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Improving NK cell therapy
Image by Joshua Stokes
New findings published in PNAS may help scientists improve the efficacy of natural killer (NK) cell therapy for patients with leukemia.
The preclinical research revealed a tolerance mechanism that restrains the activity of NK cells, as well as a potential way to overcome this problem.
Investigators found that a transcription factor, Kruppel-like factor 2 (KFL2), is critical for NK cell expansion and survival.
Specifically, KLF2 limits immature NK cell proliferation and instructs mature NK cells to home to niches rich in interleukin 15 (IL-15), which is necessary for their continued survival.
“This is the same process likely used by cancer cells to avoid destruction by NK cells,” said study author Eric Sebzda, PhD, of Vanderbilt University Medical Center in Nashville, Tennessee.
In particular, tumors may avoid immune clearance by promoting KLF2 destruction within the NK cell population, thereby starving these cells of IL-15.
Dr Sebzda and his colleagues noted that increased expression of IL-15 can improve immune responses against tumors. Unfortunately, it’s not easy to introduce the cytokine only within a tumor microenvironment, and high systemic levels of IL-15 can be toxic.
Recruiting cells that transpresent IL-15 to the tumor microenvironment may overcome this barrier and therefore improve NK cell-mediated cancer therapy, the investigators said. However, the methodology hasn’t been worked out yet.
“Our paper should encourage this line of inquiry,” Dr Sebzda concluded. 
Image by Joshua Stokes
New findings published in PNAS may help scientists improve the efficacy of natural killer (NK) cell therapy for patients with leukemia.
The preclinical research revealed a tolerance mechanism that restrains the activity of NK cells, as well as a potential way to overcome this problem.
Investigators found that a transcription factor, Kruppel-like factor 2 (KFL2), is critical for NK cell expansion and survival.
Specifically, KLF2 limits immature NK cell proliferation and instructs mature NK cells to home to niches rich in interleukin 15 (IL-15), which is necessary for their continued survival.
“This is the same process likely used by cancer cells to avoid destruction by NK cells,” said study author Eric Sebzda, PhD, of Vanderbilt University Medical Center in Nashville, Tennessee.
In particular, tumors may avoid immune clearance by promoting KLF2 destruction within the NK cell population, thereby starving these cells of IL-15.
Dr Sebzda and his colleagues noted that increased expression of IL-15 can improve immune responses against tumors. Unfortunately, it’s not easy to introduce the cytokine only within a tumor microenvironment, and high systemic levels of IL-15 can be toxic.
Recruiting cells that transpresent IL-15 to the tumor microenvironment may overcome this barrier and therefore improve NK cell-mediated cancer therapy, the investigators said. However, the methodology hasn’t been worked out yet.
“Our paper should encourage this line of inquiry,” Dr Sebzda concluded.
Image by Joshua Stokes
New findings published in PNAS may help scientists improve the efficacy of natural killer (NK) cell therapy for patients with leukemia.
The preclinical research revealed a tolerance mechanism that restrains the activity of NK cells, as well as a potential way to overcome this problem.
Investigators found that a transcription factor, Kruppel-like factor 2 (KFL2), is critical for NK cell expansion and survival.
Specifically, KLF2 limits immature NK cell proliferation and instructs mature NK cells to home to niches rich in interleukin 15 (IL-15), which is necessary for their continued survival.
“This is the same process likely used by cancer cells to avoid destruction by NK cells,” said study author Eric Sebzda, PhD, of Vanderbilt University Medical Center in Nashville, Tennessee.
In particular, tumors may avoid immune clearance by promoting KLF2 destruction within the NK cell population, thereby starving these cells of IL-15.
Dr Sebzda and his colleagues noted that increased expression of IL-15 can improve immune responses against tumors. Unfortunately, it’s not easy to introduce the cytokine only within a tumor microenvironment, and high systemic levels of IL-15 can be toxic.
Recruiting cells that transpresent IL-15 to the tumor microenvironment may overcome this barrier and therefore improve NK cell-mediated cancer therapy, the investigators said. However, the methodology hasn’t been worked out yet.
“Our paper should encourage this line of inquiry,” Dr Sebzda concluded.
Drug may reduce severity of AEs from dexamethasone
Photo by Bill Branson
Adding a physiologic dose of hydrocortisone to treatment with dexamethasone can reduce the severity of certain adverse effects (AEs) in pediatric patients with acute lymphoblastic leukemia (ALL), according to researchers.
Hydrocortisone did not decrease the incidence of psychosocial problems or sleep-related issues in these patients, but the drug did reduce the severity of these problems among patients who experienced them.
Lidewij T. Warris, MD, of Erasmus MC-Sophia Children’s Hospital in Rotterdam, the Netherlands, and her colleagues reported these results in the Journal of Clinical Oncology.
The team conducted this study to determine whether a physiologic dose of hydrocortisone could reduce neuropsychologic and metabolic AEs in children with ALL who were receiving dexamethasone.
