Hematology Times

Aspirin tablets

Photo by Sage Ross

A systematic review of published evidence has failed to elucidate the optimal duration of dual antiplatelet therapy (DAPT) in patients who have a drug-eluting stent.

The data showed that patients who received DAPT for a longer period had a small reduction in myocardial infarction as well as a small increase in major bleeding and an even smaller increase in all-cause mortality, compared to patients who received DAPT for a shorter period.

Frederick A. Spencer, MD, of McMaster University in Hamilton, Ontario, Canada, and his colleagues reported these findings in Annals of Internal Medicine.

The team searched databases for trials of DAPT published from 1996 to March 2015. They identified 9 randomized, controlled trials including a total of 29,531 patients. There was complete data for 28,808 patients who had coronary artery disease and received DAPT after drug-eluting stent placement.

In 4 of the trials, patients were randomized to DAPT when they received their stent. Patients in the shorter-duration arm received DAPT for 3 to 6 months, and patients in the longer-duration arm received DAPT for 12 to 24 months.

In a fifth study, patients were randomized to DAPT at stent placement, but thrombotic events occurring during the first 6 months (when both arms received DAPT) were excluded.

In the 4 remaining trials, patients were randomized to DAPT 6 months or more after stent placement. Patients in the shorter-duration arm received DAPT for 6 to 18 months, and patients in the longer-duration arm received DAPT for 12 to 42 months.

Analyzing data from these trials together, Dr Spencer and his colleagues found moderate-quality evidence suggesting that receiving DAPT for a longer period decreased the risk of myocardial infarction (risk ratio [RR]=0.73) but increased the risk of mortality (RR=1.19).

The team also said there was high-quality evidence suggesting that longer-duration DAPT increased the risk of major bleeding (RR=1.63).

Receiving DAPT for a longer period was associated with approximately 8 fewer myocardial infarctions per 1000 patients per year, 6 more major bleeding events per 1000 patients per year, and 2 more deaths per 1000 patients per year, when compared to shorter-duration DAPT.

Because these differences are small, Dr Spencer and his colleagues said the duration of DAPT therapy should probably be based on patient preference, following a discussion of the potential risks and benefits.

Aspirin tablets

Photo by Sage Ross

A systematic review of published evidence has failed to elucidate the optimal duration of dual antiplatelet therapy (DAPT) in patients who have a drug-eluting stent.

The data showed that patients who received DAPT for a longer period had a small reduction in myocardial infarction as well as a small increase in major bleeding and an even smaller increase in all-cause mortality, compared to patients who received DAPT for a shorter period.

Frederick A. Spencer, MD, of McMaster University in Hamilton, Ontario, Canada, and his colleagues reported these findings in Annals of Internal Medicine.

The team searched databases for trials of DAPT published from 1996 to March 2015. They identified 9 randomized, controlled trials including a total of 29,531 patients. There was complete data for 28,808 patients who had coronary artery disease and received DAPT after drug-eluting stent placement.

In 4 of the trials, patients were randomized to DAPT when they received their stent. Patients in the shorter-duration arm received DAPT for 3 to 6 months, and patients in the longer-duration arm received DAPT for 12 to 24 months.

In a fifth study, patients were randomized to DAPT at stent placement, but thrombotic events occurring during the first 6 months (when both arms received DAPT) were excluded.

In the 4 remaining trials, patients were randomized to DAPT 6 months or more after stent placement. Patients in the shorter-duration arm received DAPT for 6 to 18 months, and patients in the longer-duration arm received DAPT for 12 to 42 months.

Analyzing data from these trials together, Dr Spencer and his colleagues found moderate-quality evidence suggesting that receiving DAPT for a longer period decreased the risk of myocardial infarction (risk ratio [RR]=0.73) but increased the risk of mortality (RR=1.19).

The team also said there was high-quality evidence suggesting that longer-duration DAPT increased the risk of major bleeding (RR=1.63).

Receiving DAPT for a longer period was associated with approximately 8 fewer myocardial infarctions per 1000 patients per year, 6 more major bleeding events per 1000 patients per year, and 2 more deaths per 1000 patients per year, when compared to shorter-duration DAPT.

Because these differences are small, Dr Spencer and his colleagues said the duration of DAPT therapy should probably be based on patient preference, following a discussion of the potential risks and benefits.

Aspirin tablets

Photo by Sage Ross

A systematic review of published evidence has failed to elucidate the optimal duration of dual antiplatelet therapy (DAPT) in patients who have a drug-eluting stent.

The data showed that patients who received DAPT for a longer period had a small reduction in myocardial infarction as well as a small increase in major bleeding and an even smaller increase in all-cause mortality, compared to patients who received DAPT for a shorter period.

Frederick A. Spencer, MD, of McMaster University in Hamilton, Ontario, Canada, and his colleagues reported these findings in Annals of Internal Medicine.

The team searched databases for trials of DAPT published from 1996 to March 2015. They identified 9 randomized, controlled trials including a total of 29,531 patients. There was complete data for 28,808 patients who had coronary artery disease and received DAPT after drug-eluting stent placement.

In 4 of the trials, patients were randomized to DAPT when they received their stent. Patients in the shorter-duration arm received DAPT for 3 to 6 months, and patients in the longer-duration arm received DAPT for 12 to 24 months.

In a fifth study, patients were randomized to DAPT at stent placement, but thrombotic events occurring during the first 6 months (when both arms received DAPT) were excluded.

In the 4 remaining trials, patients were randomized to DAPT 6 months or more after stent placement. Patients in the shorter-duration arm received DAPT for 6 to 18 months, and patients in the longer-duration arm received DAPT for 12 to 42 months.

Analyzing data from these trials together, Dr Spencer and his colleagues found moderate-quality evidence suggesting that receiving DAPT for a longer period decreased the risk of myocardial infarction (risk ratio [RR]=0.73) but increased the risk of mortality (RR=1.19).

The team also said there was high-quality evidence suggesting that longer-duration DAPT increased the risk of major bleeding (RR=1.63).

Receiving DAPT for a longer period was associated with approximately 8 fewer myocardial infarctions per 1000 patients per year, 6 more major bleeding events per 1000 patients per year, and 2 more deaths per 1000 patients per year, when compared to shorter-duration DAPT.

Because these differences are small, Dr Spencer and his colleagues said the duration of DAPT therapy should probably be based on patient preference, following a discussion of the potential risks and benefits.

Herbs and spices

Photo by Alexander Baxevanis

An herbal mixture used in traditional Chinese medicine can reduce fatigue in cancer patients, results of a phase 1/2 study suggest.

The mixture, Ren Shen Yangrong Tang (RSYRT), is a soup containing 12 herbs.

In the study, cancer patients suffering from moderate to severe fatigue reported significantly less fatigue after taking RSYRT for 2 to 3 weeks.

Researchers reported these results in the Journal of Alternative and Complementary Medicine.

Yichen Xu, MD, of Beijing Cancer Hospital & Institute in China, and colleagues evaluated RSYRT in 33 patients who had completed cancer treatment. The patients had stable disease and no anemia.

Eleven patients had moderate fatigue (a score of 4-6 on a 0-10 scale), and 22 had severe fatigue (a score of 7-10). All patients had experienced fatigue for at least 4 months.

Patients took RSYRT twice a day for 6 weeks and experienced a significant decrease in fatigue severity. The mean fatigue score decreased from 7.06 at baseline to 3.30 at the 6-week mark (P<0.001).

The fatigue category also changed significantly (P=0.024). Among the 22 patients who had severe fatigue before RSYRT, half had mild fatigue after therapy, and half had moderate fatigue.

Among the 11 patients who had moderate fatigue at baseline, only 1 still had moderate fatigue after receiving RSYRT. The rest had mild fatigue.

All of the patients said they felt better after taking RSYRT for 4 weeks.

There were no “uncomfortable events” related to RSYRT, such as gastrointestinal upset, insomnia, headache, or rash. None of the patients required a dose reduction or dose interruption.

None of the patients had blood chemistry abnormalities or abnormal liver/kidney function. Two patients who had a change in ST segment before RSYRT had normal electrocardiogram results after treatment.

Herbs and spices

Photo by Alexander Baxevanis

An herbal mixture used in traditional Chinese medicine can reduce fatigue in cancer patients, results of a phase 1/2 study suggest.

The mixture, Ren Shen Yangrong Tang (RSYRT), is a soup containing 12 herbs.

In the study, cancer patients suffering from moderate to severe fatigue reported significantly less fatigue after taking RSYRT for 2 to 3 weeks.

Researchers reported these results in the Journal of Alternative and Complementary Medicine.

