.

In all, 34 patients (8%) met the Edinburgh selection criteria and were given the option of ovarian tissue cryopreservation before starting cancer treatment. Thirteen patients declined, 21 consented, and 20 had a successful procedure.

The researchers were able to assess ovarian function in 14 of the 20 patients with successful cryopreservation and 6 of the 13 patients who declined the procedure.

Of the 14 evaluable patients who underwent cryopreservation, 6 developed premature ovarian insufficiency at a median age of 13.4 years (range, 12.5–14.6), but 1 of these patients also had a natural pregnancy.

One patient each among the 6 evaluable patients who declined cryopreservation and the 141 evaluable patients who were not offered cryopreservation developed premature ovarian insufficiency.

So, overall, the probability of ovarian insufficiency was significantly higher for patients who met the Edinburgh selection criteria than for those who did not. The 15-year probability was 35% and 1%, respectively (P<0.0001).

The researchers said these results validate the use of the selection criteria, as they can accurately identify patients who will likely develop premature ovarian insufficiency.

“Advances in life-saving treatments mean that more and more young people with cancer are surviving the disease,” Dr Wallace said. “Here, we have an opportunity to help young women to have families of their own when they grow up, if they so choose.”

Doctor consults with cancer

patient and her father

Credit: Rhoda Baer

Guidelines developed almost 20 years ago can accurately predict infertility in girls with cancer, according to research published in The Lancet Oncology.

Researchers found the criteria in these guidelines can help healthcare professionals select which girls should be given the option of ovarian tissue cryopreservation.

The team noted that taking the initial samples of ovarian tissue involves a surgical technique that is still relatively experimental.

So it is crucial to accurately predict which patients are most likely to benefit from the procedure and when it can be safely performed.

The guidelines, known as the Edinburgh selection criteria, were instituted in 1996 to help healthcare professionals decide which girls should be given the option of cryopreservation, based on their age, type of cancer treatment, and their chance of cure.

Specifically, patients were required to meet the following criteria:

• Age younger than 35 years
• No previous chemotherapy or radiotherapy if 15 years or older at diagnosis, but mild, non-gonadotoxic chemotherapy was acceptable if a patient was younger than 15
• A realistic chance of surviving for 5 years
• A high risk of premature ovarian insufficiency (>50%)
• Informed consent (from parents and the patient, if possible)
• Negative serology results for HIV, syphilis, and hepatitis B
• Not pregnant and no existing children.

Testing the guidelines

To validate the selection criteria, W. Hamish B. Wallace, MD, of the Royal Hospital for Sick Children in Edinburgh, UK, and his colleagues analyzed 410 female cancer patients who were younger than 18 years at their time of diagnosis.

The patients were treated between January 1, 1996, and June 30, 2012, at the Edinburgh Children’s Cancer Centre, which serves the southeast region of Scotland.

In all, 34 patients (8%) met the Edinburgh selection criteria and were given the option of ovarian tissue cryopreservation before starting cancer treatment. Thirteen patients declined, 21 consented, and 20 had a successful procedure.

The researchers were able to assess ovarian function in 14 of the 20 patients with successful cryopreservation and 6 of the 13 patients who declined the procedure.

Of the 14 evaluable patients who underwent cryopreservation, 6 developed premature ovarian insufficiency at a median age of 13.4 years (range, 12.5–14.6), but 1 of these patients also had a natural pregnancy.

One patient each among the 6 evaluable patients who declined cryopreservation and the 141 evaluable patients who were not offered cryopreservation developed premature ovarian insufficiency.

So, overall, the probability of ovarian insufficiency was significantly higher for patients who met the Edinburgh selection criteria than for those who did not. The 15-year probability was 35% and 1%, respectively (P<0.0001).

The researchers said these results validate the use of the selection criteria, as they can accurately identify patients who will likely develop premature ovarian insufficiency.

“Advances in life-saving treatments mean that more and more young people with cancer are surviving the disease,” Dr Wallace said. “Here, we have an opportunity to help young women to have families of their own when they grow up, if they so choose.”

Doctor consults with cancer

patient and her father

Credit: Rhoda Baer

Guidelines developed almost 20 years ago can accurately predict infertility in girls with cancer, according to research published in The Lancet Oncology.