The study enrolled 50 patients (ages 3 to 16) who were set to receive 2 consecutive courses of dexamethasone in accordance with Dutch Childhood Oncology Group ALL protocols.
The patients were randomized to receive either hydrocortisone or placebo in a circadian rhythm (10 mg/m2/d) during their first dexamethasone course. During their second course, the patients were assigned to the opposite arm.
The treatment groups were similar with regard to age, type of leukemia, treatment protocol, and CNS status at diagnosis.
Psychosocial problems
The researchers assessed psychosocial problems by having parents complete the Strength and Difficulties Questionnaire (SDQ). Forty-six parents completed the questionnaire at all 4 time points tested.
The results showed that 4 days of dexamethasone treatment significantly increased patient problems, as reported by all SDQ scales and subscales. However, one-third of the population did not have any increase in SDQ total difficulties with dexamethasone.
The addition of hydrocortisone did not affect patients’ total difficulties score (mean difference, -0.8 ± 5.5; P=0.33), emotional symptoms (mean difference, -0.6 ± 2.3; P=0.08), conduct problems (mean difference, 0.0 ± 1.5; P=1.00), or other SDQ subscales.
However, hydrocortisone did have a clinically significant effect in the subset of 16 patients who had clinically relevant dexamethasone-related AEs. This was defined as an increase of ≥5 in their SDQ total difficulties score.
In these patients, hydrocortisone improved the total difficulties delta-score (median difference, -5.0; IQR, -7.8 to -3.0), emotional symptoms score (median difference, -1.5; IQR, -4.0 to -1.0), conduct problems score (median difference, -1.0; IQR, -2.0 to 0.0), and impact of stress score (median difference, -1.0; IQR, -2.0 to 0.0).
Sleep issues
The researchers used the Sleep Disturbance Scale for Children (SDSC) to assess sleep quality and sleep disturbances. Forty-seven parents completed the questionnaire at all 4 time points tested.
Results showed that dexamethasone significantly increased disorders of arousal (P=0.04), sleep-wake transition disorders (P=0.01), and disorders of excessive somnolence (P=0.01).
The addition of hydrocortisone had no significant effect on patients’ total SDSC score (P=0.84), disorders of initiating and maintaining sleep (P=0.74), disorders of excessive somnolence (P=0.29), or sleep-wake transition disorder (P=0.29).
However, hydrocortisone did have a clinically significant effect in the subset of 9 children who had clinically relevant dexamethasone-induced sleeping problems, which were defined as a change of ≥7 in SDSC total score.
Hydrocortisone reduced SDSC total scores (median difference, -11.0; IQR, -16.0 to 0.0) and disorders of initiating and maintaining sleep scores (median difference, -3.0; IQR, -7.0 to –0.5).
Other outcomes
The researchers also found that dexamethasone treatment alone did not affect patients’ attention, visual-spatial functions, memory, or processing speed.
However, the addition of hydrocortisone significantly improved patients’ long-term visual memory (P=0.01).
Hydrocortisone did not have any effect on other neuropsychological tests or on metabolic parameters.
Photo by Bill Branson
Adding a physiologic dose of hydrocortisone to treatment with dexamethasone can reduce the severity of certain adverse effects (AEs) in pediatric patients with acute lymphoblastic leukemia (ALL), according to researchers.
Hydrocortisone did not decrease the incidence of psychosocial problems or sleep-related issues in these patients, but the drug did reduce the severity of these problems among patients who experienced them.
Lidewij T. Warris, MD, of Erasmus MC-Sophia Children’s Hospital in Rotterdam, the Netherlands, and her colleagues reported these results in the Journal of Clinical Oncology.
The team conducted this study to determine whether a physiologic dose of hydrocortisone could reduce neuropsychologic and metabolic AEs in children with ALL who were receiving dexamethasone.
The study enrolled 50 patients (ages 3 to 16) who were set to receive 2 consecutive courses of dexamethasone in accordance with Dutch Childhood Oncology Group ALL protocols.
The patients were randomized to receive either hydrocortisone or placebo in a circadian rhythm (10 mg/m2/d) during their first dexamethasone course. During their second course, the patients were assigned to the opposite arm.
The treatment groups were similar with regard to age, type of leukemia, treatment protocol, and CNS status at diagnosis.
Psychosocial problems
The researchers assessed psychosocial problems by having parents complete the Strength and Difficulties Questionnaire (SDQ). Forty-six parents completed the questionnaire at all 4 time points tested.
The results showed that 4 days of dexamethasone treatment significantly increased patient problems, as reported by all SDQ scales and subscales. However, one-third of the population did not have any increase in SDQ total difficulties with dexamethasone.
The addition of hydrocortisone did not affect patients’ total difficulties score (mean difference, -0.8 ± 5.5; P=0.33), emotional symptoms (mean difference, -0.6 ± 2.3; P=0.08), conduct problems (mean difference, 0.0 ± 1.5; P=1.00), or other SDQ subscales.