Yichen Xu, MD, of Beijing Cancer Hospital & Institute in China, and colleagues evaluated RSYRT in 33 patients who had completed cancer treatment. The patients had stable disease and no anemia.

Eleven patients had moderate fatigue (a score of 4-6 on a 0-10 scale), and 22 had severe fatigue (a score of 7-10). All patients had experienced fatigue for at least 4 months.

Patients took RSYRT twice a day for 6 weeks and experienced a significant decrease in fatigue severity. The mean fatigue score decreased from 7.06 at baseline to 3.30 at the 6-week mark (P<0.001).

The fatigue category also changed significantly (P=0.024). Among the 22 patients who had severe fatigue before RSYRT, half had mild fatigue after therapy, and half had moderate fatigue.

Among the 11 patients who had moderate fatigue at baseline, only 1 still had moderate fatigue after receiving RSYRT. The rest had mild fatigue.

All of the patients said they felt better after taking RSYRT for 4 weeks.

There were no “uncomfortable events” related to RSYRT, such as gastrointestinal upset, insomnia, headache, or rash. None of the patients required a dose reduction or dose interruption.

None of the patients had blood chemistry abnormalities or abnormal liver/kidney function. Two patients who had a change in ST segment before RSYRT had normal electrocardiogram results after treatment.

Herbs and spices

Photo by Alexander Baxevanis

An herbal mixture used in traditional Chinese medicine can reduce fatigue in cancer patients, results of a phase 1/2 study suggest.

The mixture, Ren Shen Yangrong Tang (RSYRT), is a soup containing 12 herbs.

In the study, cancer patients suffering from moderate to severe fatigue reported significantly less fatigue after taking RSYRT for 2 to 3 weeks.

Researchers reported these results in the Journal of Alternative and Complementary Medicine.

Yichen Xu, MD, of Beijing Cancer Hospital & Institute in China, and colleagues evaluated RSYRT in 33 patients who had completed cancer treatment. The patients had stable disease and no anemia.

Eleven patients had moderate fatigue (a score of 4-6 on a 0-10 scale), and 22 had severe fatigue (a score of 7-10). All patients had experienced fatigue for at least 4 months.

Patients took RSYRT twice a day for 6 weeks and experienced a significant decrease in fatigue severity. The mean fatigue score decreased from 7.06 at baseline to 3.30 at the 6-week mark (P<0.001).

The fatigue category also changed significantly (P=0.024). Among the 22 patients who had severe fatigue before RSYRT, half had mild fatigue after therapy, and half had moderate fatigue.

Among the 11 patients who had moderate fatigue at baseline, only 1 still had moderate fatigue after receiving RSYRT. The rest had mild fatigue.

All of the patients said they felt better after taking RSYRT for 4 weeks.

There were no “uncomfortable events” related to RSYRT, such as gastrointestinal upset, insomnia, headache, or rash. None of the patients required a dose reduction or dose interruption.

None of the patients had blood chemistry abnormalities or abnormal liver/kidney function. Two patients who had a change in ST segment before RSYRT had normal electrocardiogram results after treatment.

CLL cells

PHILADELPHIA—A DNA-dependent protein kinase (DNA-PK) inhibitor can sensitize chronic lymphocytic leukemia (CLL) cells to chemotherapy, according to

preclinical research.

The inhibitor, NDD0004, sensitized CLL cells—even those from patients with high-risk cytogenetics—to treatment with mitoxantrone.

However, not all CLL samples were sensitive to treatment, so researchers are now trying to determine which patients might derive benefit from DNA-PK inhibitors.

Gesa Junge, a PhD student at Newcastle University in the UK, and her colleagues conducted this research and presented the results at the AACR Annual Meeting 2015 (abstract 3624*). The work was supported by AstraZeneca.

The researchers’ goal was to validate that DNA-PK inhibition is a valid approach to chemosensitization in CLL. So the team tested NU7441—a compound that inhibits DNA-PK and PI3 kinase—and NDD0004—a more selective DNA-PK inhibitor.

The team isolated CLL cells from patients’ peripheral blood, cultured the cells, and treated them with mitoxantrone and/or 1μM of NDD0004 or 1μM of NU7441.

Junge and her colleagues found that NDD0004 sensitized cells to mitoxantrone more effectively than NU7441. Sensitization was 202-fold higher with NDD004 plus mitoxantrone than with mitoxantrone alone and 69-fold higher with NU7441 plus mitoxantrone than with mitoxantrone alone (P=0.02).

However, sensitization varied between CLL samples, and the researchers have yet to determine why. Their experiments showed that variability was not a result of DNA-PK levels.

Still, the team found that CLL cells from patients with poor prognostic markers were sensitive to DNA-PK inhibition.

Sensitization with NU7441 plus mitoxantrone was 69-fold higher than mitoxantrone alone in CLL samples with del(13q), 25-fold higher in samples with del(11q), 12-fold higher in samples with TP53 mutation, and 16-fold higher in samples with ATM dysfunction.

Sensitization with NDD0004 plus mitoxantrone was 201-fold higher than mitoxantrone alone in CLL samples with del(13q), 314-fold higher in samples with del(11q), 27-fold higher in samples with TP53 mutation, and 18-fold higher in samples with ATM dysfunction.

To confirm that sensitization was a result of DNA-PK inhibition, Junge and her colleagues tested NDD0004 in an isogenic pair of DNA-PK-deficient and DNA-PK-proficient HCT116 cells. They found that HCT116 cells lacking DNA-PK were not sensitive to NDD0004, but cells with DNA-PK were sensitive.

The researchers also investigated the mechanism of NDD0004. Their results suggest the drug works by inhibiting the repair of DNA double-strand breaks.

“What we think is happening is that we are inducing DNA damage with mitoxantrone, and that gets repaired by 24 hours,” Junge said. “But if the DNA-PK inhibitor is there, the damage persists, and that seems to translate quite nicely into an apoptosis response.”

To further this research, Junge and her colleagues are hoping to identify biomarkers that can help them determine which CLL patients are likely to respond to DNA-PK inhibitors.

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

CLL cells

PHILADELPHIA—A DNA-dependent protein kinase (DNA-PK) inhibitor can sensitize chronic lymphocytic leukemia (CLL) cells to chemotherapy, according to

preclinical research.

The inhibitor, NDD0004, sensitized CLL cells—even those from patients with high-risk cytogenetics—to treatment with mitoxantrone.

However, not all CLL samples were sensitive to treatment, so researchers are now trying to determine which patients might derive benefit from DNA-PK inhibitors.

Gesa Junge, a PhD student at Newcastle University in the UK, and her colleagues conducted this research and presented the results at the AACR Annual Meeting 2015 (abstract 3624*). The work was supported by AstraZeneca.

The researchers’ goal was to validate that DNA-PK inhibition is a valid approach to chemosensitization in CLL. So the team tested NU7441—a compound that inhibits DNA-PK and PI3 kinase—and NDD0004—a more selective DNA-PK inhibitor.

The team isolated CLL cells from patients’ peripheral blood, cultured the cells, and treated them with mitoxantrone and/or 1μM of NDD0004 or 1μM of NU7441.

Junge and her colleagues found that NDD0004 sensitized cells to mitoxantrone more effectively than NU7441. Sensitization was 202-fold higher with NDD004 plus mitoxantrone than with mitoxantrone alone and 69-fold higher with NU7441 plus mitoxantrone than with mitoxantrone alone (P=0.02).

However, sensitization varied between CLL samples, and the researchers have yet to determine why. Their experiments showed that variability was not a result of DNA-PK levels.

Still, the team found that CLL cells from patients with poor prognostic markers were sensitive to DNA-PK inhibition.

Sensitization with NU7441 plus mitoxantrone was 69-fold higher than mitoxantrone alone in CLL samples with del(13q), 25-fold higher in samples with del(11q), 12-fold higher in samples with TP53 mutation, and 16-fold higher in samples with ATM dysfunction.

Sensitization with NDD0004 plus mitoxantrone was 201-fold higher than mitoxantrone alone in CLL samples with del(13q), 314-fold higher in samples with del(11q), 27-fold higher in samples with TP53 mutation, and 18-fold higher in samples with ATM dysfunction.

To confirm that sensitization was a result of DNA-PK inhibition, Junge and her colleagues tested NDD0004 in an isogenic pair of DNA-PK-deficient and DNA-PK-proficient HCT116 cells. They found that HCT116 cells lacking DNA-PK were not sensitive to NDD0004, but cells with DNA-PK were sensitive.

