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Cell-free DNA kit receives CE-IVD mark
Vela Diagnostics’ Sentosa® SX Cell-free DNA (cfDNA) Kit has received the CE-IVD mark, which means this kit is approved for in vitro diagnostics use in the European Union.
The Sentosa® SX cfDNA Kit is intended to extract free-circulating DNA from human plasma.
The kit was developed for use in next-generation sequencing and real-time polymerase chain reaction workflows.
The kit is designed to run on the Sentosa® SX101 instrument and works with whole blood samples collected in Cell-free DNA BCT from Streck, K2, or K3 EDTA tubes.
Automated sample extraction with the Sentosa® SX cfDNA Kit takes approximately 3.5 hours. It requires 20 minutes of operator hands-on time and 4 mL of plasma from the clinical sample.
The Sentosa® SX cfDNA Kit is able to recover low-frequency DNA variants in blood, according to Vela Diagnostics.
Results from a pilot study testing the kit were presented in a poster at the AMP 2016 Annual Meeting. 
Vela Diagnostics’ Sentosa® SX Cell-free DNA (cfDNA) Kit has received the CE-IVD mark, which means this kit is approved for in vitro diagnostics use in the European Union.
The Sentosa® SX cfDNA Kit is intended to extract free-circulating DNA from human plasma.
The kit was developed for use in next-generation sequencing and real-time polymerase chain reaction workflows.
The kit is designed to run on the Sentosa® SX101 instrument and works with whole blood samples collected in Cell-free DNA BCT from Streck, K2, or K3 EDTA tubes.
Automated sample extraction with the Sentosa® SX cfDNA Kit takes approximately 3.5 hours. It requires 20 minutes of operator hands-on time and 4 mL of plasma from the clinical sample.
The Sentosa® SX cfDNA Kit is able to recover low-frequency DNA variants in blood, according to Vela Diagnostics.
Results from a pilot study testing the kit were presented in a poster at the AMP 2016 Annual Meeting.
Vela Diagnostics’ Sentosa® SX Cell-free DNA (cfDNA) Kit has received the CE-IVD mark, which means this kit is approved for in vitro diagnostics use in the European Union.
The Sentosa® SX cfDNA Kit is intended to extract free-circulating DNA from human plasma.
The kit was developed for use in next-generation sequencing and real-time polymerase chain reaction workflows.
The kit is designed to run on the Sentosa® SX101 instrument and works with whole blood samples collected in Cell-free DNA BCT from Streck, K2, or K3 EDTA tubes.
Automated sample extraction with the Sentosa® SX cfDNA Kit takes approximately 3.5 hours. It requires 20 minutes of operator hands-on time and 4 mL of plasma from the clinical sample.
The Sentosa® SX cfDNA Kit is able to recover low-frequency DNA variants in blood, according to Vela Diagnostics.
Results from a pilot study testing the kit were presented in a poster at the AMP 2016 Annual Meeting.
Antimalarial could aid treatment of ALL
An antimalarial drug and a BH3 mimetic have demonstrated promise for treating BCR-ABL-positive acute lymphoblastic leukemia (ALL), according to work published in Clinical Cancer Research.
Investigators found the widely used antimalarial dihydroartemisinin (DHA) sensitized BCR-ABL+ ALL to the BH3 mimetic navitoclax (formerly ABT-263).
The combination therapy had a synergistic effect on mouse and human BCR-ABL+ leukemic cell death and extended the lives of mice with BCR-ABL+ ALL.
“Survival rates for children and adults with this leukemia still lag, highlighting the urgent need for new therapies,” said study author Joseph Opferman, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“Our findings suggest that combining DHA with ABT-263 can significantly improve treatment response.”
As opposed to mice that received navitoclax alone, there was no evidence of navitoclax resistance in mice treated with navitoclax and DHA.
The investigators determined that DHA worked by repressing production of MCL-1, a protein that is elevated in many cancers and helps malignant cells resist BH3 mimetics.
“MCL-1 is widely recognized as an important survival molecule in many normal cell types as well as cancer,” Dr Opferman said. “MCL-1 inhibitors are in development, but none are currently available for treating patients.”
“And because MCL-1 is essential for proper functioning of many normal cell types, there is concern about potential toxicity. We sought to identify drugs that are available now to augment treatment of BCR-ABL+ ALL.”
The search for a drug to sensitize BCR-ABL+ ALL to navitoclax and related compounds led Dr Opferman and his colleagues to DHA. A drug screen showed that DHA killed BCR-ABL+ ALL cells from mice.
The investigators showed how DHA induced expression of the protein CHOP, which is a key regulator of the endoplasmic reticulum stress pathway in cells. CHOP expression triggered the stress pathway in BCR-ABL+ ALL cells from mice and led to the suppression of MCL-1.
“MCL-1 has a short half-life, so the cell’s MCL-1 stores are rapidly depleted if the protein’s translation is repressed,” said study author Amit Budhraja, PhD, a postdoctoral fellow in Dr Opferman’s lab.
Now, the investigators are studying the mechanism in human BCR-ABL+ leukemic cells as well as in other cancers.
“Identifying the mechanism will allow us to study the pathway in detail for other points to target for anticancer drug development,” Dr Opferman said.
An antimalarial drug and a BH3 mimetic have demonstrated promise for treating BCR-ABL-positive acute lymphoblastic leukemia (ALL), according to work published in Clinical Cancer Research.
Investigators found the widely used antimalarial dihydroartemisinin (DHA) sensitized BCR-ABL+ ALL to the BH3 mimetic navitoclax (formerly ABT-263).
The combination therapy had a synergistic effect on mouse and human BCR-ABL+ leukemic cell death and extended the lives of mice with BCR-ABL+ ALL.
“Survival rates for children and adults with this leukemia still lag, highlighting the urgent need for new therapies,” said study author Joseph Opferman, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“Our findings suggest that combining DHA with ABT-263 can significantly improve treatment response.”
As opposed to mice that received navitoclax alone, there was no evidence of navitoclax resistance in mice treated with navitoclax and DHA.
The investigators determined that DHA worked by repressing production of MCL-1, a protein that is elevated in many cancers and helps malignant cells resist BH3 mimetics.
“MCL-1 is widely recognized as an important survival molecule in many normal cell types as well as cancer,” Dr Opferman said. “MCL-1 inhibitors are in development, but none are currently available for treating patients.”
“And because MCL-1 is essential for proper functioning of many normal cell types, there is concern about potential toxicity. We sought to identify drugs that are available now to augment treatment of BCR-ABL+ ALL.”
The search for a drug to sensitize BCR-ABL+ ALL to navitoclax and related compounds led Dr Opferman and his colleagues to DHA. A drug screen showed that DHA killed BCR-ABL+ ALL cells from mice.
The investigators showed how DHA induced expression of the protein CHOP, which is a key regulator of the endoplasmic reticulum stress pathway in cells. CHOP expression triggered the stress pathway in BCR-ABL+ ALL cells from mice and led to the suppression of MCL-1.
“MCL-1 has a short half-life, so the cell’s MCL-1 stores are rapidly depleted if the protein’s translation is repressed,” said study author Amit Budhraja, PhD, a postdoctoral fellow in Dr Opferman’s lab.
Now, the investigators are studying the mechanism in human BCR-ABL+ leukemic cells as well as in other cancers.
“Identifying the mechanism will allow us to study the pathway in detail for other points to target for anticancer drug development,” Dr Opferman said.
An antimalarial drug and a BH3 mimetic have demonstrated promise for treating BCR-ABL-positive acute lymphoblastic leukemia (ALL), according to work published in Clinical Cancer Research.
Investigators found the widely used antimalarial dihydroartemisinin (DHA) sensitized BCR-ABL+ ALL to the BH3 mimetic navitoclax (formerly ABT-263).
The combination therapy had a synergistic effect on mouse and human BCR-ABL+ leukemic cell death and extended the lives of mice with BCR-ABL+ ALL.