However, hydrocortisone did have a clinically significant effect in the subset of 16 patients who had clinically relevant dexamethasone-related AEs. This was defined as an increase of ≥5 in their SDQ total difficulties score.
In these patients, hydrocortisone improved the total difficulties delta-score (median difference, -5.0; IQR, -7.8 to -3.0), emotional symptoms score (median difference, -1.5; IQR, -4.0 to -1.0), conduct problems score (median difference, -1.0; IQR, -2.0 to 0.0), and impact of stress score (median difference, -1.0; IQR, -2.0 to 0.0).
Sleep issues
The researchers used the Sleep Disturbance Scale for Children (SDSC) to assess sleep quality and sleep disturbances. Forty-seven parents completed the questionnaire at all 4 time points tested.
Results showed that dexamethasone significantly increased disorders of arousal (P=0.04), sleep-wake transition disorders (P=0.01), and disorders of excessive somnolence (P=0.01).
The addition of hydrocortisone had no significant effect on patients’ total SDSC score (P=0.84), disorders of initiating and maintaining sleep (P=0.74), disorders of excessive somnolence (P=0.29), or sleep-wake transition disorder (P=0.29).
However, hydrocortisone did have a clinically significant effect in the subset of 9 children who had clinically relevant dexamethasone-induced sleeping problems, which were defined as a change of ≥7 in SDSC total score.
Hydrocortisone reduced SDSC total scores (median difference, -11.0; IQR, -16.0 to 0.0) and disorders of initiating and maintaining sleep scores (median difference, -3.0; IQR, -7.0 to –0.5).
Other outcomes
The researchers also found that dexamethasone treatment alone did not affect patients’ attention, visual-spatial functions, memory, or processing speed.
However, the addition of hydrocortisone significantly improved patients’ long-term visual memory (P=0.01).
Hydrocortisone did not have any effect on other neuropsychological tests or on metabolic parameters.
Photo by Bill Branson
Adding a physiologic dose of hydrocortisone to treatment with dexamethasone can reduce the severity of certain adverse effects (AEs) in pediatric patients with acute lymphoblastic leukemia (ALL), according to researchers.
Hydrocortisone did not decrease the incidence of psychosocial problems or sleep-related issues in these patients, but the drug did reduce the severity of these problems among patients who experienced them.
Lidewij T. Warris, MD, of Erasmus MC-Sophia Children’s Hospital in Rotterdam, the Netherlands, and her colleagues reported these results in the Journal of Clinical Oncology.
The team conducted this study to determine whether a physiologic dose of hydrocortisone could reduce neuropsychologic and metabolic AEs in children with ALL who were receiving dexamethasone.
The study enrolled 50 patients (ages 3 to 16) who were set to receive 2 consecutive courses of dexamethasone in accordance with Dutch Childhood Oncology Group ALL protocols.
The patients were randomized to receive either hydrocortisone or placebo in a circadian rhythm (10 mg/m2/d) during their first dexamethasone course. During their second course, the patients were assigned to the opposite arm.
The treatment groups were similar with regard to age, type of leukemia, treatment protocol, and CNS status at diagnosis.
Psychosocial problems
The researchers assessed psychosocial problems by having parents complete the Strength and Difficulties Questionnaire (SDQ). Forty-six parents completed the questionnaire at all 4 time points tested.
The results showed that 4 days of dexamethasone treatment significantly increased patient problems, as reported by all SDQ scales and subscales. However, one-third of the population did not have any increase in SDQ total difficulties with dexamethasone.
The addition of hydrocortisone did not affect patients’ total difficulties score (mean difference, -0.8 ± 5.5; P=0.33), emotional symptoms (mean difference, -0.6 ± 2.3; P=0.08), conduct problems (mean difference, 0.0 ± 1.5; P=1.00), or other SDQ subscales.
However, hydrocortisone did have a clinically significant effect in the subset of 16 patients who had clinically relevant dexamethasone-related AEs. This was defined as an increase of ≥5 in their SDQ total difficulties score.
In these patients, hydrocortisone improved the total difficulties delta-score (median difference, -5.0; IQR, -7.8 to -3.0), emotional symptoms score (median difference, -1.5; IQR, -4.0 to -1.0), conduct problems score (median difference, -1.0; IQR, -2.0 to 0.0), and impact of stress score (median difference, -1.0; IQR, -2.0 to 0.0).
Sleep issues
The researchers used the Sleep Disturbance Scale for Children (SDSC) to assess sleep quality and sleep disturbances. Forty-seven parents completed the questionnaire at all 4 time points tested.
Results showed that dexamethasone significantly increased disorders of arousal (P=0.04), sleep-wake transition disorders (P=0.01), and disorders of excessive somnolence (P=0.01).