Researchers found the criteria in these guidelines can help healthcare professionals select which girls should be given the option of ovarian tissue cryopreservation.

The team noted that taking the initial samples of ovarian tissue involves a surgical technique that is still relatively experimental.

So it is crucial to accurately predict which patients are most likely to benefit from the procedure and when it can be safely performed.

The guidelines, known as the Edinburgh selection criteria, were instituted in 1996 to help healthcare professionals decide which girls should be given the option of cryopreservation, based on their age, type of cancer treatment, and their chance of cure.

Specifically, patients were required to meet the following criteria:

• Age younger than 35 years
• No previous chemotherapy or radiotherapy if 15 years or older at diagnosis, but mild, non-gonadotoxic chemotherapy was acceptable if a patient was younger than 15
• A realistic chance of surviving for 5 years
• A high risk of premature ovarian insufficiency (>50%)
• Informed consent (from parents and the patient, if possible)
• Negative serology results for HIV, syphilis, and hepatitis B
• Not pregnant and no existing children.

Testing the guidelines

To validate the selection criteria, W. Hamish B. Wallace, MD, of the Royal Hospital for Sick Children in Edinburgh, UK, and his colleagues analyzed 410 female cancer patients who were younger than 18 years at their time of diagnosis.

The patients were treated between January 1, 1996, and June 30, 2012, at the Edinburgh Children’s Cancer Centre, which serves the southeast region of Scotland.

In all, 34 patients (8%) met the Edinburgh selection criteria and were given the option of ovarian tissue cryopreservation before starting cancer treatment. Thirteen patients declined, 21 consented, and 20 had a successful procedure.

The researchers were able to assess ovarian function in 14 of the 20 patients with successful cryopreservation and 6 of the 13 patients who declined the procedure.

Of the 14 evaluable patients who underwent cryopreservation, 6 developed premature ovarian insufficiency at a median age of 13.4 years (range, 12.5–14.6), but 1 of these patients also had a natural pregnancy.

One patient each among the 6 evaluable patients who declined cryopreservation and the 141 evaluable patients who were not offered cryopreservation developed premature ovarian insufficiency.

So, overall, the probability of ovarian insufficiency was significantly higher for patients who met the Edinburgh selection criteria than for those who did not. The 15-year probability was 35% and 1%, respectively (P<0.0001).

The researchers said these results validate the use of the selection criteria, as they can accurately identify patients who will likely develop premature ovarian insufficiency.

“Advances in life-saving treatments mean that more and more young people with cancer are surviving the disease,” Dr Wallace said. “Here, we have an opportunity to help young women to have families of their own when they grow up, if they so choose.”

Researcher in the lab

Credit: Rhoda Baer

Indirectly targeting the prosurvival protein Mcl-1 can reverse chemoresistance in lymphoma and other cancer cells, investigators have reported in The Journal of Biological Chemistry.

The team found that targeting an enzyme known as protein phosphatase 2A (PP2A) inhibited Mcl-1 dephosphorylation, which prompted the loss of Mcl-1 in chemoresistant Burkitt lymphoma cells.

“These findings may lead to a new target for chemoresistant cancer cells,” said Ruth W. Craig, PhD, of Geisel School of Medicine at Dartmouth in Hanover, New Hampshire.

“These cells are resistant to multiple types of standard chemotherapeutic agents because of [Mcl-1] overexpression. However, Mcl-1 expression plummets when we inhibit [PP2A], and then cancer cells subsequently die.”

Dr Craig and her colleagues found that PP2A can be inhibited to stop the removal of phosphate groups from a regulatory motif in Mcl-1 referred to as the PEST region (enriched with amino acids proline, glutamic acid, serine, and threonine).

And inhibiting the removal of phosphate groups, such as at threonine-163 and serine-159, targets the Mcl-1 protein for rapid destruction.

To reach this conclusion, the investigators studied BL41-3 cells, a Burkitt lymphoma cell line that overexpresses Mcl-1 and has proven resistant to multiple treatments.