“Survival rates for children and adults with this leukemia still lag, highlighting the urgent need for new therapies,” said study author Joseph Opferman, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“Our findings suggest that combining DHA with ABT-263 can significantly improve treatment response.”
As opposed to mice that received navitoclax alone, there was no evidence of navitoclax resistance in mice treated with navitoclax and DHA.
The investigators determined that DHA worked by repressing production of MCL-1, a protein that is elevated in many cancers and helps malignant cells resist BH3 mimetics.
“MCL-1 is widely recognized as an important survival molecule in many normal cell types as well as cancer,” Dr Opferman said. “MCL-1 inhibitors are in development, but none are currently available for treating patients.”
“And because MCL-1 is essential for proper functioning of many normal cell types, there is concern about potential toxicity. We sought to identify drugs that are available now to augment treatment of BCR-ABL+ ALL.”
The search for a drug to sensitize BCR-ABL+ ALL to navitoclax and related compounds led Dr Opferman and his colleagues to DHA. A drug screen showed that DHA killed BCR-ABL+ ALL cells from mice.
The investigators showed how DHA induced expression of the protein CHOP, which is a key regulator of the endoplasmic reticulum stress pathway in cells. CHOP expression triggered the stress pathway in BCR-ABL+ ALL cells from mice and led to the suppression of MCL-1.
“MCL-1 has a short half-life, so the cell’s MCL-1 stores are rapidly depleted if the protein’s translation is repressed,” said study author Amit Budhraja, PhD, a postdoctoral fellow in Dr Opferman’s lab.
Now, the investigators are studying the mechanism in human BCR-ABL+ leukemic cells as well as in other cancers.
“Identifying the mechanism will allow us to study the pathway in detail for other points to target for anticancer drug development,” Dr Opferman said.
Plek2 may be therapeutic target in MPNs
New research suggests plecktrin-2 (Plek2) may be a therapeutic target for myeloproliferative neoplasms (MPNs).
Plek2 was previously shown to be involved in red blood cell production.
Now, researchers have found Plek2 is upregulated in patients with JAK2V617F-positive MPNs.
And loss of Plek2 ameliorated JAK2V617F-induced myeloproliferative phenotypes in a mouse model.
Peng Ji, MD, PhD, of Northwestern University in Chicago, Illinois, and his colleagues conducted this research and reported the results in The Journal of Clinical Investigation.
The researchers found that Plek2 was significantly upregulated in patients with JAK2V617F-positive MPNs, including myelofibrosis, essential thrombocythemia, and polycythemia vera.
Plek2 was also upregulated in myeloid, lymphoid, and erythroid cells in a JAK2V617F hematopoietic-specific knock-in mouse model that mimics the pathogenesis of MPNs.
The researchers assessed the effects of turning off Plek2 in this model and found that loss of Plek2 significantly reverted neutrophilia and thrombocytosis, partially reverted reticulocytosis, mildly reduced red blood cell count, significantly reduced megakaryocyte numbers and clusters, and reduced spleen size.
Loss of Plek2 also reduced red blood cell mass, which was the main contributing factor in the reversion of vascular occlusions, according to the researchers. The team detected “widespread vascular occlusions” in mice with Plek2, but mice without Plek2 had “relatively clear vasculature.”
“The risk of thrombosis was not completely cured because there are other factors aside from pleckstrin-2, but we saw a very dramatic amelioration in blood clotting,” Dr Ji said.
Finally, loss of Plek2 improved survival. All mice with Plek2 died at around 30 weeks, but more than 80% of the mice without Plek2 survived beyond 40 weeks.
Dr Ji and his colleagues hope to build upon these findings by developing a Plek2 inhibitor.
“We are looking for a molecule that can bind with pleckstrin-2 and block its functions,” Dr Ji said. “We’ve already screened compounds, and we have about 40 we are testing right now.”
“Mice with pleckstrin-2 deactivated experienced fewer side effects compared to mice without JAK2, so we believe the pleckstrin-2 inhibitor will generate fewer side effects as well.”
New research suggests plecktrin-2 (Plek2) may be a therapeutic target for myeloproliferative neoplasms (MPNs).
Plek2 was previously shown to be involved in red blood cell production.
Now, researchers have found Plek2 is upregulated in patients with JAK2V617F-positive MPNs.
And loss of Plek2 ameliorated JAK2V617F-induced myeloproliferative phenotypes in a mouse model.
Peng Ji, MD, PhD, of Northwestern University in Chicago, Illinois, and his colleagues conducted this research and reported the results in The Journal of Clinical Investigation.
The researchers found that Plek2 was significantly upregulated in patients with JAK2V617F-positive MPNs, including myelofibrosis, essential thrombocythemia, and polycythemia vera.
Plek2 was also upregulated in myeloid, lymphoid, and erythroid cells in a JAK2V617F hematopoietic-specific knock-in mouse model that mimics the pathogenesis of MPNs.
The researchers assessed the effects of turning off Plek2 in this model and found that loss of Plek2 significantly reverted neutrophilia and thrombocytosis, partially reverted reticulocytosis, mildly reduced red blood cell count, significantly reduced megakaryocyte numbers and clusters, and reduced spleen size.
Loss of Plek2 also reduced red blood cell mass, which was the main contributing factor in the reversion of vascular occlusions, according to the researchers. The team detected “widespread vascular occlusions” in mice with Plek2, but mice without Plek2 had “relatively clear vasculature.”
“The risk of thrombosis was not completely cured because there are other factors aside from pleckstrin-2, but we saw a very dramatic amelioration in blood clotting,” Dr Ji said.
Finally, loss of Plek2 improved survival. All mice with Plek2 died at around 30 weeks, but more than 80% of the mice without Plek2 survived beyond 40 weeks.
Dr Ji and his colleagues hope to build upon these findings by developing a Plek2 inhibitor.
“We are looking for a molecule that can bind with pleckstrin-2 and block its functions,” Dr Ji said. “We’ve already screened compounds, and we have about 40 we are testing right now.”
“Mice with pleckstrin-2 deactivated experienced fewer side effects compared to mice without JAK2, so we believe the pleckstrin-2 inhibitor will generate fewer side effects as well.”
New research suggests plecktrin-2 (Plek2) may be a therapeutic target for myeloproliferative neoplasms (MPNs).
Plek2 was previously shown to be involved in red blood cell production.
Now, researchers have found Plek2 is upregulated in patients with JAK2V617F-positive MPNs.
And loss of Plek2 ameliorated JAK2V617F-induced myeloproliferative phenotypes in a mouse model.
Peng Ji, MD, PhD, of Northwestern University in Chicago, Illinois, and his colleagues conducted this research and reported the results in The Journal of Clinical Investigation.
The researchers found that Plek2 was significantly upregulated in patients with JAK2V617F-positive MPNs, including myelofibrosis, essential thrombocythemia, and polycythemia vera.
Plek2 was also upregulated in myeloid, lymphoid, and erythroid cells in a JAK2V617F hematopoietic-specific knock-in mouse model that mimics the pathogenesis of MPNs.
The researchers assessed the effects of turning off Plek2 in this model and found that loss of Plek2 significantly reverted neutrophilia and thrombocytosis, partially reverted reticulocytosis, mildly reduced red blood cell count, significantly reduced megakaryocyte numbers and clusters, and reduced spleen size.
Loss of Plek2 also reduced red blood cell mass, which was the main contributing factor in the reversion of vascular occlusions, according to the researchers. The team detected “widespread vascular occlusions” in mice with Plek2, but mice without Plek2 had “relatively clear vasculature.”
“The risk of thrombosis was not completely cured because there are other factors aside from pleckstrin-2, but we saw a very dramatic amelioration in blood clotting,” Dr Ji said.
Finally, loss of Plek2 improved survival. All mice with Plek2 died at around 30 weeks, but more than 80% of the mice without Plek2 survived beyond 40 weeks.
Dr Ji and his colleagues hope to build upon these findings by developing a Plek2 inhibitor.
“We are looking for a molecule that can bind with pleckstrin-2 and block its functions,” Dr Ji said. “We’ve already screened compounds, and we have about 40 we are testing right now.”