The addition of hydrocortisone had no significant effect on patients’ total SDSC score (P=0.84), disorders of initiating and maintaining sleep (P=0.74), disorders of excessive somnolence (P=0.29), or sleep-wake transition disorder (P=0.29).
However, hydrocortisone did have a clinically significant effect in the subset of 9 children who had clinically relevant dexamethasone-induced sleeping problems, which were defined as a change of ≥7 in SDSC total score.
Hydrocortisone reduced SDSC total scores (median difference, -11.0; IQR, -16.0 to 0.0) and disorders of initiating and maintaining sleep scores (median difference, -3.0; IQR, -7.0 to –0.5).
Other outcomes
The researchers also found that dexamethasone treatment alone did not affect patients’ attention, visual-spatial functions, memory, or processing speed.
However, the addition of hydrocortisone significantly improved patients’ long-term visual memory (P=0.01).
Hydrocortisone did not have any effect on other neuropsychological tests or on metabolic parameters.
Study reveals potential treatment avenue for DBA, MDS
The production of two components of hemoglobin may be out of sync in Diamond Blackfan anemia (DBA) and myelodysplastic syndromes (MDS), according to a new study.
Researchers found that, in samples from patients with DBA or MDS, ribosome dysfunction delayed globin production, while heme synthesis proceeded normally.
This disruption in heme-globin coordination led to a buildup of toxic heme that killed red blood cell (RBC) precursors.
However, treating patient samples with a compound that blocks heme synthesis increased RBC production in both DBA and MDS.
Zhantao Yang, MD, of the University of Washington in Seattle, and his colleagues reported these findings in Science Translational Medicine.
Both DBA and MDS have been linked to defects in ribosome assembly, which is critical to protein production, but how this leads to anemia remains unknown.
To find out, Dr Yang and his colleagues analyzed bone marrow cells from patients with DBA (n=3) or MDS with del(5q) (n=6).
The researchers found that globin translation proceeded slowly in these samples, but heme synthesis proceeded normally.
This resulted in insufficient globin, excess heme, and excess reactive oxygen species in early erythroid precursors and, ultimately, the death of colony-forming unit–erythroid/proerythroblast cells.
The cells that were able to rapidly export heme or slow its synthesis survived and matured into RBCs, but the other colony-forming unit–erythroid cells/early proerythroblasts died.
The researchers noted that it is not clear how excess heme induces cell death in RBC precursors, but they said it likely involves both ferroptosis and apoptosis.
Regardless of the mechanism of cell death, the team found that treating the patients’ cells with succinylacetone (10 mM), a compound that blocks heme synthesis, improved RBC production.
The treatment improved RBC production in DBA and del(5q) MDS marrow cultures by 68% to 95% (P=0.03 to 0.05). In comparison, RBC production in control marrow cultures decreased by 4% to 13%.
The researchers said their experiments revealed additional important findings. First, they found that erythroid differentiation in the marrow cultures “excellently” phenocopied erythroid differentiation in vivo. This suggests these cultures can serve as a reliable platform in preclinical studies.
Second, the team said the fact that epigenetic differences between RBC precursors can lead to their preferential death or survival has broad implications. And querying the cells that preferentially survive could provide important insights.
The production of two components of hemoglobin may be out of sync in Diamond Blackfan anemia (DBA) and myelodysplastic syndromes (MDS), according to a new study.
Researchers found that, in samples from patients with DBA or MDS, ribosome dysfunction delayed globin production, while heme synthesis proceeded normally.
This disruption in heme-globin coordination led to a buildup of toxic heme that killed red blood cell (RBC) precursors.
However, treating patient samples with a compound that blocks heme synthesis increased RBC production in both DBA and MDS.
Zhantao Yang, MD, of the University of Washington in Seattle, and his colleagues reported these findings in Science Translational Medicine.
Both DBA and MDS have been linked to defects in ribosome assembly, which is critical to protein production, but how this leads to anemia remains unknown.
To find out, Dr Yang and his colleagues analyzed bone marrow cells from patients with DBA (n=3) or MDS with del(5q) (n=6).
The researchers found that globin translation proceeded slowly in these samples, but heme synthesis proceeded normally.
This resulted in insufficient globin, excess heme, and excess reactive oxygen species in early erythroid precursors and, ultimately, the death of colony-forming unit–erythroid/proerythroblast cells.
The cells that were able to rapidly export heme or slow its synthesis survived and matured into RBCs, but the other colony-forming unit–erythroid cells/early proerythroblasts died.
The researchers noted that it is not clear how excess heme induces cell death in RBC precursors, but they said it likely involves both ferroptosis and apoptosis.
Regardless of the mechanism of cell death, the team found that treating the patients’ cells with succinylacetone (10 mM), a compound that blocks heme synthesis, improved RBC production.