The team exposed BL41-3 cells to 2 different PP2A inhibitors, okadaic acid and calyculin A. Both drugs prompted an increase in phosphorylation at threonine-163 and serine-159, as well as a decrease in Mcl-1 expression.

Further investigation confirmed that PP2A interacts with Mcl-1. And, as with therapeutic targeting, shRNA knockdown of PP2A/Aα increased phosphorylation while decreasing Mcl-1 expression.

Finally, the investigators showed the increase in Mcl-1 phosphorylation and decrease in its expression occurred well before markers of cell death appeared—about 2 to 3 hours before.

“PP2A is a complex multi-subunit enzyme, and we hope to identify more specifically which form of PP2A is involved in dephosphorylating Mcl-1,” Dr Craig said. “This could [provide us with] a more specific way of causing Mcl-1 destruction.”

Researcher in the lab

Credit: Rhoda Baer

Indirectly targeting the prosurvival protein Mcl-1 can reverse chemoresistance in lymphoma and other cancer cells, investigators have reported in The Journal of Biological Chemistry.

The team found that targeting an enzyme known as protein phosphatase 2A (PP2A) inhibited Mcl-1 dephosphorylation, which prompted the loss of Mcl-1 in chemoresistant Burkitt lymphoma cells.

“These findings may lead to a new target for chemoresistant cancer cells,” said Ruth W. Craig, PhD, of Geisel School of Medicine at Dartmouth in Hanover, New Hampshire.

“These cells are resistant to multiple types of standard chemotherapeutic agents because of [Mcl-1] overexpression. However, Mcl-1 expression plummets when we inhibit [PP2A], and then cancer cells subsequently die.”

Dr Craig and her colleagues found that PP2A can be inhibited to stop the removal of phosphate groups from a regulatory motif in Mcl-1 referred to as the PEST region (enriched with amino acids proline, glutamic acid, serine, and threonine).

And inhibiting the removal of phosphate groups, such as at threonine-163 and serine-159, targets the Mcl-1 protein for rapid destruction.

To reach this conclusion, the investigators studied BL41-3 cells, a Burkitt lymphoma cell line that overexpresses Mcl-1 and has proven resistant to multiple treatments.

The team exposed BL41-3 cells to 2 different PP2A inhibitors, okadaic acid and calyculin A. Both drugs prompted an increase in phosphorylation at threonine-163 and serine-159, as well as a decrease in Mcl-1 expression.

Further investigation confirmed that PP2A interacts with Mcl-1. And, as with therapeutic targeting, shRNA knockdown of PP2A/Aα increased phosphorylation while decreasing Mcl-1 expression.

Finally, the investigators showed the increase in Mcl-1 phosphorylation and decrease in its expression occurred well before markers of cell death appeared—about 2 to 3 hours before.

“PP2A is a complex multi-subunit enzyme, and we hope to identify more specifically which form of PP2A is involved in dephosphorylating Mcl-1,” Dr Craig said. “This could [provide us with] a more specific way of causing Mcl-1 destruction.”

Researcher in the lab

Credit: Rhoda Baer

Indirectly targeting the prosurvival protein Mcl-1 can reverse chemoresistance in lymphoma and other cancer cells, investigators have reported in The Journal of Biological Chemistry.

The team found that targeting an enzyme known as protein phosphatase 2A (PP2A) inhibited Mcl-1 dephosphorylation, which prompted the loss of Mcl-1 in chemoresistant Burkitt lymphoma cells.

“These findings may lead to a new target for chemoresistant cancer cells,” said Ruth W. Craig, PhD, of Geisel School of Medicine at Dartmouth in Hanover, New Hampshire.

“These cells are resistant to multiple types of standard chemotherapeutic agents because of [Mcl-1] overexpression. However, Mcl-1 expression plummets when we inhibit [PP2A], and then cancer cells subsequently die.”

Dr Craig and her colleagues found that PP2A can be inhibited to stop the removal of phosphate groups from a regulatory motif in Mcl-1 referred to as the PEST region (enriched with amino acids proline, glutamic acid, serine, and threonine).

And inhibiting the removal of phosphate groups, such as at threonine-163 and serine-159, targets the Mcl-1 protein for rapid destruction.