“Mice with pleckstrin-2 deactivated experienced fewer side effects compared to mice without JAK2, so we believe the pleckstrin-2 inhibitor will generate fewer side effects as well.”
Drug receives fast track designation for FLT3+ rel/ref AML
The US Food and Drug Administration (FDA) has granted fast track designation to crenolanib for the treatment of patients with FLT3 mutation-positive relapsed or refractory acute myeloid leukemia (AML).
Crenolanib is a benzimidazole type I tyrosine kinase inhibitor (TKI) that selectively inhibits signaling of wild-type and mutant isoforms of FLT3 and PDGFRα/β.
Crenolanib is being developed by Arog Pharmaceuticals, Inc.
The company is preparing for a phase 3, randomized, double-blind trial of crenolanib versus placebo in combination with best supportive care in patients with FLT3+ relapsed or refractory AML.
Results from a phase 2 trial of crenolanib in relapsed/refractory FLT3+ AML were presented at the 2016 ASCO Annual Meeting (abstract 7008).
The trial enrolled 69 patients who had a median age of 60 (range, 21-87). Twenty-nine patients had FLT3 ITD, 29 had ITD and D835, and 11 had D835.
Nineteen patients were TKI-naïve, 39 had received a prior TKI, and 11 had secondary AML.
Patients received crenolanib at 100 mg three times a day (n=43) or 66 mg/m2 three times a day (n=26).
In the TKI-naïve patients, the overall response rate (ORR) was 47% (n=9), and 37% of patients had a complete response (CR) or CR with incomplete count recovery (CRi). The median overall survival (OS) was 238 days (range, 25-547).
In patients who previously received a TKI, the ORR was 28% (n=11), and the CR/CRi rate was 15% (n=6). The median OS was 94 days (range, 8-338).
In patients with secondary AML, the ORR was 9% (n=1, partial response). The median OS in this group was 64 days (range, 27-221).
Treatment-emergent adverse events (all grades and grade 3/4, respectively) included nausea (70%, 9%), vomiting (58%, 9%), diarrhea (56%, 2%), fatigue (36%, 11%), febrile neutropenia (35%, 35%), pneumonia (32%, 23%), peripheral edema (30%, 2%), pleural effusion (21%, 8%), dyspnea (20%, 5%), and epistaxis (20%, 8%).
Two patients discontinued crenolanib due to adverse events. One patient discontinued due to grade 3 fatigue, abdominal pain, and headache. The other discontinued due to grade 3 pneumonia.
There were 2 neutropenic septic deaths, which occurred 2 days and 21 days after the discontinuation of crenolanib.
About fast track designation
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologics license application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
The US Food and Drug Administration (FDA) has granted fast track designation to crenolanib for the treatment of patients with FLT3 mutation-positive relapsed or refractory acute myeloid leukemia (AML).
Crenolanib is a benzimidazole type I tyrosine kinase inhibitor (TKI) that selectively inhibits signaling of wild-type and mutant isoforms of FLT3 and PDGFRα/β.
Crenolanib is being developed by Arog Pharmaceuticals, Inc.
The company is preparing for a phase 3, randomized, double-blind trial of crenolanib versus placebo in combination with best supportive care in patients with FLT3+ relapsed or refractory AML.
Results from a phase 2 trial of crenolanib in relapsed/refractory FLT3+ AML were presented at the 2016 ASCO Annual Meeting (abstract 7008).
The trial enrolled 69 patients who had a median age of 60 (range, 21-87). Twenty-nine patients had FLT3 ITD, 29 had ITD and D835, and 11 had D835.
Nineteen patients were TKI-naïve, 39 had received a prior TKI, and 11 had secondary AML.
Patients received crenolanib at 100 mg three times a day (n=43) or 66 mg/m2 three times a day (n=26).
In the TKI-naïve patients, the overall response rate (ORR) was 47% (n=9), and 37% of patients had a complete response (CR) or CR with incomplete count recovery (CRi). The median overall survival (OS) was 238 days (range, 25-547).
In patients who previously received a TKI, the ORR was 28% (n=11), and the CR/CRi rate was 15% (n=6). The median OS was 94 days (range, 8-338).
In patients with secondary AML, the ORR was 9% (n=1, partial response). The median OS in this group was 64 days (range, 27-221).
Treatment-emergent adverse events (all grades and grade 3/4, respectively) included nausea (70%, 9%), vomiting (58%, 9%), diarrhea (56%, 2%), fatigue (36%, 11%), febrile neutropenia (35%, 35%), pneumonia (32%, 23%), peripheral edema (30%, 2%), pleural effusion (21%, 8%), dyspnea (20%, 5%), and epistaxis (20%, 8%).
Two patients discontinued crenolanib due to adverse events. One patient discontinued due to grade 3 fatigue, abdominal pain, and headache. The other discontinued due to grade 3 pneumonia.
There were 2 neutropenic septic deaths, which occurred 2 days and 21 days after the discontinuation of crenolanib.
About fast track designation
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologics license application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
The US Food and Drug Administration (FDA) has granted fast track designation to crenolanib for the treatment of patients with FLT3 mutation-positive relapsed or refractory acute myeloid leukemia (AML).
Crenolanib is a benzimidazole type I tyrosine kinase inhibitor (TKI) that selectively inhibits signaling of wild-type and mutant isoforms of FLT3 and PDGFRα/β.
Crenolanib is being developed by Arog Pharmaceuticals, Inc.
The company is preparing for a phase 3, randomized, double-blind trial of crenolanib versus placebo in combination with best supportive care in patients with FLT3+ relapsed or refractory AML.
Results from a phase 2 trial of crenolanib in relapsed/refractory FLT3+ AML were presented at the 2016 ASCO Annual Meeting (abstract 7008).
The trial enrolled 69 patients who had a median age of 60 (range, 21-87). Twenty-nine patients had FLT3 ITD, 29 had ITD and D835, and 11 had D835.
Nineteen patients were TKI-naïve, 39 had received a prior TKI, and 11 had secondary AML.
Patients received crenolanib at 100 mg three times a day (n=43) or 66 mg/m2 three times a day (n=26).
In the TKI-naïve patients, the overall response rate (ORR) was 47% (n=9), and 37% of patients had a complete response (CR) or CR with incomplete count recovery (CRi). The median overall survival (OS) was 238 days (range, 25-547).
In patients who previously received a TKI, the ORR was 28% (n=11), and the CR/CRi rate was 15% (n=6). The median OS was 94 days (range, 8-338).
In patients with secondary AML, the ORR was 9% (n=1, partial response). The median OS in this group was 64 days (range, 27-221).
Treatment-emergent adverse events (all grades and grade 3/4, respectively) included nausea (70%, 9%), vomiting (58%, 9%), diarrhea (56%, 2%), fatigue (36%, 11%), febrile neutropenia (35%, 35%), pneumonia (32%, 23%), peripheral edema (30%, 2%), pleural effusion (21%, 8%), dyspnea (20%, 5%), and epistaxis (20%, 8%).
Two patients discontinued crenolanib due to adverse events. One patient discontinued due to grade 3 fatigue, abdominal pain, and headache. The other discontinued due to grade 3 pneumonia.
There were 2 neutropenic septic deaths, which occurred 2 days and 21 days after the discontinuation of crenolanib.
About fast track designation
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologics license application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
Combo prolongs survival in lymphoma models
Combination treatment with 2 monoclonal antibodies (mAbs) has demonstrated preclinical efficacy against B-cell lymphomas, according to researchers.
The investigators tested different combinations of mAbs to see how they interact with each other and what effect this has on how the immune system fights cancer.
One combination—an anti-CD27 mAb and anti-CD20 mAb—greatly increased survival in mouse models of B-cell lymphoma.
The researchers reported these results in Cancer Cell.
“By combining 2 specific antibodies—anti-CD27 and anti-CD20—we’ve increased the ability of the immune system to destroy cancer cells,” said study author Sean Lim, MBChB, PhD, of the University of Southampton in the UK.