The treatment improved RBC production in DBA and del(5q) MDS marrow cultures by 68% to 95% (P=0.03 to 0.05). In comparison, RBC production in control marrow cultures decreased by 4% to 13%.
The researchers said their experiments revealed additional important findings. First, they found that erythroid differentiation in the marrow cultures “excellently” phenocopied erythroid differentiation in vivo. This suggests these cultures can serve as a reliable platform in preclinical studies.
Second, the team said the fact that epigenetic differences between RBC precursors can lead to their preferential death or survival has broad implications. And querying the cells that preferentially survive could provide important insights.
The production of two components of hemoglobin may be out of sync in Diamond Blackfan anemia (DBA) and myelodysplastic syndromes (MDS), according to a new study.
Researchers found that, in samples from patients with DBA or MDS, ribosome dysfunction delayed globin production, while heme synthesis proceeded normally.
This disruption in heme-globin coordination led to a buildup of toxic heme that killed red blood cell (RBC) precursors.
However, treating patient samples with a compound that blocks heme synthesis increased RBC production in both DBA and MDS.
Zhantao Yang, MD, of the University of Washington in Seattle, and his colleagues reported these findings in Science Translational Medicine.
Both DBA and MDS have been linked to defects in ribosome assembly, which is critical to protein production, but how this leads to anemia remains unknown.
To find out, Dr Yang and his colleagues analyzed bone marrow cells from patients with DBA (n=3) or MDS with del(5q) (n=6).
The researchers found that globin translation proceeded slowly in these samples, but heme synthesis proceeded normally.
This resulted in insufficient globin, excess heme, and excess reactive oxygen species in early erythroid precursors and, ultimately, the death of colony-forming unit–erythroid/proerythroblast cells.
The cells that were able to rapidly export heme or slow its synthesis survived and matured into RBCs, but the other colony-forming unit–erythroid cells/early proerythroblasts died.
The researchers noted that it is not clear how excess heme induces cell death in RBC precursors, but they said it likely involves both ferroptosis and apoptosis.
Regardless of the mechanism of cell death, the team found that treating the patients’ cells with succinylacetone (10 mM), a compound that blocks heme synthesis, improved RBC production.
The treatment improved RBC production in DBA and del(5q) MDS marrow cultures by 68% to 95% (P=0.03 to 0.05). In comparison, RBC production in control marrow cultures decreased by 4% to 13%.
The researchers said their experiments revealed additional important findings. First, they found that erythroid differentiation in the marrow cultures “excellently” phenocopied erythroid differentiation in vivo. This suggests these cultures can serve as a reliable platform in preclinical studies.
Second, the team said the fact that epigenetic differences between RBC precursors can lead to their preferential death or survival has broad implications. And querying the cells that preferentially survive could provide important insights.
CAR T-cell start-up launched
Dr. Siddhartha Mukherjee has partnered with Puretech Health to launch a new biotechnology and immuno-oncology company to broaden the use of chimeric antigen receptor (CAR) T-cell therapy. Dr. Mukherjee, a Columbia University researcher, hematologist, oncologist, and Pulitzer Prize–winning author of “The Emperor of All Maladies: A Biography of Cancer,” (New York: Scribner, a division of Simon & Schuster, 2011) is licensing his CAR T-cell technology to the joint venture, called Vor BioPharma.
Vor BioPharma will focus on advancing and expanding CAR T-cell therapy, a relatively new cancer treatment where T cells are first collected from a patient’s blood and then genetically engineered to produce CAR proteins on their surface. The CAR proteins are designed to bind specific antigens found on the patient’s cancer cells. These genetically engineered T cells are grown in a laboratory and then infused into the patient. As of now, CAR T-cell therapy is primarily used to treat B-cell leukemias and other chronic lymphocytic leukemia.
“We continue to make great strides in developing new ways to treat cancer using the body’s immune system,” said Dr. Mukherjee in a written statement announcing the partnership. “The positive clinical response researchers have achieved with CAR T-cell therapies in B-cell leukemias has led to great interest within the oncology community and is something we hope to achieve in other cancers over time,” he said.
“CAR T-cell therapies have shown remarkable progress in the clinic, yet their applicability beyond a small subset of cancers is currently very limited,” said Dr. Sanjiv Sam Gambhir of Stanford University and a member of the Vor Scientific Advisory Board. “This technology seeks to address bottlenecks that prevent CAR T-cell therapy from becoming more broadly useful in treating cancers outside of B-cell cancers.”
Other Vor BioPharma employees and Scientific Advisory Board members include Dr. Joseph Bolen, former President and Chief Scientific Officer of Moderna Therapeutics; Dr. Dan Littman of the Howard Hughes Medical Institute; and Dr. Derrick Rossi of Harvard University.