The researchers also investigated the mechanism of NDD0004. Their results suggest the drug works by inhibiting the repair of DNA double-strand breaks.

“What we think is happening is that we are inducing DNA damage with mitoxantrone, and that gets repaired by 24 hours,” Junge said. “But if the DNA-PK inhibitor is there, the damage persists, and that seems to translate quite nicely into an apoptosis response.”

To further this research, Junge and her colleagues are hoping to identify biomarkers that can help them determine which CLL patients are likely to respond to DNA-PK inhibitors.

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

CLL cells

PHILADELPHIA—A DNA-dependent protein kinase (DNA-PK) inhibitor can sensitize chronic lymphocytic leukemia (CLL) cells to chemotherapy, according to

preclinical research.

The inhibitor, NDD0004, sensitized CLL cells—even those from patients with high-risk cytogenetics—to treatment with mitoxantrone.

However, not all CLL samples were sensitive to treatment, so researchers are now trying to determine which patients might derive benefit from DNA-PK inhibitors.

Gesa Junge, a PhD student at Newcastle University in the UK, and her colleagues conducted this research and presented the results at the AACR Annual Meeting 2015 (abstract 3624*). The work was supported by AstraZeneca.

The researchers’ goal was to validate that DNA-PK inhibition is a valid approach to chemosensitization in CLL. So the team tested NU7441—a compound that inhibits DNA-PK and PI3 kinase—and NDD0004—a more selective DNA-PK inhibitor.

The team isolated CLL cells from patients’ peripheral blood, cultured the cells, and treated them with mitoxantrone and/or 1μM of NDD0004 or 1μM of NU7441.

Junge and her colleagues found that NDD0004 sensitized cells to mitoxantrone more effectively than NU7441. Sensitization was 202-fold higher with NDD004 plus mitoxantrone than with mitoxantrone alone and 69-fold higher with NU7441 plus mitoxantrone than with mitoxantrone alone (P=0.02).

However, sensitization varied between CLL samples, and the researchers have yet to determine why. Their experiments showed that variability was not a result of DNA-PK levels.

Still, the team found that CLL cells from patients with poor prognostic markers were sensitive to DNA-PK inhibition.

Sensitization with NU7441 plus mitoxantrone was 69-fold higher than mitoxantrone alone in CLL samples with del(13q), 25-fold higher in samples with del(11q), 12-fold higher in samples with TP53 mutation, and 16-fold higher in samples with ATM dysfunction.

Sensitization with NDD0004 plus mitoxantrone was 201-fold higher than mitoxantrone alone in CLL samples with del(13q), 314-fold higher in samples with del(11q), 27-fold higher in samples with TP53 mutation, and 18-fold higher in samples with ATM dysfunction.

To confirm that sensitization was a result of DNA-PK inhibition, Junge and her colleagues tested NDD0004 in an isogenic pair of DNA-PK-deficient and DNA-PK-proficient HCT116 cells. They found that HCT116 cells lacking DNA-PK were not sensitive to NDD0004, but cells with DNA-PK were sensitive.

The researchers also investigated the mechanism of NDD0004. Their results suggest the drug works by inhibiting the repair of DNA double-strand breaks.

“What we think is happening is that we are inducing DNA damage with mitoxantrone, and that gets repaired by 24 hours,” Junge said. “But if the DNA-PK inhibitor is there, the damage persists, and that seems to translate quite nicely into an apoptosis response.”

To further this research, Junge and her colleagues are hoping to identify biomarkers that can help them determine which CLL patients are likely to respond to DNA-PK inhibitors.

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

Micrograph showing WM

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) is  recommending that ibrutinib (Imbruvica) be approved to treat Waldenström’s macroglobulinemia (WM).

The CHMP is recommending the drug for use in WM patients who have received at least 1 prior therapy as well as previously untreated WM patients who are not suitable candidates for chemo-immunotherapy.

The European Commission will review this recommendation and should make a decision later this year.

Ibrutinib is already approved to treat WM in the US. The drug is also approved in the European Union, the US, and other countries to treat chronic lymphocytic leukemia and mantle cell lymphoma.

Janssen-Cilag International NV (Janssen) holds the marketing authorization for ibrutinib in Europe, and its affiliates market the drug in Europe and the rest of the world. In the US, ibrutinib is under joint development by Pharmacyclics and Janssen Biotech, Inc.

Phase 2 study

The CHMP’s recommendation for ibrutinib was based on a multicenter, phase 2 study in which researchers tested the drug in 63 patients with previously treated WM. Initial data showed an overall response rate of 87.3% in patients who received the drug for a median of 11.7 months.

Updated results from the study were published in NEJM in April. After a median treatment duration of 19.1 months, the overall response rate was 91%.

At 24 months, the estimated rate of progression-free survival was 69%, and the estimated rate of overall survival was 95%.

The most common grade 2-4 adverse events were neutropenia (22%) and thrombocytopenia (14%). Ibrutinib-related neutropenia and thrombocytopenia were reversible but required a dose reduction in 3 patients and treatment discontinuation in 4 patients.

Grade 2 or higher bleeding events occurred in 4 patients, and there were 15 infections considered possibly related to ibrutinib.

Treatment-related atrial fibrillation (AFib) occurred in 3 patients, all of whom had a prior history of paroxysmal AFib. AFib resolved when treatment was withheld, and all 3 patients were able to continue on therapy per protocol without an additional event.

Micrograph showing WM

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) is  recommending that ibrutinib (Imbruvica) be approved to treat Waldenström’s macroglobulinemia (WM).

The CHMP is recommending the drug for use in WM patients who have received at least 1 prior therapy as well as previously untreated WM patients who are not suitable candidates for chemo-immunotherapy.

The European Commission will review this recommendation and should make a decision later this year.

Ibrutinib is already approved to treat WM in the US. The drug is also approved in the European Union, the US, and other countries to treat chronic lymphocytic leukemia and mantle cell lymphoma.

Janssen-Cilag International NV (Janssen) holds the marketing authorization for ibrutinib in Europe, and its affiliates market the drug in Europe and the rest of the world. In the US, ibrutinib is under joint development by Pharmacyclics and Janssen Biotech, Inc.

Phase 2 study

The CHMP’s recommendation for ibrutinib was based on a multicenter, phase 2 study in which researchers tested the drug in 63 patients with previously treated WM. Initial data showed an overall response rate of 87.3% in patients who received the drug for a median of 11.7 months.

Updated results from the study were published in NEJM in April. After a median treatment duration of 19.1 months, the overall response rate was 91%.

At 24 months, the estimated rate of progression-free survival was 69%, and the estimated rate of overall survival was 95%.

The most common grade 2-4 adverse events were neutropenia (22%) and thrombocytopenia (14%). Ibrutinib-related neutropenia and thrombocytopenia were reversible but required a dose reduction in 3 patients and treatment discontinuation in 4 patients.

Grade 2 or higher bleeding events occurred in 4 patients, and there were 15 infections considered possibly related to ibrutinib.

Treatment-related atrial fibrillation (AFib) occurred in 3 patients, all of whom had a prior history of paroxysmal AFib. AFib resolved when treatment was withheld, and all 3 patients were able to continue on therapy per protocol without an additional event.

Micrograph showing WM

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) is  recommending that ibrutinib (Imbruvica) be approved to treat Waldenström’s macroglobulinemia (WM).

The CHMP is recommending the drug for use in WM patients who have received at least 1 prior therapy as well as previously untreated WM patients who are not suitable candidates for chemo-immunotherapy.

The European Commission will review this recommendation and should make a decision later this year.

Ibrutinib is already approved to treat WM in the US. The drug is also approved in the European Union, the US, and other countries to treat chronic lymphocytic leukemia and mantle cell lymphoma.

Janssen-Cilag International NV (Janssen) holds the marketing authorization for ibrutinib in Europe, and its affiliates market the drug in Europe and the rest of the world. In the US, ibrutinib is under joint development by Pharmacyclics and Janssen Biotech, Inc.

Phase 2 study

The CHMP’s recommendation for ibrutinib was based on a multicenter, phase 2 study in which researchers tested the drug in 63 patients with previously treated WM. Initial data showed an overall response rate of 87.3% in patients who received the drug for a median of 11.7 months.

Updated results from the study were published in NEJM in April. After a median treatment duration of 19.1 months, the overall response rate was 91%.

At 24 months, the estimated rate of progression-free survival was 69%, and the estimated rate of overall survival was 95%.

The most common grade 2-4 adverse events were neutropenia (22%) and thrombocytopenia (14%). Ibrutinib-related neutropenia and thrombocytopenia were reversible but required a dose reduction in 3 patients and treatment discontinuation in 4 patients.