“It’s very exciting to see that this drug combination has an impact on survival of mice with lymphoma, as improvements in treatment are urgently needed. The next stage will be to see if what we’ve discovered can be replicated in patients.”
For this study, Dr Lim and her colleagues tested combinations of tumor-targeting mAbs and immunomodulatory mAbs. The group found that an anti-CD27 mAb enhanced anti-CD20 therapy in various preclinical models.
The investigators first tested anti-CD20 and anti-CD27 (both alone and in combination) in the murine B-cell lymphoma model BCL1.
All control BCL1 mice had died by 30 days from baseline, all mice that received anti-CD20 alone died by day 40, and 30% of mice that received anti-CD27 alone were still alive past 100 days.
In contrast, 100% of mice that received anti-CD20 and anti-CD27 in combination were still alive and lymphoma-free past the 100-day mark.
The researchers also tested the mAbs in the A31 B-cell lymphoma model and the Eµ-TCL1 B-chronic lymphocytic leukemia model.
Results were similar to those observed with the BCL1 model. The combination of anti-CD20 and anti-CD27 significantly improved survival in A31 and Eµ-TCL1 mice, with all mice that received this combination surviving past 100 days.
As far as mechanisms of action, the investigators noted that anti-CD20 binds to B cells and mediates antibody-dependent cellular phagocytosis of the mAb-opsonized cells.
The researchers said the addition of anti-CD27 stimulates CD8+ T cells and natural killer cells, which induces the release of CCL3, CCL4, and CCL5, and this potentially attracts myeloid cells.
In addition, anti-CD27 (via the stimulation of CD8+ T and natural killer cells) induces the release of interferon gamma, which activates macrophages to express more Fc gamma receptor IV and promotes their inflammatory capacity. This increases the number of macrophages available for antibody-dependent cellular phagocytosis as well as the cells’ phagocytic ability.
Based on these findings, researchers are now conducting a phase 2 trial to test the anti-CD20 mAb rituximab and the anti-CD27 mAb varililumab in patients with relapsed and/or refractory B-cell non-Hodgkin lymphoma.
Combination treatment with 2 monoclonal antibodies (mAbs) has demonstrated preclinical efficacy against B-cell lymphomas, according to researchers.
The investigators tested different combinations of mAbs to see how they interact with each other and what effect this has on how the immune system fights cancer.
One combination—an anti-CD27 mAb and anti-CD20 mAb—greatly increased survival in mouse models of B-cell lymphoma.
The researchers reported these results in Cancer Cell.
“By combining 2 specific antibodies—anti-CD27 and anti-CD20—we’ve increased the ability of the immune system to destroy cancer cells,” said study author Sean Lim, MBChB, PhD, of the University of Southampton in the UK.
“It’s very exciting to see that this drug combination has an impact on survival of mice with lymphoma, as improvements in treatment are urgently needed. The next stage will be to see if what we’ve discovered can be replicated in patients.”
For this study, Dr Lim and her colleagues tested combinations of tumor-targeting mAbs and immunomodulatory mAbs. The group found that an anti-CD27 mAb enhanced anti-CD20 therapy in various preclinical models.
The investigators first tested anti-CD20 and anti-CD27 (both alone and in combination) in the murine B-cell lymphoma model BCL1.
All control BCL1 mice had died by 30 days from baseline, all mice that received anti-CD20 alone died by day 40, and 30% of mice that received anti-CD27 alone were still alive past 100 days.
In contrast, 100% of mice that received anti-CD20 and anti-CD27 in combination were still alive and lymphoma-free past the 100-day mark.
The researchers also tested the mAbs in the A31 B-cell lymphoma model and the Eµ-TCL1 B-chronic lymphocytic leukemia model.
Results were similar to those observed with the BCL1 model. The combination of anti-CD20 and anti-CD27 significantly improved survival in A31 and Eµ-TCL1 mice, with all mice that received this combination surviving past 100 days.
As far as mechanisms of action, the investigators noted that anti-CD20 binds to B cells and mediates antibody-dependent cellular phagocytosis of the mAb-opsonized cells.
The researchers said the addition of anti-CD27 stimulates CD8+ T cells and natural killer cells, which induces the release of CCL3, CCL4, and CCL5, and this potentially attracts myeloid cells.
In addition, anti-CD27 (via the stimulation of CD8+ T and natural killer cells) induces the release of interferon gamma, which activates macrophages to express more Fc gamma receptor IV and promotes their inflammatory capacity. This increases the number of macrophages available for antibody-dependent cellular phagocytosis as well as the cells’ phagocytic ability.
Based on these findings, researchers are now conducting a phase 2 trial to test the anti-CD20 mAb rituximab and the anti-CD27 mAb varililumab in patients with relapsed and/or refractory B-cell non-Hodgkin lymphoma.
Combination treatment with 2 monoclonal antibodies (mAbs) has demonstrated preclinical efficacy against B-cell lymphomas, according to researchers.
The investigators tested different combinations of mAbs to see how they interact with each other and what effect this has on how the immune system fights cancer.
One combination—an anti-CD27 mAb and anti-CD20 mAb—greatly increased survival in mouse models of B-cell lymphoma.
The researchers reported these results in Cancer Cell.
“By combining 2 specific antibodies—anti-CD27 and anti-CD20—we’ve increased the ability of the immune system to destroy cancer cells,” said study author Sean Lim, MBChB, PhD, of the University of Southampton in the UK.
“It’s very exciting to see that this drug combination has an impact on survival of mice with lymphoma, as improvements in treatment are urgently needed. The next stage will be to see if what we’ve discovered can be replicated in patients.”
For this study, Dr Lim and her colleagues tested combinations of tumor-targeting mAbs and immunomodulatory mAbs. The group found that an anti-CD27 mAb enhanced anti-CD20 therapy in various preclinical models.
The investigators first tested anti-CD20 and anti-CD27 (both alone and in combination) in the murine B-cell lymphoma model BCL1.
All control BCL1 mice had died by 30 days from baseline, all mice that received anti-CD20 alone died by day 40, and 30% of mice that received anti-CD27 alone were still alive past 100 days.
In contrast, 100% of mice that received anti-CD20 and anti-CD27 in combination were still alive and lymphoma-free past the 100-day mark.
The researchers also tested the mAbs in the A31 B-cell lymphoma model and the Eµ-TCL1 B-chronic lymphocytic leukemia model.
Results were similar to those observed with the BCL1 model. The combination of anti-CD20 and anti-CD27 significantly improved survival in A31 and Eµ-TCL1 mice, with all mice that received this combination surviving past 100 days.
As far as mechanisms of action, the investigators noted that anti-CD20 binds to B cells and mediates antibody-dependent cellular phagocytosis of the mAb-opsonized cells.
The researchers said the addition of anti-CD27 stimulates CD8+ T cells and natural killer cells, which induces the release of CCL3, CCL4, and CCL5, and this potentially attracts myeloid cells.
In addition, anti-CD27 (via the stimulation of CD8+ T and natural killer cells) induces the release of interferon gamma, which activates macrophages to express more Fc gamma receptor IV and promotes their inflammatory capacity. This increases the number of macrophages available for antibody-dependent cellular phagocytosis as well as the cells’ phagocytic ability.
Based on these findings, researchers are now conducting a phase 2 trial to test the anti-CD20 mAb rituximab and the anti-CD27 mAb varililumab in patients with relapsed and/or refractory B-cell non-Hodgkin lymphoma.
AVP stimulates red blood cell production
Researchers say they have uncovered a new function of arginine vasopressin (AVP).
It seems this hormone does more than maintain fluid balance for the kidneys.
AVP also stimulates the proliferation and differentiation of red blood cell precursors and improves recovery from anemia, according to the researchers.
The group speculates that drugs targeting an AVP receptor could be used to replenish red blood cells lost due to bleeding or treatment toxicity.