On Twitter @jess_craig94
Dr. Siddhartha Mukherjee has partnered with Puretech Health to launch a new biotechnology and immuno-oncology company to broaden the use of chimeric antigen receptor (CAR) T-cell therapy. Dr. Mukherjee, a Columbia University researcher, hematologist, oncologist, and Pulitzer Prize–winning author of “The Emperor of All Maladies: A Biography of Cancer,” (New York: Scribner, a division of Simon & Schuster, 2011) is licensing his CAR T-cell technology to the joint venture, called Vor BioPharma.
Vor BioPharma will focus on advancing and expanding CAR T-cell therapy, a relatively new cancer treatment where T cells are first collected from a patient’s blood and then genetically engineered to produce CAR proteins on their surface. The CAR proteins are designed to bind specific antigens found on the patient’s cancer cells. These genetically engineered T cells are grown in a laboratory and then infused into the patient. As of now, CAR T-cell therapy is primarily used to treat B-cell leukemias and other chronic lymphocytic leukemia.
“We continue to make great strides in developing new ways to treat cancer using the body’s immune system,” said Dr. Mukherjee in a written statement announcing the partnership. “The positive clinical response researchers have achieved with CAR T-cell therapies in B-cell leukemias has led to great interest within the oncology community and is something we hope to achieve in other cancers over time,” he said.
“CAR T-cell therapies have shown remarkable progress in the clinic, yet their applicability beyond a small subset of cancers is currently very limited,” said Dr. Sanjiv Sam Gambhir of Stanford University and a member of the Vor Scientific Advisory Board. “This technology seeks to address bottlenecks that prevent CAR T-cell therapy from becoming more broadly useful in treating cancers outside of B-cell cancers.”
Other Vor BioPharma employees and Scientific Advisory Board members include Dr. Joseph Bolen, former President and Chief Scientific Officer of Moderna Therapeutics; Dr. Dan Littman of the Howard Hughes Medical Institute; and Dr. Derrick Rossi of Harvard University.
On Twitter @jess_craig94
Dr. Siddhartha Mukherjee has partnered with Puretech Health to launch a new biotechnology and immuno-oncology company to broaden the use of chimeric antigen receptor (CAR) T-cell therapy. Dr. Mukherjee, a Columbia University researcher, hematologist, oncologist, and Pulitzer Prize–winning author of “The Emperor of All Maladies: A Biography of Cancer,” (New York: Scribner, a division of Simon & Schuster, 2011) is licensing his CAR T-cell technology to the joint venture, called Vor BioPharma.
Vor BioPharma will focus on advancing and expanding CAR T-cell therapy, a relatively new cancer treatment where T cells are first collected from a patient’s blood and then genetically engineered to produce CAR proteins on their surface. The CAR proteins are designed to bind specific antigens found on the patient’s cancer cells. These genetically engineered T cells are grown in a laboratory and then infused into the patient. As of now, CAR T-cell therapy is primarily used to treat B-cell leukemias and other chronic lymphocytic leukemia.
“We continue to make great strides in developing new ways to treat cancer using the body’s immune system,” said Dr. Mukherjee in a written statement announcing the partnership. “The positive clinical response researchers have achieved with CAR T-cell therapies in B-cell leukemias has led to great interest within the oncology community and is something we hope to achieve in other cancers over time,” he said.
“CAR T-cell therapies have shown remarkable progress in the clinic, yet their applicability beyond a small subset of cancers is currently very limited,” said Dr. Sanjiv Sam Gambhir of Stanford University and a member of the Vor Scientific Advisory Board. “This technology seeks to address bottlenecks that prevent CAR T-cell therapy from becoming more broadly useful in treating cancers outside of B-cell cancers.”
Other Vor BioPharma employees and Scientific Advisory Board members include Dr. Joseph Bolen, former President and Chief Scientific Officer of Moderna Therapeutics; Dr. Dan Littman of the Howard Hughes Medical Institute; and Dr. Derrick Rossi of Harvard University.
On Twitter @jess_craig94
Company warns of counterfeit drug
Photo by Bill Branson
Heritage Pharmaceuticals Inc., has announced the existence of a counterfeit drug product labeled as BiCNU® (carmustine for injection) 100 mg.
The company said that, to the best of its knowledge, the counterfeit product has only been distributed in India, Ireland, and Israel.
However, Heritage is consulting with the US Food and Drug Administration (FDA) to aid the agency’s evaluations of this product, assist with determining the source of the counterfeit drug, and prevent the further distribution of this product or its introduction into the US.
BiCNU® is primarily used for chemotherapy in the treatment of lymphomas, multiple myeloma, and brain cancers. But the drug is also used for immunosuppression before organ transplant or hematopoietic stem cell transplant.
Heritage said it has directly notified all customers and provided detailed information that will help them identify a counterfeit BiCNU® product. Customers have been instructed to examine their inventory immediately and to quarantine, discontinue distribution of, and return any suspected counterfeit product.
Any customers who may have recently distributed the BiCNU® products to their own customers have been asked to convey this information to their customers so they will be able to carefully examine all BiCNU® products before use and identify the characteristics of a suspected counterfeit product.