Grade 2 or higher bleeding events occurred in 4 patients, and there were 15 infections considered possibly related to ibrutinib.

Treatment-related atrial fibrillation (AFib) occurred in 3 patients, all of whom had a prior history of paroxysmal AFib. AFib resolved when treatment was withheld, and all 3 patients were able to continue on therapy per protocol without an additional event.

James Bradner, MD

Photo by Sam Ogden

A chemical strategy may allow researchers to target “undruggable” proteins and overcome resistance to current targeted therapies, according to a report published in Science.

The strategy uses tumor cells’ own protein-elimination system to break down and dispose of the proteins that drive cancer growth.

When tested in vitro and in vivo, the approach caused leukemia cells to die more quickly than they do with conventional targeted

therapies.

“One of the reasons [treatment] resistance occurs is that cancer-related proteins often have multiple functions within the cell, and conventional targeted therapies inhibit just one or a few of those functions,” said study author James Bradner, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.

“Conventional drugs allow the targeted protein to adapt to the drug, and the cell finds alternate routes for its growth signals. We began designing approaches that cause the target protein to disintegrate, rather than merely be inhibited. It would be very powerful if we could chemically convert an inhibitor drug into a degrader drug.”

With this in mind, Dr Bradner’s team designed a chemical adapter that attaches to a targeted drug molecule. The adapter enables the drug to tow the cell’s protein-degradation machinery directly to the protein of interest. Once bound to the protein, the combination drug-and-protein-degrader essentially demolishes it.

The investigators tested the technology in leukemia cells. They built an adapter out of phthalimide, a chemical derivative of the drug thalidomide, and attached it to the BRD4 inhibitor JQ1. The phthalimide was designed to “hijack” the cereblon E3 ubiquitin ligase complex.

When the researchers treated the leukemia cells with a JQ1-phthalimide conjugate called dBET1, the BRD4 protein within the cells was degraded in less than an hour. The team said such rapid and extensive degradation suggests conjugates may be able to prevent or hinder cancer cells from developing resistance to targeted therapies.

“The potency, selectivity, and rapidity of this approach—namely, the ability to home in specifically on BRD4—are unprecedented in clinical approaches to protein degradation,” Dr Bradner said.

To determine how selective dBET1 actually is, the investigators measured the levels of all proteins in leukemia cells at 1 hour and 2 hours after treatment.

“We were stunned to find that only 3 proteins of more than 7000 in the entire cell were degraded: BRD2, 3, and 4, an exceptional degree of selectivity guided by the intended targets of JQ1,” Dr Bradner said. “It’s as though dBET1 is laser-guided to deliver protein-degrading machinery to targeted proteins.”

The researchers then tested dBET1 in mice bearing leukemia. As in the cell samples, there was a rapid degradation of BRD4 in the tumor cells and a potent anti-leukemic effect, with few noticeable side effects.

To see if compounds other than JQ1 can be used as a guidance system for a conjugate, the investigators created a set of molecules that lock the protein-degradation machinery onto a compound called SLF, which targets the protein FKBP12.

When they treated cancer cells with SLF, the team found it degraded the vast majority of FKBP12 in the cells within a few hours.

Buoyed by these results, the researchers are working to create a derivative of dBET1 that can be used as a drug in humans and to extend the conjugate strategy for the treatment of other diseases.

“The dBET1 and the dFKBP12 compounds are presently in a late stage of lead optimization for therapeutic development in both cancer and non-malignant diseases,” said Prem Das, PhD, chief research business development officer at Dana-Farber.

“Composition-of-matter and method-of-use patent applications have been filed on these and other additional targeted agents, as well as on the chemistry platform. They will be licensed for commercialization to an appropriate company according to standard Dana-Farber practice.”

James Bradner, MD

Photo by Sam Ogden

A chemical strategy may allow researchers to target “undruggable” proteins and overcome resistance to current targeted therapies, according to a report published in Science.

The strategy uses tumor cells’ own protein-elimination system to break down and dispose of the proteins that drive cancer growth.

When tested in vitro and in vivo, the approach caused leukemia cells to die more quickly than they do with conventional targeted

therapies.

“One of the reasons [treatment] resistance occurs is that cancer-related proteins often have multiple functions within the cell, and conventional targeted therapies inhibit just one or a few of those functions,” said study author James Bradner, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.

“Conventional drugs allow the targeted protein to adapt to the drug, and the cell finds alternate routes for its growth signals. We began designing approaches that cause the target protein to disintegrate, rather than merely be inhibited. It would be very powerful if we could chemically convert an inhibitor drug into a degrader drug.”

With this in mind, Dr Bradner’s team designed a chemical adapter that attaches to a targeted drug molecule. The adapter enables the drug to tow the cell’s protein-degradation machinery directly to the protein of interest. Once bound to the protein, the combination drug-and-protein-degrader essentially demolishes it.

The investigators tested the technology in leukemia cells. They built an adapter out of phthalimide, a chemical derivative of the drug thalidomide, and attached it to the BRD4 inhibitor JQ1. The phthalimide was designed to “hijack” the cereblon E3 ubiquitin ligase complex.

When the researchers treated the leukemia cells with a JQ1-phthalimide conjugate called dBET1, the BRD4 protein within the cells was degraded in less than an hour. The team said such rapid and extensive degradation suggests conjugates may be able to prevent or hinder cancer cells from developing resistance to targeted therapies.

“The potency, selectivity, and rapidity of this approach—namely, the ability to home in specifically on BRD4—are unprecedented in clinical approaches to protein degradation,” Dr Bradner said.

To determine how selective dBET1 actually is, the investigators measured the levels of all proteins in leukemia cells at 1 hour and 2 hours after treatment.

“We were stunned to find that only 3 proteins of more than 7000 in the entire cell were degraded: BRD2, 3, and 4, an exceptional degree of selectivity guided by the intended targets of JQ1,” Dr Bradner said. “It’s as though dBET1 is laser-guided to deliver protein-degrading machinery to targeted proteins.”

The researchers then tested dBET1 in mice bearing leukemia. As in the cell samples, there was a rapid degradation of BRD4 in the tumor cells and a potent anti-leukemic effect, with few noticeable side effects.

To see if compounds other than JQ1 can be used as a guidance system for a conjugate, the investigators created a set of molecules that lock the protein-degradation machinery onto a compound called SLF, which targets the protein FKBP12.

When they treated cancer cells with SLF, the team found it degraded the vast majority of FKBP12 in the cells within a few hours.

Buoyed by these results, the researchers are working to create a derivative of dBET1 that can be used as a drug in humans and to extend the conjugate strategy for the treatment of other diseases.

“The dBET1 and the dFKBP12 compounds are presently in a late stage of lead optimization for therapeutic development in both cancer and non-malignant diseases,” said Prem Das, PhD, chief research business development officer at Dana-Farber.

“Composition-of-matter and method-of-use patent applications have been filed on these and other additional targeted agents, as well as on the chemistry platform. They will be licensed for commercialization to an appropriate company according to standard Dana-Farber practice.”

James Bradner, MD

Photo by Sam Ogden

A chemical strategy may allow researchers to target “undruggable” proteins and overcome resistance to current targeted therapies, according to a report published in Science.

The strategy uses tumor cells’ own protein-elimination system to break down and dispose of the proteins that drive cancer growth.

When tested in vitro and in vivo, the approach caused leukemia cells to die more quickly than they do with conventional targeted

therapies.

“One of the reasons [treatment] resistance occurs is that cancer-related proteins often have multiple functions within the cell, and conventional targeted therapies inhibit just one or a few of those functions,” said study author James Bradner, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.

“Conventional drugs allow the targeted protein to adapt to the drug, and the cell finds alternate routes for its growth signals. We began designing approaches that cause the target protein to disintegrate, rather than merely be inhibited. It would be very powerful if we could chemically convert an inhibitor drug into a degrader drug.”

With this in mind, Dr Bradner’s team designed a chemical adapter that attaches to a targeted drug molecule. The adapter enables the drug to tow the cell’s protein-degradation machinery directly to the protein of interest. Once bound to the protein, the combination drug-and-protein-degrader essentially demolishes it.

The investigators tested the technology in leukemia cells. They built an adapter out of phthalimide, a chemical derivative of the drug thalidomide, and attached it to the BRD4 inhibitor JQ1. The phthalimide was designed to “hijack” the cereblon E3 ubiquitin ligase complex.

When the researchers treated the leukemia cells with a JQ1-phthalimide conjugate called dBET1, the BRD4 protein within the cells was degraded in less than an hour. The team said such rapid and extensive degradation suggests conjugates may be able to prevent or hinder cancer cells from developing resistance to targeted therapies.