Eva Mezey, MD, PhD, of the National Institutes of Health in Bethesda, Maryland, and her colleagues conducted this research and reported the results in Science Translational Medicine.
The team uncovered the unexpected role for AVP by examining clinical data from 92 patients with central diabetes insipidus, a condition that causes AVP deficiency.
Of those individuals, 87% of males and 51% of females had anemia. In comparison, anemia rates in the US general population range from 1.5% to 6% for men and 4.4% to 12% for women.
The researchers also found that all 3 AVP receptors are present on human and murine hematopoietic stem and progenitor cells.
One of these receptors, AVPR1B, plays a predominant role in red blood cell production.
Further experiments revealed that AVP-deficient rats had delayed recovery from anemia, but treatment with AVP or the AVPR1B agonist d(Leu4Lys8)VP was able to speed up anemia recovery in mice.
The researchers tested AVP and the AVPR1B agonist in mouse models of hemorrhage. Compared to vehicle-treated mice, AVP-treated mice had an increase in hematocrit and reticulocyte numbers by day 2. Mice that received d(Leu4Lys8)VP only had an increase in reticulocytes.
The team also tested mice exposed to sublethal irradiation. When the mice received AVP for 2 days, they saw increases in hematocrit and corrected reticulocyte numbers.
The researchers then tested splenectomized mice subjected to hemorrhage. AVP-treated mice had an increase in hematocrit that was similar to that observed in non-splenectomized mice.
Finally, the researchers found that AVP’s effect on hematocrit is independent of erythropoietin. The team said AVP “appears to jump-start peripheral blood cell replenishment,” but later, erythropoietin seems to take over.
Researchers say they have uncovered a new function of arginine vasopressin (AVP).
It seems this hormone does more than maintain fluid balance for the kidneys.
AVP also stimulates the proliferation and differentiation of red blood cell precursors and improves recovery from anemia, according to the researchers.
The group speculates that drugs targeting an AVP receptor could be used to replenish red blood cells lost due to bleeding or treatment toxicity.
Eva Mezey, MD, PhD, of the National Institutes of Health in Bethesda, Maryland, and her colleagues conducted this research and reported the results in Science Translational Medicine.
The team uncovered the unexpected role for AVP by examining clinical data from 92 patients with central diabetes insipidus, a condition that causes AVP deficiency.
Of those individuals, 87% of males and 51% of females had anemia. In comparison, anemia rates in the US general population range from 1.5% to 6% for men and 4.4% to 12% for women.
The researchers also found that all 3 AVP receptors are present on human and murine hematopoietic stem and progenitor cells.
One of these receptors, AVPR1B, plays a predominant role in red blood cell production.
Further experiments revealed that AVP-deficient rats had delayed recovery from anemia, but treatment with AVP or the AVPR1B agonist d(Leu4Lys8)VP was able to speed up anemia recovery in mice.
The researchers tested AVP and the AVPR1B agonist in mouse models of hemorrhage. Compared to vehicle-treated mice, AVP-treated mice had an increase in hematocrit and reticulocyte numbers by day 2. Mice that received d(Leu4Lys8)VP only had an increase in reticulocytes.
The team also tested mice exposed to sublethal irradiation. When the mice received AVP for 2 days, they saw increases in hematocrit and corrected reticulocyte numbers.
The researchers then tested splenectomized mice subjected to hemorrhage. AVP-treated mice had an increase in hematocrit that was similar to that observed in non-splenectomized mice.
Finally, the researchers found that AVP’s effect on hematocrit is independent of erythropoietin. The team said AVP “appears to jump-start peripheral blood cell replenishment,” but later, erythropoietin seems to take over.
Researchers say they have uncovered a new function of arginine vasopressin (AVP).
It seems this hormone does more than maintain fluid balance for the kidneys.
AVP also stimulates the proliferation and differentiation of red blood cell precursors and improves recovery from anemia, according to the researchers.
The group speculates that drugs targeting an AVP receptor could be used to replenish red blood cells lost due to bleeding or treatment toxicity.
Eva Mezey, MD, PhD, of the National Institutes of Health in Bethesda, Maryland, and her colleagues conducted this research and reported the results in Science Translational Medicine.
The team uncovered the unexpected role for AVP by examining clinical data from 92 patients with central diabetes insipidus, a condition that causes AVP deficiency.
Of those individuals, 87% of males and 51% of females had anemia. In comparison, anemia rates in the US general population range from 1.5% to 6% for men and 4.4% to 12% for women.
The researchers also found that all 3 AVP receptors are present on human and murine hematopoietic stem and progenitor cells.
One of these receptors, AVPR1B, plays a predominant role in red blood cell production.
Further experiments revealed that AVP-deficient rats had delayed recovery from anemia, but treatment with AVP or the AVPR1B agonist d(Leu4Lys8)VP was able to speed up anemia recovery in mice.
The researchers tested AVP and the AVPR1B agonist in mouse models of hemorrhage. Compared to vehicle-treated mice, AVP-treated mice had an increase in hematocrit and reticulocyte numbers by day 2. Mice that received d(Leu4Lys8)VP only had an increase in reticulocytes.
The team also tested mice exposed to sublethal irradiation. When the mice received AVP for 2 days, they saw increases in hematocrit and corrected reticulocyte numbers.
The researchers then tested splenectomized mice subjected to hemorrhage. AVP-treated mice had an increase in hematocrit that was similar to that observed in non-splenectomized mice.
Finally, the researchers found that AVP’s effect on hematocrit is independent of erythropoietin. The team said AVP “appears to jump-start peripheral blood cell replenishment,” but later, erythropoietin seems to take over.
Team finds no evidence that gadolinium causes neurologic harm
CHICAGO—There is no evidence to suggest that accumulation of gadolinium in the brain speeds cognitive decline, according to research presented at RSNA 2017, the annual meeting of the Radiological Society of North America.*
Recent studies have revealed that traces of the contrast agent gadolinium can be retained in the brain for years after magnetic resonance imaging (MRI).
Earlier this year, the US Food and Drug Administration recommended cautious use of gadolinium-based contrast agents due to the risk of gadolinium retention in various organs, including the brain.
The European Medicines Agency went a step further, recommending restricting the use of some linear gadolinium agents and suspending the authorization of other agents.
Still, very little is known about the health effects of gadolinium that is retained in the brain.
Robert J. McDonald, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, and his colleagues conducted a study to gain some insight.
The team used the Mayo Clinic Study of Aging (MCSA), the world’s largest prospective population-based cohort on aging, to study the effects of gadolinium exposure on neurologic and neurocognitive function.
All MCSA participants underwent extensive neurologic evaluation and neuropsychological testing at baseline and 15-month follow-up intervals.
The researchers compared neurologic and neurocognitive scores of patients with no history of prior gadolinium exposure and patients who underwent prior MRI with gadolinium-based contrast agents.
The team adjusted their analysis for age, sex, education level, baseline neurocognitive performance, and other factors.
The study included 4261 cognitively normal men and women with a mean age of 72 (range, 50-90). The mean duration of study participation was 3.7 years.
Roughly a quarter of the patients (25.6%, n=1092) had received gadolinium-based contrast agents. These patients received a median of 2 doses (range, 1-28), and the median time since first gadolinium exposure was 5.6 years.
The researchers found that gadolinium exposure was not a significant predictor of cognitive decline, as assessed by changes in clinical dementia rating (P=0.48), Blessed dementia scale (P=0.68), and mental status exam score (P=0.55).
Likewise, gadolinium exposure was not a significant predictor of diminished neuropsychological performance (P=0.13) or diminished motor performance (P=0.43), as assessed by the Unified Parkinson’s Disease Rating Scale.
Finally, gadolinium exposure was not an independent risk factor in the rate of cognitive decline from normal cognitive status to dementia (P=0.91).
“Right now, there is concern over the safety of gadolinium-based contrast agents, particularly relating to gadolinium retention in the brain and other tissues,” Dr McDonald said.
“This study provides useful data that, at the reasonable doses 95% of the population is likely to receive in their lifetime, there is no evidence, at this point, that gadolinium retention in the brain is associated with adverse clinical outcomes.”