Any end users who believe they may have received a counterfeit drug should return the product to the pharmacy that dispensed the medicine.
Any US health practitioners who determine they are in possession of a counterfeit product should contact the FDA through MedWatch. Instructions for such reporting are available on the FDA website.
Anyone with questions about the counterfeit product should contact the Heritage customer call center directly at (866) 901-3784, which is open Monday through Friday, from 9 am to 5 pm EST.
Photo by Bill Branson
Heritage Pharmaceuticals Inc., has announced the existence of a counterfeit drug product labeled as BiCNU® (carmustine for injection) 100 mg.
The company said that, to the best of its knowledge, the counterfeit product has only been distributed in India, Ireland, and Israel.
However, Heritage is consulting with the US Food and Drug Administration (FDA) to aid the agency’s evaluations of this product, assist with determining the source of the counterfeit drug, and prevent the further distribution of this product or its introduction into the US.
BiCNU® is primarily used for chemotherapy in the treatment of lymphomas, multiple myeloma, and brain cancers. But the drug is also used for immunosuppression before organ transplant or hematopoietic stem cell transplant.
Heritage said it has directly notified all customers and provided detailed information that will help them identify a counterfeit BiCNU® product. Customers have been instructed to examine their inventory immediately and to quarantine, discontinue distribution of, and return any suspected counterfeit product.
Any customers who may have recently distributed the BiCNU® products to their own customers have been asked to convey this information to their customers so they will be able to carefully examine all BiCNU® products before use and identify the characteristics of a suspected counterfeit product.
Any end users who believe they may have received a counterfeit drug should return the product to the pharmacy that dispensed the medicine.
Any US health practitioners who determine they are in possession of a counterfeit product should contact the FDA through MedWatch. Instructions for such reporting are available on the FDA website.
Anyone with questions about the counterfeit product should contact the Heritage customer call center directly at (866) 901-3784, which is open Monday through Friday, from 9 am to 5 pm EST.
Photo by Bill Branson
Heritage Pharmaceuticals Inc., has announced the existence of a counterfeit drug product labeled as BiCNU® (carmustine for injection) 100 mg.
The company said that, to the best of its knowledge, the counterfeit product has only been distributed in India, Ireland, and Israel.
However, Heritage is consulting with the US Food and Drug Administration (FDA) to aid the agency’s evaluations of this product, assist with determining the source of the counterfeit drug, and prevent the further distribution of this product or its introduction into the US.
BiCNU® is primarily used for chemotherapy in the treatment of lymphomas, multiple myeloma, and brain cancers. But the drug is also used for immunosuppression before organ transplant or hematopoietic stem cell transplant.
Heritage said it has directly notified all customers and provided detailed information that will help them identify a counterfeit BiCNU® product. Customers have been instructed to examine their inventory immediately and to quarantine, discontinue distribution of, and return any suspected counterfeit product.
Any customers who may have recently distributed the BiCNU® products to their own customers have been asked to convey this information to their customers so they will be able to carefully examine all BiCNU® products before use and identify the characteristics of a suspected counterfeit product.
Any end users who believe they may have received a counterfeit drug should return the product to the pharmacy that dispensed the medicine.
Any US health practitioners who determine they are in possession of a counterfeit product should contact the FDA through MedWatch. Instructions for such reporting are available on the FDA website.
Anyone with questions about the counterfeit product should contact the Heritage customer call center directly at (866) 901-3784, which is open Monday through Friday, from 9 am to 5 pm EST.
Tools may aid transition from pediatric to adult care
Photo courtesy of the CDC
WASHINGTON, DC—The American Society of Hematology (ASH) has created a toolkit to help hematologists aid patients who are transitioning from pediatric to adult practices.
The toolkit contains general resources for all hematologic conditions, as well as specific resources for patients with hemophilia and sickle cell disease.
It includes 2 types of forms—a transition-readiness assessment and a clinical summary.
The toolkit was presented at the American College of Physicians (ACP) Internal Medicine Meeting 2016.
“Transitioning from pediatric to adult healthcare practices is often a challenge for patients with chronic medical issues because it can be difficult to adhere to a treatment regimen or attend regular appointments without the assistance of a parent or guardian,” said ASH President Charles S. Abrams, MD, of the University of Pennsylvania in Philadelphia.
“ASH recognizes that understanding a patient’s preparedness to take control of his or her medical condition in adulthood can make a huge difference in quality of care, which is why we are pleased to join the American College of Physicians and partner societies in this important initiative.”
ASH joined more than 2 dozen groups to participate in the ACP’s Pediatric to Adult Care Transition Initiative. The goal of this initiative was to develop guidance and tools that both primary care internal medicine and subspecialty practices can use for patients who are transitioning from pediatric/adolescent practices to adult care.