“The potency, selectivity, and rapidity of this approach—namely, the ability to home in specifically on BRD4—are unprecedented in clinical approaches to protein degradation,” Dr Bradner said.

To determine how selective dBET1 actually is, the investigators measured the levels of all proteins in leukemia cells at 1 hour and 2 hours after treatment.

“We were stunned to find that only 3 proteins of more than 7000 in the entire cell were degraded: BRD2, 3, and 4, an exceptional degree of selectivity guided by the intended targets of JQ1,” Dr Bradner said. “It’s as though dBET1 is laser-guided to deliver protein-degrading machinery to targeted proteins.”

The researchers then tested dBET1 in mice bearing leukemia. As in the cell samples, there was a rapid degradation of BRD4 in the tumor cells and a potent anti-leukemic effect, with few noticeable side effects.

To see if compounds other than JQ1 can be used as a guidance system for a conjugate, the investigators created a set of molecules that lock the protein-degradation machinery onto a compound called SLF, which targets the protein FKBP12.

When they treated cancer cells with SLF, the team found it degraded the vast majority of FKBP12 in the cells within a few hours.

Buoyed by these results, the researchers are working to create a derivative of dBET1 that can be used as a drug in humans and to extend the conjugate strategy for the treatment of other diseases.

“The dBET1 and the dFKBP12 compounds are presently in a late stage of lead optimization for therapeutic development in both cancer and non-malignant diseases,” said Prem Das, PhD, chief research business development officer at Dana-Farber.

“Composition-of-matter and method-of-use patent applications have been filed on these and other additional targeted agents, as well as on the chemistry platform. They will be licensed for commercialization to an appropriate company according to standard Dana-Farber practice.”

Vial of heparin

PARIS—New research suggests that patients who have undergone primary percutaneous coronary intervention (PCI) have a low risk of stent thrombosis, regardless of the anticoagulant therapy they receive.

In a large, registry-based study, stent thrombosis occurred in less than 1% of patients, regardless of whether they received bivalirudin with or without heparin, heparin alone, or a GP IIb/IIIa inhibitor (GPI) with or without heparin.

The study also showed that patients who experienced stent thrombosis between days 2 and 30, regardless of drug regimen, were more likely to die within a year than patients who developed stent thrombosis within the first 24 hours of their procedure.

Per Grimfjard, of Vasteras Hospital/Uppsala University in Sweden, presented these findings at EuroPCR 2015.

A number of recent studies have raised concerns that bivalirudin may increase the risk of stent thrombosis compared with heparin. But rates of stent thrombosis have differed substantially between studies.

So Dr Grimfjard and his colleagues decided to review stent thrombosis rates by drug choice among more than 30,000 patients who were treated with primary PCI for ST-elevation myocardial infarction (STEMI) between January 2007 and July 2014 in the Swedish Coronary Angiography and Angioplasty Register (SCAAR).

The researchers divided patients into 3 treatment groups: bivalirudin, heparin, and GPI. However, 77% of patients in the bivalirudin group also received heparin, and 3.6% received a GPI prior to or during the PCI procedure. In the GPI group, 77% of patients also received heparin.

The rates of stent thrombosis were low in all 3 groups—0.84% in the bivalirudin group, 0.94% in the heparin group, and 0.83% in the GPI group.

For all 3 drugs, mortality at 1 year was numerically higher if the stent thrombosis occurred between 2 and 30 days, as compared with day 0 to 1 post-PCI.

“[A] possible explanation is that a stent thrombosis that happens once the patient has left the hospital is likely to cause a more substantial infarction, the reason being longer delay from symptoms to revascularization,” Dr Grimfjard said.

He added that a more substantial myocardial infarction typically leads to more heart failure and arrhythmia long-term. Unfortunately, the findings regarding the timing of stent thrombosis do not offer any guidance for choosing optimal antithrombotic treatment.

He and his colleagues are currently enrolling patients in a 6000-patient, registry-based, randomized clinical trial called SWEDEHART-Validate. The team will compare heparin alone to bivalirudin and optional low-dose heparin in STEMI and non-STEMI patients undergoing PCI.

“Hopefully, this large, randomized trial will bring clarity to the choice of antithrombotic treatment strategy in these patients,” Dr Grimfjard said.

Vial of heparin

PARIS—New research suggests that patients who have undergone primary percutaneous coronary intervention (PCI) have a low risk of stent thrombosis, regardless of the anticoagulant therapy they receive.

In a large, registry-based study, stent thrombosis occurred in less than 1% of patients, regardless of whether they received bivalirudin with or without heparin, heparin alone, or a GP IIb/IIIa inhibitor (GPI) with or without heparin.

The study also showed that patients who experienced stent thrombosis between days 2 and 30, regardless of drug regimen, were more likely to die within a year than patients who developed stent thrombosis within the first 24 hours of their procedure.

Per Grimfjard, of Vasteras Hospital/Uppsala University in Sweden, presented these findings at EuroPCR 2015.

A number of recent studies have raised concerns that bivalirudin may increase the risk of stent thrombosis compared with heparin. But rates of stent thrombosis have differed substantially between studies.

So Dr Grimfjard and his colleagues decided to review stent thrombosis rates by drug choice among more than 30,000 patients who were treated with primary PCI for ST-elevation myocardial infarction (STEMI) between January 2007 and July 2014 in the Swedish Coronary Angiography and Angioplasty Register (SCAAR).

The researchers divided patients into 3 treatment groups: bivalirudin, heparin, and GPI. However, 77% of patients in the bivalirudin group also received heparin, and 3.6% received a GPI prior to or during the PCI procedure. In the GPI group, 77% of patients also received heparin.

The rates of stent thrombosis were low in all 3 groups—0.84% in the bivalirudin group, 0.94% in the heparin group, and 0.83% in the GPI group.

For all 3 drugs, mortality at 1 year was numerically higher if the stent thrombosis occurred between 2 and 30 days, as compared with day 0 to 1 post-PCI.

“[A] possible explanation is that a stent thrombosis that happens once the patient has left the hospital is likely to cause a more substantial infarction, the reason being longer delay from symptoms to revascularization,” Dr Grimfjard said.

He added that a more substantial myocardial infarction typically leads to more heart failure and arrhythmia long-term. Unfortunately, the findings regarding the timing of stent thrombosis do not offer any guidance for choosing optimal antithrombotic treatment.

He and his colleagues are currently enrolling patients in a 6000-patient, registry-based, randomized clinical trial called SWEDEHART-Validate. The team will compare heparin alone to bivalirudin and optional low-dose heparin in STEMI and non-STEMI patients undergoing PCI.

“Hopefully, this large, randomized trial will bring clarity to the choice of antithrombotic treatment strategy in these patients,” Dr Grimfjard said.

Vial of heparin

PARIS—New research suggests that patients who have undergone primary percutaneous coronary intervention (PCI) have a low risk of stent thrombosis, regardless of the anticoagulant therapy they receive.

In a large, registry-based study, stent thrombosis occurred in less than 1% of patients, regardless of whether they received bivalirudin with or without heparin, heparin alone, or a GP IIb/IIIa inhibitor (GPI) with or without heparin.

The study also showed that patients who experienced stent thrombosis between days 2 and 30, regardless of drug regimen, were more likely to die within a year than patients who developed stent thrombosis within the first 24 hours of their procedure.

Per Grimfjard, of Vasteras Hospital/Uppsala University in Sweden, presented these findings at EuroPCR 2015.

A number of recent studies have raised concerns that bivalirudin may increase the risk of stent thrombosis compared with heparin. But rates of stent thrombosis have differed substantially between studies.

So Dr Grimfjard and his colleagues decided to review stent thrombosis rates by drug choice among more than 30,000 patients who were treated with primary PCI for ST-elevation myocardial infarction (STEMI) between January 2007 and July 2014 in the Swedish Coronary Angiography and Angioplasty Register (SCAAR).

The researchers divided patients into 3 treatment groups: bivalirudin, heparin, and GPI. However, 77% of patients in the bivalirudin group also received heparin, and 3.6% received a GPI prior to or during the PCI procedure. In the GPI group, 77% of patients also received heparin.

The rates of stent thrombosis were low in all 3 groups—0.84% in the bivalirudin group, 0.94% in the heparin group, and 0.83% in the GPI group.

For all 3 drugs, mortality at 1 year was numerically higher if the stent thrombosis occurred between 2 and 30 days, as compared with day 0 to 1 post-PCI.