*Abstract SSM16-01: Assessment of the Neurologic Effects of Intracranial Gadolinium Deposition Using a Large Population Based Cohort.
CHICAGO—There is no evidence to suggest that accumulation of gadolinium in the brain speeds cognitive decline, according to research presented at RSNA 2017, the annual meeting of the Radiological Society of North America.*
Recent studies have revealed that traces of the contrast agent gadolinium can be retained in the brain for years after magnetic resonance imaging (MRI).
Earlier this year, the US Food and Drug Administration recommended cautious use of gadolinium-based contrast agents due to the risk of gadolinium retention in various organs, including the brain.
The European Medicines Agency went a step further, recommending restricting the use of some linear gadolinium agents and suspending the authorization of other agents.
Still, very little is known about the health effects of gadolinium that is retained in the brain.
Robert J. McDonald, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, and his colleagues conducted a study to gain some insight.
The team used the Mayo Clinic Study of Aging (MCSA), the world’s largest prospective population-based cohort on aging, to study the effects of gadolinium exposure on neurologic and neurocognitive function.
All MCSA participants underwent extensive neurologic evaluation and neuropsychological testing at baseline and 15-month follow-up intervals.
The researchers compared neurologic and neurocognitive scores of patients with no history of prior gadolinium exposure and patients who underwent prior MRI with gadolinium-based contrast agents.
The team adjusted their analysis for age, sex, education level, baseline neurocognitive performance, and other factors.
The study included 4261 cognitively normal men and women with a mean age of 72 (range, 50-90). The mean duration of study participation was 3.7 years.
Roughly a quarter of the patients (25.6%, n=1092) had received gadolinium-based contrast agents. These patients received a median of 2 doses (range, 1-28), and the median time since first gadolinium exposure was 5.6 years.
The researchers found that gadolinium exposure was not a significant predictor of cognitive decline, as assessed by changes in clinical dementia rating (P=0.48), Blessed dementia scale (P=0.68), and mental status exam score (P=0.55).
Likewise, gadolinium exposure was not a significant predictor of diminished neuropsychological performance (P=0.13) or diminished motor performance (P=0.43), as assessed by the Unified Parkinson’s Disease Rating Scale.
Finally, gadolinium exposure was not an independent risk factor in the rate of cognitive decline from normal cognitive status to dementia (P=0.91).
“Right now, there is concern over the safety of gadolinium-based contrast agents, particularly relating to gadolinium retention in the brain and other tissues,” Dr McDonald said.
“This study provides useful data that, at the reasonable doses 95% of the population is likely to receive in their lifetime, there is no evidence, at this point, that gadolinium retention in the brain is associated with adverse clinical outcomes.”
*Abstract SSM16-01: Assessment of the Neurologic Effects of Intracranial Gadolinium Deposition Using a Large Population Based Cohort.
CHICAGO—There is no evidence to suggest that accumulation of gadolinium in the brain speeds cognitive decline, according to research presented at RSNA 2017, the annual meeting of the Radiological Society of North America.*
Recent studies have revealed that traces of the contrast agent gadolinium can be retained in the brain for years after magnetic resonance imaging (MRI).
Earlier this year, the US Food and Drug Administration recommended cautious use of gadolinium-based contrast agents due to the risk of gadolinium retention in various organs, including the brain.
The European Medicines Agency went a step further, recommending restricting the use of some linear gadolinium agents and suspending the authorization of other agents.
Still, very little is known about the health effects of gadolinium that is retained in the brain.
Robert J. McDonald, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, and his colleagues conducted a study to gain some insight.
The team used the Mayo Clinic Study of Aging (MCSA), the world’s largest prospective population-based cohort on aging, to study the effects of gadolinium exposure on neurologic and neurocognitive function.
All MCSA participants underwent extensive neurologic evaluation and neuropsychological testing at baseline and 15-month follow-up intervals.
The researchers compared neurologic and neurocognitive scores of patients with no history of prior gadolinium exposure and patients who underwent prior MRI with gadolinium-based contrast agents.
The team adjusted their analysis for age, sex, education level, baseline neurocognitive performance, and other factors.
The study included 4261 cognitively normal men and women with a mean age of 72 (range, 50-90). The mean duration of study participation was 3.7 years.
Roughly a quarter of the patients (25.6%, n=1092) had received gadolinium-based contrast agents. These patients received a median of 2 doses (range, 1-28), and the median time since first gadolinium exposure was 5.6 years.
The researchers found that gadolinium exposure was not a significant predictor of cognitive decline, as assessed by changes in clinical dementia rating (P=0.48), Blessed dementia scale (P=0.68), and mental status exam score (P=0.55).
Likewise, gadolinium exposure was not a significant predictor of diminished neuropsychological performance (P=0.13) or diminished motor performance (P=0.43), as assessed by the Unified Parkinson’s Disease Rating Scale.
Finally, gadolinium exposure was not an independent risk factor in the rate of cognitive decline from normal cognitive status to dementia (P=0.91).
“Right now, there is concern over the safety of gadolinium-based contrast agents, particularly relating to gadolinium retention in the brain and other tissues,” Dr McDonald said.
“This study provides useful data that, at the reasonable doses 95% of the population is likely to receive in their lifetime, there is no evidence, at this point, that gadolinium retention in the brain is associated with adverse clinical outcomes.”
*Abstract SSM16-01: Assessment of the Neurologic Effects of Intracranial Gadolinium Deposition Using a Large Population Based Cohort.
Study reveals potential target for AML treatment
New research has revealed a potential therapeutic target for acute myeloid leukemia (AML)—the methyl transferase enzyme METTL3.
Researchers found that inhibiting METTL3 destroys human and mouse AML cells without harming non-leukemic blood cells.
The team also discovered why METTL3 is required for AML cell survival by deciphering the mechanism it uses to regulate several other leukemia genes.
The researchers described this work in Nature.
“New treatments for AML are desperately needed, and we have been looking for genes that would be good drug targets,” said study author Tony Kouzarides, PhD, of University of Cambridge in the UK.
“We identified the methyl transferase enzyme METTL3 as a highly viable target against AML. Our study will inspire pharmaceutical efforts to find drugs that specifically inhibit METTL3 to treat AML.”
In their attempt to find therapeutic targets for AML, Dr Kouzarides and his colleagues used CRISPR-Cas9 to screen AML cells for vulnerable points.
The researchers created mouse leukemia cells with mutations in genes that may be targeted in human AML cells and systematically tested each gene, finding which were essential for AML survival.
The team ended up with 46 likely candidate genes, many of which produce proteins that could modify RNA. Among these, METTL3 was one of the genes with the strongest effect.
Experiments revealed that METTL3 was essential for the survival of AML cells, but it was not required for healthy blood cells.
Having found a potential target in METTL3, the researchers investigated how it worked.
They discovered that the protein produced by METTL3 bound to the beginning of 126 different genes, including several required for AML cell survival.
As RNAs were produced, the METTL3 protein added methyl groups to their middle section, something which had not been previously observed. These middle methyl groups increased the ability of the RNAs to be translated into proteins.
The researchers then found that when METTL3 was inhibited, no methyl groups were added to the RNA. This prevented the production of their essential proteins, so the AML cells started dying.
“This study uncovered an entirely new mechanism of gene regulation in AML that operates through modifications of RNA,” said study author Konstantinos Tzelepis, PhD, of Wellcome Trust Sanger Institute in Cambridge, UK.
“We discovered that inhibiting the methyl transferase activity of METTL3 would stop the translation of a whole set of proteins that the leukemia needs. This mechanism shows that a drug to inhibit methylation could be effective against AML without affecting normal cells.”
New research has revealed a potential therapeutic target for acute myeloid leukemia (AML)—the methyl transferase enzyme METTL3.
Researchers found that inhibiting METTL3 destroys human and mouse AML cells without harming non-leukemic blood cells.
The team also discovered why METTL3 is required for AML cell survival by deciphering the mechanism it uses to regulate several other leukemia genes.