To reach this conclusion, the investigators studied BL41-3 cells, a Burkitt lymphoma cell line that overexpresses Mcl-1 and has proven resistant to multiple treatments.

The team exposed BL41-3 cells to 2 different PP2A inhibitors, okadaic acid and calyculin A. Both drugs prompted an increase in phosphorylation at threonine-163 and serine-159, as well as a decrease in Mcl-1 expression.

Further investigation confirmed that PP2A interacts with Mcl-1. And, as with therapeutic targeting, shRNA knockdown of PP2A/Aα increased phosphorylation while decreasing Mcl-1 expression.

Finally, the investigators showed the increase in Mcl-1 phosphorylation and decrease in its expression occurred well before markers of cell death appeared—about 2 to 3 hours before.

“PP2A is a complex multi-subunit enzyme, and we hope to identify more specifically which form of PP2A is involved in dephosphorylating Mcl-1,” Dr Craig said. “This could [provide us with] a more specific way of causing Mcl-1 destruction.”

Child with leukemia

Credit: Bill Branson

Childhood cancer survivors are no more likely than their cancer-free peers to adhere to healthy living guidelines, according to a study published in the Journal of Cancer Survivorship.

Survivors were less likely to be smokers and had a lower average body mass index (BMI).

But there were no significant differences between survivors and cancer-free control subjects with regard to overall diet, physical activity, or alcohol consumption.

Chloe Berdan, of Promedica in Toledo, Ohio, and her colleagues uncovered these results by examining data from the Chicago Healthy Living Study.

The team assessed adherence to American Cancer Society Guidelines on Nutrition and Physical Activity via interviews with 431 childhood cancer survivors and 361 control subjects who never had cancer. The survivors, ages 18 to 59, were all diagnosed with a malignant cancer before their 21st birthdays.

There were no significant differences in sex or race between survivors and controls. Survivors were younger than controls (28.4±7.8 vs 29.6± 8.3 years, P=0.04) and had less education (14.0±2.0 vs 14.4±2.0 years, P=0.01).

Overall, there was no significant difference between survivors and control subjects in adhering to the American Cancer Society guidelines.

Survivors and controls also had similar scores for several individual measures, including alcohol consumption, overall physical activity, overall diet, the servings of fruits/vegetables consumed, and the consumption of red/processed meat.

However, survivors were significantly less likely than controls to be smokers—11.4% vs 17.5% (P=0.02). Survivors had, on average, a BMI of about 1.2 kg/m² lower than controls (P=0.01). And survivors consumed significantly less fiber than controls—9.2±3.5 vs 9.7±3.8 kcal (P=0.05).

Only about 1 in 10 survivors (10.2%) met fiber recommendations, 17.7% ate 5 fruits or vegetables per day, and 46.2% met the red/processed meat recommendation of less than 18 oz per week. On average, survivors scored under 50% for the quality of their diets.

Survivors were better at meeting the goal of at least 5 hours of moderate activity per week (60.5%) than to sticking to any of the other guidelines.

About 36% of survivors were within a healthy BMI range, 2.9% were underweight, 28.9% were overweight, and 32.4% were obese.

The 0.7% of survivors who adhered fully to the guidelines tended to be women, non-smokers, and people with a good view of their own health.

“There is still much room for improvement in educating and encouraging survivors to follow healthier diets and lifestyles,” Berdan said. “Adopting such behavior during early adulthood may have a lasting impact on their quality of life and overall survival.”

Child with leukemia

Credit: Bill Branson

Childhood cancer survivors are no more likely than their cancer-free peers to adhere to healthy living guidelines, according to a study published in the Journal of Cancer Survivorship.

Survivors were less likely to be smokers and had a lower average body mass index (BMI).

But there were no significant differences between survivors and cancer-free control subjects with regard to overall diet, physical activity, or alcohol consumption.

Chloe Berdan, of Promedica in Toledo, Ohio, and her colleagues uncovered these results by examining data from the Chicago Healthy Living Study.

The team assessed adherence to American Cancer Society Guidelines on Nutrition and Physical Activity via interviews with 431 childhood cancer survivors and 361 control subjects who never had cancer. The survivors, ages 18 to 59, were all diagnosed with a malignant cancer before their 21st birthdays.