“[A] possible explanation is that a stent thrombosis that happens once the patient has left the hospital is likely to cause a more substantial infarction, the reason being longer delay from symptoms to revascularization,” Dr Grimfjard said.

He added that a more substantial myocardial infarction typically leads to more heart failure and arrhythmia long-term. Unfortunately, the findings regarding the timing of stent thrombosis do not offer any guidance for choosing optimal antithrombotic treatment.

He and his colleagues are currently enrolling patients in a 6000-patient, registry-based, randomized clinical trial called SWEDEHART-Validate. The team will compare heparin alone to bivalirudin and optional low-dose heparin in STEMI and non-STEMI patients undergoing PCI.

“Hopefully, this large, randomized trial will bring clarity to the choice of antithrombotic treatment strategy in these patients,” Dr Grimfjard said.

Blood samples

Photo by Graham Colm

A new method for identifying immune cells could pave the way for rapid detection of hematologic malignancies from a small blood sample, according to researchers.

The team found they could use wavelength modulated Raman spectroscopy (WMRS) to identify subsets of T cells, natural killer cells, and dendritic cells.

Traditional methods of identifying these cells usually involve labeling them with fluorescent or magnetically labeled antibodies.

Using WMRS, the researchers were able to identify immune cells with no labeling at all, thus permitting rapid identification and further analysis to take place with no potential alteration to the cells.

Simon Powis, PhD, of the University of St Andrews in Fife, Scotland, and his colleagues described this work in PLOS ONE.

Raman scattering refers to light scattering from molecules in a sample where the light energy can be shifted up or down and recorded as a “molecular fingerprint” that can be used for identification. Normally, this process is very weak and further hampered by other background light (eg, fluorescence).

WMRS subtly changes the incident laser light that, in turn, results in a modulation of the Raman signal, allowing it to be extracted from any (stationary) interfering signal.

Using WMRS, Dr Powis and his colleagues found they could identify CD4⁺ T cells, CD8⁺ T cells, CD56⁺ natural killer cells, CD303⁺ lymphoid/plasmacytoid dendritic cells, and CD1c⁺ myeloid dendritic cells.

“Under a normal light microscope, these immune cells essentially all look identical,” Dr Powis said. “With this new method, we can identify key cell types without any labeling.”

“Our next goal is to make a full catalogue of all the normal cell types of the immune system that can be detected in the bloodstream. Once we have this completed, we can then collaborate with our clinical colleagues to start identifying when these immune cells are altered, in conditions such as leukemia and lymphoma, potentially providing a rapid detection system from just a small blood sample.”

Blood samples

Photo by Graham Colm

A new method for identifying immune cells could pave the way for rapid detection of hematologic malignancies from a small blood sample, according to researchers.

The team found they could use wavelength modulated Raman spectroscopy (WMRS) to identify subsets of T cells, natural killer cells, and dendritic cells.

Traditional methods of identifying these cells usually involve labeling them with fluorescent or magnetically labeled antibodies.

Using WMRS, the researchers were able to identify immune cells with no labeling at all, thus permitting rapid identification and further analysis to take place with no potential alteration to the cells.

Simon Powis, PhD, of the University of St Andrews in Fife, Scotland, and his colleagues described this work in PLOS ONE.

Raman scattering refers to light scattering from molecules in a sample where the light energy can be shifted up or down and recorded as a “molecular fingerprint” that can be used for identification. Normally, this process is very weak and further hampered by other background light (eg, fluorescence).

WMRS subtly changes the incident laser light that, in turn, results in a modulation of the Raman signal, allowing it to be extracted from any (stationary) interfering signal.

Using WMRS, Dr Powis and his colleagues found they could identify CD4⁺ T cells, CD8⁺ T cells, CD56⁺ natural killer cells, CD303⁺ lymphoid/plasmacytoid dendritic cells, and CD1c⁺ myeloid dendritic cells.

“Under a normal light microscope, these immune cells essentially all look identical,” Dr Powis said. “With this new method, we can identify key cell types without any labeling.”

“Our next goal is to make a full catalogue of all the normal cell types of the immune system that can be detected in the bloodstream. Once we have this completed, we can then collaborate with our clinical colleagues to start identifying when these immune cells are altered, in conditions such as leukemia and lymphoma, potentially providing a rapid detection system from just a small blood sample.”

Blood samples

Photo by Graham Colm

A new method for identifying immune cells could pave the way for rapid detection of hematologic malignancies from a small blood sample, according to researchers.

The team found they could use wavelength modulated Raman spectroscopy (WMRS) to identify subsets of T cells, natural killer cells, and dendritic cells.

Traditional methods of identifying these cells usually involve labeling them with fluorescent or magnetically labeled antibodies.

Using WMRS, the researchers were able to identify immune cells with no labeling at all, thus permitting rapid identification and further analysis to take place with no potential alteration to the cells.

Simon Powis, PhD, of the University of St Andrews in Fife, Scotland, and his colleagues described this work in PLOS ONE.

Raman scattering refers to light scattering from molecules in a sample where the light energy can be shifted up or down and recorded as a “molecular fingerprint” that can be used for identification. Normally, this process is very weak and further hampered by other background light (eg, fluorescence).

WMRS subtly changes the incident laser light that, in turn, results in a modulation of the Raman signal, allowing it to be extracted from any (stationary) interfering signal.

Using WMRS, Dr Powis and his colleagues found they could identify CD4⁺ T cells, CD8⁺ T cells, CD56⁺ natural killer cells, CD303⁺ lymphoid/plasmacytoid dendritic cells, and CD1c⁺ myeloid dendritic cells.

“Under a normal light microscope, these immune cells essentially all look identical,” Dr Powis said. “With this new method, we can identify key cell types without any labeling.”

“Our next goal is to make a full catalogue of all the normal cell types of the immune system that can be detected in the bloodstream. Once we have this completed, we can then collaborate with our clinical colleagues to start identifying when these immune cells are altered, in conditions such as leukemia and lymphoma, potentially providing a rapid detection system from just a small blood sample.”

Lab mouse

Co-infection with malaria and a virus closely related to the Epstein-Barr virus (EBV) may make the malaria lethal, according to preclinical research published in PLOS Pathogens.

Children in sub-Saharan Africa become infected with EBV in infancy.

Within the same time period, they become susceptible to malaria parasite infection because protective antibodies from their mothers fade away.

“Where we think kids get into trouble is when both infections are happening at the same time, because case reports show EBV can produce a weeks-long suppression of the immune system,” said Tracey Lamb, PhD, of Emory University School of Medicine in Atlanta, Georgia.

Dr Lamb and her colleagues studied mice infected by the malaria parasite Plasmodium yoelii, which is usually non-lethal because the mice develop antibodies that control the parasites.

The researchers found that co-infection with murine gammaherpesvirus 68 (MHV68), a close relative of EBV that infects mice, made P yoelii lethal.

However, mice that had entered the chronic phase of MHV68 infection (several weeks to months after primary infection) were not affected.

The experiments indicated that MHV68 infection hinders the immune system in developing antibodies against P yoelii.

“These results are part of a pattern of evidence suggesting that clinicians treating severe malaria should check for acute EBV co-infection, and that ongoing malaria studies should include EBV as a potential risk factor for more severe forms of the disease,” said Caline Matar, a graduate student at Emory University School of Medicine.

“This phenomenon may not be unique to EBV,” added Sam Speck, PhD, also of Emory University School of Medicine.

“[I]nfections with other pathogens may also exacerbate malarial disease, since many pathogens have the capacity to suppress various components of the host immune response.”

Lab mouse

Co-infection with malaria and a virus closely related to the Epstein-Barr virus (EBV) may make the malaria lethal, according to preclinical research published in PLOS Pathogens.

Children in sub-Saharan Africa become infected with EBV in infancy.

Within the same time period, they become susceptible to malaria parasite infection because protective antibodies from their mothers fade away.

“Where we think kids get into trouble is when both infections are happening at the same time, because case reports show EBV can produce a weeks-long suppression of the immune system,” said Tracey Lamb, PhD, of Emory University School of Medicine in Atlanta, Georgia.

Dr Lamb and her colleagues studied mice infected by the malaria parasite Plasmodium yoelii, which is usually non-lethal because the mice develop antibodies that control the parasites.

The researchers found that co-infection with murine gammaherpesvirus 68 (MHV68), a close relative of EBV that infects mice, made P yoelii lethal.

However, mice that had entered the chronic phase of MHV68 infection (several weeks to months after primary infection) were not affected.

The experiments indicated that MHV68 infection hinders the immune system in developing antibodies against P yoelii.