The researchers described this work in Nature.
“New treatments for AML are desperately needed, and we have been looking for genes that would be good drug targets,” said study author Tony Kouzarides, PhD, of University of Cambridge in the UK.
“We identified the methyl transferase enzyme METTL3 as a highly viable target against AML. Our study will inspire pharmaceutical efforts to find drugs that specifically inhibit METTL3 to treat AML.”
In their attempt to find therapeutic targets for AML, Dr Kouzarides and his colleagues used CRISPR-Cas9 to screen AML cells for vulnerable points.
The researchers created mouse leukemia cells with mutations in genes that may be targeted in human AML cells and systematically tested each gene, finding which were essential for AML survival.
The team ended up with 46 likely candidate genes, many of which produce proteins that could modify RNA. Among these, METTL3 was one of the genes with the strongest effect.
Experiments revealed that METTL3 was essential for the survival of AML cells, but it was not required for healthy blood cells.
Having found a potential target in METTL3, the researchers investigated how it worked.
They discovered that the protein produced by METTL3 bound to the beginning of 126 different genes, including several required for AML cell survival.
As RNAs were produced, the METTL3 protein added methyl groups to their middle section, something which had not been previously observed. These middle methyl groups increased the ability of the RNAs to be translated into proteins.
The researchers then found that when METTL3 was inhibited, no methyl groups were added to the RNA. This prevented the production of their essential proteins, so the AML cells started dying.
“This study uncovered an entirely new mechanism of gene regulation in AML that operates through modifications of RNA,” said study author Konstantinos Tzelepis, PhD, of Wellcome Trust Sanger Institute in Cambridge, UK.
“We discovered that inhibiting the methyl transferase activity of METTL3 would stop the translation of a whole set of proteins that the leukemia needs. This mechanism shows that a drug to inhibit methylation could be effective against AML without affecting normal cells.”
New research has revealed a potential therapeutic target for acute myeloid leukemia (AML)—the methyl transferase enzyme METTL3.
Researchers found that inhibiting METTL3 destroys human and mouse AML cells without harming non-leukemic blood cells.
The team also discovered why METTL3 is required for AML cell survival by deciphering the mechanism it uses to regulate several other leukemia genes.
The researchers described this work in Nature.
“New treatments for AML are desperately needed, and we have been looking for genes that would be good drug targets,” said study author Tony Kouzarides, PhD, of University of Cambridge in the UK.
“We identified the methyl transferase enzyme METTL3 as a highly viable target against AML. Our study will inspire pharmaceutical efforts to find drugs that specifically inhibit METTL3 to treat AML.”
In their attempt to find therapeutic targets for AML, Dr Kouzarides and his colleagues used CRISPR-Cas9 to screen AML cells for vulnerable points.
The researchers created mouse leukemia cells with mutations in genes that may be targeted in human AML cells and systematically tested each gene, finding which were essential for AML survival.
The team ended up with 46 likely candidate genes, many of which produce proteins that could modify RNA. Among these, METTL3 was one of the genes with the strongest effect.
Experiments revealed that METTL3 was essential for the survival of AML cells, but it was not required for healthy blood cells.
Having found a potential target in METTL3, the researchers investigated how it worked.
They discovered that the protein produced by METTL3 bound to the beginning of 126 different genes, including several required for AML cell survival.
As RNAs were produced, the METTL3 protein added methyl groups to their middle section, something which had not been previously observed. These middle methyl groups increased the ability of the RNAs to be translated into proteins.
The researchers then found that when METTL3 was inhibited, no methyl groups were added to the RNA. This prevented the production of their essential proteins, so the AML cells started dying.
“This study uncovered an entirely new mechanism of gene regulation in AML that operates through modifications of RNA,” said study author Konstantinos Tzelepis, PhD, of Wellcome Trust Sanger Institute in Cambridge, UK.
“We discovered that inhibiting the methyl transferase activity of METTL3 would stop the translation of a whole set of proteins that the leukemia needs. This mechanism shows that a drug to inhibit methylation could be effective against AML without affecting normal cells.”
Inhibitor exhibits activity against range of lymphomas
Preclinical research suggests the dual PI3K/mTOR inhibitor PQR309 has activity against several types of lymphoma and works well in combination with other agents.
PQR309 exhibited anti-lymphoma activity as a single agent and in combination with venetoclax, panobinostat, ibrutinib, lenalidomide, ARV-825, marizomib, and rituximab.
PQR309 demonstrated greater activity against B-cell lymphoma than T-cell lymphoma, and the inhibitor was able to overcome both primary and acquired resistance to idelalisib.
Francesco Bertoni, MD, of the Institute of Oncology Research in Bellinzona, Switzerland, and his colleagues conducted this research and reported the results in Clinical Cancer Research.
The work was funded by PIQUR Therapeutics AG, the company developing PQR309, and some study authors are PIQUR employees.
The researchers tested PQR309 in 49 human lymphoma cell lines—7 activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL), 18 germinal center B-cell (GCB) DLBCL, 10 mantle cell lymphoma (MCL), 3 splenic marginal zone lymphoma (SMZL), 2 chronic lymphocytic leukemia (CLL), 4 Hodgkin lymphoma, and 5 anaplastic large-cell lymphoma (ALCL).
In most cell lines, PQR309 halted proliferation, mainly due to cell-cycle arrest with a block in G1. However, PQR309 induced apoptosis in 2 cell lines tested—SU-DHL-4 and TMD8.
The researchers noted that PQR309 was significantly more active in the B-cell lymphoma cell lines (DLBCL, MCL, CLL, and SMZL) than in the T-cell lymphoma cell line ALCL (P=0.028).
PQR309 exhibited similar activity in ABC and GCB DLBCL cell lines, de novo DLBCL, and DLBCL derived from transformed follicular lymphoma. TP53, MYC, and BCL2 status also had no significant effect on PQR309 activity.
The researchers compared cell lines that were very sensitive to PQR309 to those with low sensitivity to the drug and identified differences.
The team said that transcripts preferentially expressed in PQR309-sensitive cell lines were significantly enriched of genes involved in BCR pathway/signaling and BLIMP1 targets. Transcripts associated with less sensitive cell lines were enriched of members of proteasome pathway, response to unfolded proteins, MYC targets, XBP1 targets, genes downregulated by mTOR inhibitors, and genes involved in oxidative phosphorylation.
PQR309 demonstrated synergistic effects when combined with the BTK inhibitor ibrutinib, the immunomodulatory drug lenalidomide, the anti-CD20 monoclonal antibody rituximab, and the proteasome inhibitor marizomib.
PQR309 demonstrated synergistic or additive effects when combined with the BCL2 inhibitor venetoclax, the HDAC inhibitor panobinostat, and the PROTAC BET inhibitor ARV-825.
In addition, PQR309 was active in lymphoma cell lines with primary and secondary resistance to the PI3K inhibitor idelalisib.
The researchers believe the results of this study, together with ongoing clinical studies of PQR309, can lead to better treatments for lymphoma patients and better understanding of the mechanisms of anti-lymphoma agents.
Preclinical research suggests the dual PI3K/mTOR inhibitor PQR309 has activity against several types of lymphoma and works well in combination with other agents.
PQR309 exhibited anti-lymphoma activity as a single agent and in combination with venetoclax, panobinostat, ibrutinib, lenalidomide, ARV-825, marizomib, and rituximab.
PQR309 demonstrated greater activity against B-cell lymphoma than T-cell lymphoma, and the inhibitor was able to overcome both primary and acquired resistance to idelalisib.
Francesco Bertoni, MD, of the Institute of Oncology Research in Bellinzona, Switzerland, and his colleagues conducted this research and reported the results in Clinical Cancer Research.
The work was funded by PIQUR Therapeutics AG, the company developing PQR309, and some study authors are PIQUR employees.