There were no significant differences in sex or race between survivors and controls. Survivors were younger than controls (28.4±7.8 vs 29.6± 8.3 years, P=0.04) and had less education (14.0±2.0 vs 14.4±2.0 years, P=0.01).

Overall, there was no significant difference between survivors and control subjects in adhering to the American Cancer Society guidelines.

Survivors and controls also had similar scores for several individual measures, including alcohol consumption, overall physical activity, overall diet, the servings of fruits/vegetables consumed, and the consumption of red/processed meat.

However, survivors were significantly less likely than controls to be smokers—11.4% vs 17.5% (P=0.02). Survivors had, on average, a BMI of about 1.2 kg/m² lower than controls (P=0.01). And survivors consumed significantly less fiber than controls—9.2±3.5 vs 9.7±3.8 kcal (P=0.05).

Only about 1 in 10 survivors (10.2%) met fiber recommendations, 17.7% ate 5 fruits or vegetables per day, and 46.2% met the red/processed meat recommendation of less than 18 oz per week. On average, survivors scored under 50% for the quality of their diets.

Survivors were better at meeting the goal of at least 5 hours of moderate activity per week (60.5%) than to sticking to any of the other guidelines.

About 36% of survivors were within a healthy BMI range, 2.9% were underweight, 28.9% were overweight, and 32.4% were obese.

The 0.7% of survivors who adhered fully to the guidelines tended to be women, non-smokers, and people with a good view of their own health.

“There is still much room for improvement in educating and encouraging survivors to follow healthier diets and lifestyles,” Berdan said. “Adopting such behavior during early adulthood may have a lasting impact on their quality of life and overall survival.”

Child with leukemia

Credit: Bill Branson

Childhood cancer survivors are no more likely than their cancer-free peers to adhere to healthy living guidelines, according to a study published in the Journal of Cancer Survivorship.

Survivors were less likely to be smokers and had a lower average body mass index (BMI).

But there were no significant differences between survivors and cancer-free control subjects with regard to overall diet, physical activity, or alcohol consumption.

Chloe Berdan, of Promedica in Toledo, Ohio, and her colleagues uncovered these results by examining data from the Chicago Healthy Living Study.

The team assessed adherence to American Cancer Society Guidelines on Nutrition and Physical Activity via interviews with 431 childhood cancer survivors and 361 control subjects who never had cancer. The survivors, ages 18 to 59, were all diagnosed with a malignant cancer before their 21st birthdays.

There were no significant differences in sex or race between survivors and controls. Survivors were younger than controls (28.4±7.8 vs 29.6± 8.3 years, P=0.04) and had less education (14.0±2.0 vs 14.4±2.0 years, P=0.01).

Overall, there was no significant difference between survivors and control subjects in adhering to the American Cancer Society guidelines.

Survivors and controls also had similar scores for several individual measures, including alcohol consumption, overall physical activity, overall diet, the servings of fruits/vegetables consumed, and the consumption of red/processed meat.

However, survivors were significantly less likely than controls to be smokers—11.4% vs 17.5% (P=0.02). Survivors had, on average, a BMI of about 1.2 kg/m² lower than controls (P=0.01). And survivors consumed significantly less fiber than controls—9.2±3.5 vs 9.7±3.8 kcal (P=0.05).

Only about 1 in 10 survivors (10.2%) met fiber recommendations, 17.7% ate 5 fruits or vegetables per day, and 46.2% met the red/processed meat recommendation of less than 18 oz per week. On average, survivors scored under 50% for the quality of their diets.

Survivors were better at meeting the goal of at least 5 hours of moderate activity per week (60.5%) than to sticking to any of the other guidelines.

About 36% of survivors were within a healthy BMI range, 2.9% were underweight, 28.9% were overweight, and 32.4% were obese.

The 0.7% of survivors who adhered fully to the guidelines tended to be women, non-smokers, and people with a good view of their own health.

“There is still much room for improvement in educating and encouraging survivors to follow healthier diets and lifestyles,” Berdan said. “Adopting such behavior during early adulthood may have a lasting impact on their quality of life and overall survival.”