“These results are part of a pattern of evidence suggesting that clinicians treating severe malaria should check for acute EBV co-infection, and that ongoing malaria studies should include EBV as a potential risk factor for more severe forms of the disease,” said Caline Matar, a graduate student at Emory University School of Medicine.

“This phenomenon may not be unique to EBV,” added Sam Speck, PhD, also of Emory University School of Medicine.

“[I]nfections with other pathogens may also exacerbate malarial disease, since many pathogens have the capacity to suppress various components of the host immune response.”

Lab mouse

Co-infection with malaria and a virus closely related to the Epstein-Barr virus (EBV) may make the malaria lethal, according to preclinical research published in PLOS Pathogens.

Children in sub-Saharan Africa become infected with EBV in infancy.

Within the same time period, they become susceptible to malaria parasite infection because protective antibodies from their mothers fade away.

“Where we think kids get into trouble is when both infections are happening at the same time, because case reports show EBV can produce a weeks-long suppression of the immune system,” said Tracey Lamb, PhD, of Emory University School of Medicine in Atlanta, Georgia.

Dr Lamb and her colleagues studied mice infected by the malaria parasite Plasmodium yoelii, which is usually non-lethal because the mice develop antibodies that control the parasites.

The researchers found that co-infection with murine gammaherpesvirus 68 (MHV68), a close relative of EBV that infects mice, made P yoelii lethal.

However, mice that had entered the chronic phase of MHV68 infection (several weeks to months after primary infection) were not affected.

The experiments indicated that MHV68 infection hinders the immune system in developing antibodies against P yoelii.

“These results are part of a pattern of evidence suggesting that clinicians treating severe malaria should check for acute EBV co-infection, and that ongoing malaria studies should include EBV as a potential risk factor for more severe forms of the disease,” said Caline Matar, a graduate student at Emory University School of Medicine.

“This phenomenon may not be unique to EBV,” added Sam Speck, PhD, also of Emory University School of Medicine.

“[I]nfections with other pathogens may also exacerbate malarial disease, since many pathogens have the capacity to suppress various components of the host immune response.”

Researchers in the lab

Photo by Rhoda Baer

Researchers say they have created interleukin-2 (IL-2) variants that function as IL-2-receptor signaling “clamps” and allow for “fine tuning” of the signaling amplitude.

One variant, known as H9-RETR, was able to inhibit the actions of endogenous IL-2 and IL-15, prolong survival in a mouse model of graft-vs-host disease (GVHD), and inhibit the proliferation of cells derived from a patient with smoldering adult T-cell

leukemia (ATL).

The researchers reported these results in Immunity.

Warren J. Leonard, MD, of the National Heart, Lung, and Blood Institute in Bethesda, Maryland, and his colleagues developed IL-2 variants in which activity can be tuned to either boost or block immune responses, depending on the desired therapeutic application.

The researchers said these variants had high affinity for IL-2Rβ and inhibited binding of endogenous IL-2, but their interaction with γc was weakened, thereby weakening IL-2Rβ-γc heterodimerization.

The team found that IL-2 signaling strength was inversely correlated with the degree of mutation at the γc interface. And differential effects on cell proliferation were dependent upon the cells’ state of activation.

One of the IL-2 variants, H9-RETR, inhibited IL-2- and IL-15-mediated proliferation and cytotoxicity. H9-RETR inhibited cytokine signaling and natural killer cell activity as well or better than blocking antibodies to IL-2Rα and IL-2Rβ.

In experiments with cells isolated from a patient with smoldering ATL, H9-RETR blocked IL-2 signaling and inhibited the spontaneous proliferation of ATL cells. In this regard, H9-RETR was at least as effective as the anti-IL-2Rα antibody daclizumab and much more effective than the anti-IL-2Rβ antibody Mikβ1.

In a mouse model of GVHD, animals that received a stabilized, Fc-fusion version of H9-RETR (H9-RETR-Fc4) had significantly longer survival than control mice (which received only Fc4 protein).

All of the control mice had died by 40 days post-injection, but it took 60 days for all of the H9-RETR-Fc4-treated mice to die (P=0.0001).

The researchers believe their receptor-clamping approach could potentially be used to engineer other immune-system cytokines with therapeutic potential.

Researchers in the lab

Photo by Rhoda Baer

Researchers say they have created interleukin-2 (IL-2) variants that function as IL-2-receptor signaling “clamps” and allow for “fine tuning” of the signaling amplitude.

One variant, known as H9-RETR, was able to inhibit the actions of endogenous IL-2 and IL-15, prolong survival in a mouse model of graft-vs-host disease (GVHD), and inhibit the proliferation of cells derived from a patient with smoldering adult T-cell

leukemia (ATL).

The researchers reported these results in Immunity.

Warren J. Leonard, MD, of the National Heart, Lung, and Blood Institute in Bethesda, Maryland, and his colleagues developed IL-2 variants in which activity can be tuned to either boost or block immune responses, depending on the desired therapeutic application.

The researchers said these variants had high affinity for IL-2Rβ and inhibited binding of endogenous IL-2, but their interaction with γc was weakened, thereby weakening IL-2Rβ-γc heterodimerization.

The team found that IL-2 signaling strength was inversely correlated with the degree of mutation at the γc interface. And differential effects on cell proliferation were dependent upon the cells’ state of activation.

One of the IL-2 variants, H9-RETR, inhibited IL-2- and IL-15-mediated proliferation and cytotoxicity. H9-RETR inhibited cytokine signaling and natural killer cell activity as well or better than blocking antibodies to IL-2Rα and IL-2Rβ.

In experiments with cells isolated from a patient with smoldering ATL, H9-RETR blocked IL-2 signaling and inhibited the spontaneous proliferation of ATL cells. In this regard, H9-RETR was at least as effective as the anti-IL-2Rα antibody daclizumab and much more effective than the anti-IL-2Rβ antibody Mikβ1.

In a mouse model of GVHD, animals that received a stabilized, Fc-fusion version of H9-RETR (H9-RETR-Fc4) had significantly longer survival than control mice (which received only Fc4 protein).

All of the control mice had died by 40 days post-injection, but it took 60 days for all of the H9-RETR-Fc4-treated mice to die (P=0.0001).

The researchers believe their receptor-clamping approach could potentially be used to engineer other immune-system cytokines with therapeutic potential.

Researchers in the lab

Photo by Rhoda Baer

Researchers say they have created interleukin-2 (IL-2) variants that function as IL-2-receptor signaling “clamps” and allow for “fine tuning” of the signaling amplitude.

One variant, known as H9-RETR, was able to inhibit the actions of endogenous IL-2 and IL-15, prolong survival in a mouse model of graft-vs-host disease (GVHD), and inhibit the proliferation of cells derived from a patient with smoldering adult T-cell

leukemia (ATL).

The researchers reported these results in Immunity.

Warren J. Leonard, MD, of the National Heart, Lung, and Blood Institute in Bethesda, Maryland, and his colleagues developed IL-2 variants in which activity can be tuned to either boost or block immune responses, depending on the desired therapeutic application.

The researchers said these variants had high affinity for IL-2Rβ and inhibited binding of endogenous IL-2, but their interaction with γc was weakened, thereby weakening IL-2Rβ-γc heterodimerization.

The team found that IL-2 signaling strength was inversely correlated with the degree of mutation at the γc interface. And differential effects on cell proliferation were dependent upon the cells’ state of activation.

One of the IL-2 variants, H9-RETR, inhibited IL-2- and IL-15-mediated proliferation and cytotoxicity. H9-RETR inhibited cytokine signaling and natural killer cell activity as well or better than blocking antibodies to IL-2Rα and IL-2Rβ.

In experiments with cells isolated from a patient with smoldering ATL, H9-RETR blocked IL-2 signaling and inhibited the spontaneous proliferation of ATL cells. In this regard, H9-RETR was at least as effective as the anti-IL-2Rα antibody daclizumab and much more effective than the anti-IL-2Rβ antibody Mikβ1.

In a mouse model of GVHD, animals that received a stabilized, Fc-fusion version of H9-RETR (H9-RETR-Fc4) had significantly longer survival than control mice (which received only Fc4 protein).

All of the control mice had died by 40 days post-injection, but it took 60 days for all of the H9-RETR-Fc4-treated mice to die (P=0.0001).

The researchers believe their receptor-clamping approach could potentially be used to engineer other immune-system cytokines with therapeutic potential.

Anopheles gambiae mosquito

Photo courtesy of the CDC

Recent progress in halting the spread of malaria has hinged, in part, on the use of insecticide-treated bed nets and spraying programs that target Anopheles gambiae mosquitoes.