The researchers tested PQR309 in 49 human lymphoma cell lines—7 activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL), 18 germinal center B-cell (GCB) DLBCL, 10 mantle cell lymphoma (MCL), 3 splenic marginal zone lymphoma (SMZL), 2 chronic lymphocytic leukemia (CLL), 4 Hodgkin lymphoma, and 5 anaplastic large-cell lymphoma (ALCL).
In most cell lines, PQR309 halted proliferation, mainly due to cell-cycle arrest with a block in G1. However, PQR309 induced apoptosis in 2 cell lines tested—SU-DHL-4 and TMD8.
The researchers noted that PQR309 was significantly more active in the B-cell lymphoma cell lines (DLBCL, MCL, CLL, and SMZL) than in the T-cell lymphoma cell line ALCL (P=0.028).
PQR309 exhibited similar activity in ABC and GCB DLBCL cell lines, de novo DLBCL, and DLBCL derived from transformed follicular lymphoma. TP53, MYC, and BCL2 status also had no significant effect on PQR309 activity.
The researchers compared cell lines that were very sensitive to PQR309 to those with low sensitivity to the drug and identified differences.
The team said that transcripts preferentially expressed in PQR309-sensitive cell lines were significantly enriched of genes involved in BCR pathway/signaling and BLIMP1 targets. Transcripts associated with less sensitive cell lines were enriched of members of proteasome pathway, response to unfolded proteins, MYC targets, XBP1 targets, genes downregulated by mTOR inhibitors, and genes involved in oxidative phosphorylation.
PQR309 demonstrated synergistic effects when combined with the BTK inhibitor ibrutinib, the immunomodulatory drug lenalidomide, the anti-CD20 monoclonal antibody rituximab, and the proteasome inhibitor marizomib.
PQR309 demonstrated synergistic or additive effects when combined with the BCL2 inhibitor venetoclax, the HDAC inhibitor panobinostat, and the PROTAC BET inhibitor ARV-825.
In addition, PQR309 was active in lymphoma cell lines with primary and secondary resistance to the PI3K inhibitor idelalisib.
The researchers believe the results of this study, together with ongoing clinical studies of PQR309, can lead to better treatments for lymphoma patients and better understanding of the mechanisms of anti-lymphoma agents.
Preclinical research suggests the dual PI3K/mTOR inhibitor PQR309 has activity against several types of lymphoma and works well in combination with other agents.
PQR309 exhibited anti-lymphoma activity as a single agent and in combination with venetoclax, panobinostat, ibrutinib, lenalidomide, ARV-825, marizomib, and rituximab.
PQR309 demonstrated greater activity against B-cell lymphoma than T-cell lymphoma, and the inhibitor was able to overcome both primary and acquired resistance to idelalisib.
Francesco Bertoni, MD, of the Institute of Oncology Research in Bellinzona, Switzerland, and his colleagues conducted this research and reported the results in Clinical Cancer Research.
The work was funded by PIQUR Therapeutics AG, the company developing PQR309, and some study authors are PIQUR employees.
The researchers tested PQR309 in 49 human lymphoma cell lines—7 activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL), 18 germinal center B-cell (GCB) DLBCL, 10 mantle cell lymphoma (MCL), 3 splenic marginal zone lymphoma (SMZL), 2 chronic lymphocytic leukemia (CLL), 4 Hodgkin lymphoma, and 5 anaplastic large-cell lymphoma (ALCL).
In most cell lines, PQR309 halted proliferation, mainly due to cell-cycle arrest with a block in G1. However, PQR309 induced apoptosis in 2 cell lines tested—SU-DHL-4 and TMD8.
The researchers noted that PQR309 was significantly more active in the B-cell lymphoma cell lines (DLBCL, MCL, CLL, and SMZL) than in the T-cell lymphoma cell line ALCL (P=0.028).
PQR309 exhibited similar activity in ABC and GCB DLBCL cell lines, de novo DLBCL, and DLBCL derived from transformed follicular lymphoma. TP53, MYC, and BCL2 status also had no significant effect on PQR309 activity.
The researchers compared cell lines that were very sensitive to PQR309 to those with low sensitivity to the drug and identified differences.
The team said that transcripts preferentially expressed in PQR309-sensitive cell lines were significantly enriched of genes involved in BCR pathway/signaling and BLIMP1 targets. Transcripts associated with less sensitive cell lines were enriched of members of proteasome pathway, response to unfolded proteins, MYC targets, XBP1 targets, genes downregulated by mTOR inhibitors, and genes involved in oxidative phosphorylation.
PQR309 demonstrated synergistic effects when combined with the BTK inhibitor ibrutinib, the immunomodulatory drug lenalidomide, the anti-CD20 monoclonal antibody rituximab, and the proteasome inhibitor marizomib.
PQR309 demonstrated synergistic or additive effects when combined with the BCL2 inhibitor venetoclax, the HDAC inhibitor panobinostat, and the PROTAC BET inhibitor ARV-825.
In addition, PQR309 was active in lymphoma cell lines with primary and secondary resistance to the PI3K inhibitor idelalisib.
The researchers believe the results of this study, together with ongoing clinical studies of PQR309, can lead to better treatments for lymphoma patients and better understanding of the mechanisms of anti-lymphoma agents.
FDA grants drug orphan designation for AML, MDS
The US Food and Drug Administration (FDA) has granted orphan drug designation to AMV564, a CD33/CD3 bispecific antibody, for the treatment of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).
AMV564 is a T-cell engager, derived from human protein sequences, that binds both CD33 and CD3 to mediate T-cell directed lysis of CD33-positive cancer cells.
Amphivena Therapeutics Inc., is currently conducting a phase 1 trial of AMV564 in relapsed or refractory AML. The company plans to launch a phase 1 trial in patients with MDS in early 2018.
According to Amphivena, AMV564 has demonstrated “potent activity” in AML patient samples, and that activity was independent of CD33 expression level, disease stage, and cytogenetic risk.
AMV564 also eliminated nearly all blasts from the bone marrow and spleen in a stringent AML patient-derived xenograft murine model.
In addition, Amphivena established a therapeutic window for AMV564 in cynomolgus monkeys, with rapid and sustained elimination of CD33-expressing cells during AMV564 dosing and rapid hematopoietic recovery following dosing.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted orphan drug designation to AMV564, a CD33/CD3 bispecific antibody, for the treatment of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).
AMV564 is a T-cell engager, derived from human protein sequences, that binds both CD33 and CD3 to mediate T-cell directed lysis of CD33-positive cancer cells.
Amphivena Therapeutics Inc., is currently conducting a phase 1 trial of AMV564 in relapsed or refractory AML. The company plans to launch a phase 1 trial in patients with MDS in early 2018.
According to Amphivena, AMV564 has demonstrated “potent activity” in AML patient samples, and that activity was independent of CD33 expression level, disease stage, and cytogenetic risk.
AMV564 also eliminated nearly all blasts from the bone marrow and spleen in a stringent AML patient-derived xenograft murine model.
In addition, Amphivena established a therapeutic window for AMV564 in cynomolgus monkeys, with rapid and sustained elimination of CD33-expressing cells during AMV564 dosing and rapid hematopoietic recovery following dosing.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted orphan drug designation to AMV564, a CD33/CD3 bispecific antibody, for the treatment of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).
AMV564 is a T-cell engager, derived from human protein sequences, that binds both CD33 and CD3 to mediate T-cell directed lysis of CD33-positive cancer cells.
Amphivena Therapeutics Inc., is currently conducting a phase 1 trial of AMV564 in relapsed or refractory AML. The company plans to launch a phase 1 trial in patients with MDS in early 2018.
According to Amphivena, AMV564 has demonstrated “potent activity” in AML patient samples, and that activity was independent of CD33 expression level, disease stage, and cytogenetic risk.
AMV564 also eliminated nearly all blasts from the bone marrow and spleen in a stringent AML patient-derived xenograft murine model.
In addition, Amphivena established a therapeutic window for AMV564 in cynomolgus monkeys, with rapid and sustained elimination of CD33-expressing cells during AMV564 dosing and rapid hematopoietic recovery following dosing.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.