Unfortunately, the mosquitoes are developing resistance to insecticides such as pyrethroid.

Wondering if they could defeat the mosquitoes by developing a new insecticide,a group of researchers set out to make blood meals toxic for Anopheles gambiae.

The team described their method in The Journal of Experimental Biology.

The researchers decided to target the mosquito glutamate gated chloride channel (AgGluCl), which is an essential component of the insect’s nervous system.

They generated antibodies that specifically targeted a portion of the protein exposed on the surface of nerves, a strategy they acknowledged was somewhat risky.

“Antibodies against a single mosquito antigen have never been shown to have mosquitocidal properties before, and the majority of previous research had focused on midgut antigens, while we were targeting a neuronal antigen expressed only in tissues found outside of the midgut,” said study author Jacob Meyers, a graduate student at Colorado State University in Fort Collins.

After injecting rabbits with a tiny portion of the surface of the AgGluCl protein channel, the researchers waited for the rabbits’ immune systems to begin producing antibodies tailored to the channel.

Then, the team collected the antibodies, mixed them with fresh blood, and fed the mixture to malaria-carrying mosquitoes (Anopheles gambiae), yellow fever-carrying mosquitoes (Aedes aegypti), and mosquitoes that carry the West Nile virus (Culex tarsalis).

Neither the yellow fever nor West Nile virus mosquitoes responded to the spiked blood. However, significant numbers of Anopheles gambiae mosquitoes died after consuming the blood/antibody cocktail. The highest antibody doses killed more than 90% of the insects within a day.

The researchers looked into why the yellow fever and West Nile virus mosquitoes had been immune to the antibodies and found the antibodies could not pass across the mosquitoes’ guts into the hemolymph. But the antibodies passed into the hemolymph of Anopheles gambiae mosquitoes with ease.

Intrigued by the antibodies’ mode of action, the researchers fed the insects a blood meal laced with the antibodies and a lethal dose of ivermectin, an insecticide that also targets the AgGluCl protein channel.

Then, the team monitored the mosquitoes’ survival to find out more about how the antibodies may destroy the insects. Mosquitoes that received ivermectin with the antibodies were more likely to survive than insects that received ivermectin alone.

“We believe that ivermectin is able to bind to AgGluCl,” Meyers said, “but the antibody keeps the channel from opening and becoming active.”

Having shown that antibodies targeted to the glutamate gated chloride channel in blood meals can be effective insecticides, the researchers are interested to find out if antibody-laced blood meals are equally deadly outside the lab.

First, though, the team plans to immunize cattle against the AgGluCl antigen and feed Anopheles gambiae on the immunized cattle in the lab. If the strategy proves successful, Meyers envisages a large-scale cattle immunization program as part of a combined attack on the malaria parasite.

Anopheles gambiae mosquito

Photo courtesy of the CDC

Recent progress in halting the spread of malaria has hinged, in part, on the use of insecticide-treated bed nets and spraying programs that target Anopheles gambiae mosquitoes.

Unfortunately, the mosquitoes are developing resistance to insecticides such as pyrethroid.

Wondering if they could defeat the mosquitoes by developing a new insecticide,a group of researchers set out to make blood meals toxic for Anopheles gambiae.

The team described their method in The Journal of Experimental Biology.

The researchers decided to target the mosquito glutamate gated chloride channel (AgGluCl), which is an essential component of the insect’s nervous system.

They generated antibodies that specifically targeted a portion of the protein exposed on the surface of nerves, a strategy they acknowledged was somewhat risky.

“Antibodies against a single mosquito antigen have never been shown to have mosquitocidal properties before, and the majority of previous research had focused on midgut antigens, while we were targeting a neuronal antigen expressed only in tissues found outside of the midgut,” said study author Jacob Meyers, a graduate student at Colorado State University in Fort Collins.

After injecting rabbits with a tiny portion of the surface of the AgGluCl protein channel, the researchers waited for the rabbits’ immune systems to begin producing antibodies tailored to the channel.

Then, the team collected the antibodies, mixed them with fresh blood, and fed the mixture to malaria-carrying mosquitoes (Anopheles gambiae), yellow fever-carrying mosquitoes (Aedes aegypti), and mosquitoes that carry the West Nile virus (Culex tarsalis).

Neither the yellow fever nor West Nile virus mosquitoes responded to the spiked blood. However, significant numbers of Anopheles gambiae mosquitoes died after consuming the blood/antibody cocktail. The highest antibody doses killed more than 90% of the insects within a day.

The researchers looked into why the yellow fever and West Nile virus mosquitoes had been immune to the antibodies and found the antibodies could not pass across the mosquitoes’ guts into the hemolymph. But the antibodies passed into the hemolymph of Anopheles gambiae mosquitoes with ease.

Intrigued by the antibodies’ mode of action, the researchers fed the insects a blood meal laced with the antibodies and a lethal dose of ivermectin, an insecticide that also targets the AgGluCl protein channel.

Then, the team monitored the mosquitoes’ survival to find out more about how the antibodies may destroy the insects. Mosquitoes that received ivermectin with the antibodies were more likely to survive than insects that received ivermectin alone.

“We believe that ivermectin is able to bind to AgGluCl,” Meyers said, “but the antibody keeps the channel from opening and becoming active.”

Having shown that antibodies targeted to the glutamate gated chloride channel in blood meals can be effective insecticides, the researchers are interested to find out if antibody-laced blood meals are equally deadly outside the lab.

First, though, the team plans to immunize cattle against the AgGluCl antigen and feed Anopheles gambiae on the immunized cattle in the lab. If the strategy proves successful, Meyers envisages a large-scale cattle immunization program as part of a combined attack on the malaria parasite.

Anopheles gambiae mosquito

Photo courtesy of the CDC

Recent progress in halting the spread of malaria has hinged, in part, on the use of insecticide-treated bed nets and spraying programs that target Anopheles gambiae mosquitoes.

Unfortunately, the mosquitoes are developing resistance to insecticides such as pyrethroid.

Wondering if they could defeat the mosquitoes by developing a new insecticide,a group of researchers set out to make blood meals toxic for Anopheles gambiae.

The team described their method in The Journal of Experimental Biology.

The researchers decided to target the mosquito glutamate gated chloride channel (AgGluCl), which is an essential component of the insect’s nervous system.

They generated antibodies that specifically targeted a portion of the protein exposed on the surface of nerves, a strategy they acknowledged was somewhat risky.

“Antibodies against a single mosquito antigen have never been shown to have mosquitocidal properties before, and the majority of previous research had focused on midgut antigens, while we were targeting a neuronal antigen expressed only in tissues found outside of the midgut,” said study author Jacob Meyers, a graduate student at Colorado State University in Fort Collins.

After injecting rabbits with a tiny portion of the surface of the AgGluCl protein channel, the researchers waited for the rabbits’ immune systems to begin producing antibodies tailored to the channel.

Then, the team collected the antibodies, mixed them with fresh blood, and fed the mixture to malaria-carrying mosquitoes (Anopheles gambiae), yellow fever-carrying mosquitoes (Aedes aegypti), and mosquitoes that carry the West Nile virus (Culex tarsalis).

Neither the yellow fever nor West Nile virus mosquitoes responded to the spiked blood. However, significant numbers of Anopheles gambiae mosquitoes died after consuming the blood/antibody cocktail. The highest antibody doses killed more than 90% of the insects within a day.

The researchers looked into why the yellow fever and West Nile virus mosquitoes had been immune to the antibodies and found the antibodies could not pass across the mosquitoes’ guts into the hemolymph. But the antibodies passed into the hemolymph of Anopheles gambiae mosquitoes with ease.

Intrigued by the antibodies’ mode of action, the researchers fed the insects a blood meal laced with the antibodies and a lethal dose of ivermectin, an insecticide that also targets the AgGluCl protein channel.

Then, the team monitored the mosquitoes’ survival to find out more about how the antibodies may destroy the insects. Mosquitoes that received ivermectin with the antibodies were more likely to survive than insects that received ivermectin alone.

“We believe that ivermectin is able to bind to AgGluCl,” Meyers said, “but the antibody keeps the channel from opening and becoming active.”

Having shown that antibodies targeted to the glutamate gated chloride channel in blood meals can be effective insecticides, the researchers are interested to find out if antibody-laced blood meals are equally deadly outside the lab.

First, though, the team plans to immunize cattle against the AgGluCl antigen and feed Anopheles gambiae on the immunized cattle in the lab. If the strategy proves successful, Meyers envisages a large-scale cattle immunization program as part of a combined attack on the malaria parasite.