An ASH Transitions Work Group, made up of society members from pediatric and adult practices, developed 3 segments of the hematology-specific toolkit:
- generic forms for patients with any hematologic condition, with an addendum that includes links to additional condition-specific guidelines and resources
- specific forms for hemophilia
- specific forms for sickle cell disease.
For each segment, there are 2 types of forms— a transition-readiness assessment and a clinical summary.
The transition-readiness assessment should be completed by the patient. It assesses the patient’s readiness for the transition to adult care by evaluating the patient’s understanding of his or her condition and ability to manage medications, appointments, insurance, and medical privacy issues.
This assessment should be used by the adult care team to assess any remaining gaps in the patient’s self-care knowledge or additional issues that should be addressed to ensure optimal care.
The clinical summary is a medical record summary to be completed by the referring provider and the patient. The summary contains essential clinical information regarding the patient’s condition that is to be included in the patient’s medical record upon transfer to the adult practice.
More information on the ACP Pediatric to Adult Care Transitions Initiative is available on the ACP website. The forms for the ASH transitions toolkit are available in the “Hematology” section of the Condition-Specific Tools page.
Photo courtesy of the CDC
WASHINGTON, DC—The American Society of Hematology (ASH) has created a toolkit to help hematologists aid patients who are transitioning from pediatric to adult practices.
The toolkit contains general resources for all hematologic conditions, as well as specific resources for patients with hemophilia and sickle cell disease.
It includes 2 types of forms—a transition-readiness assessment and a clinical summary.
The toolkit was presented at the American College of Physicians (ACP) Internal Medicine Meeting 2016.
“Transitioning from pediatric to adult healthcare practices is often a challenge for patients with chronic medical issues because it can be difficult to adhere to a treatment regimen or attend regular appointments without the assistance of a parent or guardian,” said ASH President Charles S. Abrams, MD, of the University of Pennsylvania in Philadelphia.
“ASH recognizes that understanding a patient’s preparedness to take control of his or her medical condition in adulthood can make a huge difference in quality of care, which is why we are pleased to join the American College of Physicians and partner societies in this important initiative.”
ASH joined more than 2 dozen groups to participate in the ACP’s Pediatric to Adult Care Transition Initiative. The goal of this initiative was to develop guidance and tools that both primary care internal medicine and subspecialty practices can use for patients who are transitioning from pediatric/adolescent practices to adult care.
An ASH Transitions Work Group, made up of society members from pediatric and adult practices, developed 3 segments of the hematology-specific toolkit:
- generic forms for patients with any hematologic condition, with an addendum that includes links to additional condition-specific guidelines and resources
- specific forms for hemophilia
- specific forms for sickle cell disease.
For each segment, there are 2 types of forms— a transition-readiness assessment and a clinical summary.
The transition-readiness assessment should be completed by the patient. It assesses the patient’s readiness for the transition to adult care by evaluating the patient’s understanding of his or her condition and ability to manage medications, appointments, insurance, and medical privacy issues.
This assessment should be used by the adult care team to assess any remaining gaps in the patient’s self-care knowledge or additional issues that should be addressed to ensure optimal care.
The clinical summary is a medical record summary to be completed by the referring provider and the patient. The summary contains essential clinical information regarding the patient’s condition that is to be included in the patient’s medical record upon transfer to the adult practice.
More information on the ACP Pediatric to Adult Care Transitions Initiative is available on the ACP website. The forms for the ASH transitions toolkit are available in the “Hematology” section of the Condition-Specific Tools page.
Photo courtesy of the CDC
WASHINGTON, DC—The American Society of Hematology (ASH) has created a toolkit to help hematologists aid patients who are transitioning from pediatric to adult practices.
The toolkit contains general resources for all hematologic conditions, as well as specific resources for patients with hemophilia and sickle cell disease.
It includes 2 types of forms—a transition-readiness assessment and a clinical summary.
The toolkit was presented at the American College of Physicians (ACP) Internal Medicine Meeting 2016.
“Transitioning from pediatric to adult healthcare practices is often a challenge for patients with chronic medical issues because it can be difficult to adhere to a treatment regimen or attend regular appointments without the assistance of a parent or guardian,” said ASH President Charles S. Abrams, MD, of the University of Pennsylvania in Philadelphia.
“ASH recognizes that understanding a patient’s preparedness to take control of his or her medical condition in adulthood can make a huge difference in quality of care, which is why we are pleased to join the American College of Physicians and partner societies in this important initiative.”
ASH joined more than 2 dozen groups to participate in the ACP’s Pediatric to Adult Care Transition Initiative. The goal of this initiative was to develop guidance and tools that both primary care internal medicine and subspecialty practices can use for patients who are transitioning from pediatric/adolescent practices to adult care.
An ASH Transitions Work Group, made up of society members from pediatric and adult practices, developed 3 segments of the hematology-specific toolkit:
- generic forms for patients with any hematologic condition, with an addendum that includes links to additional condition-specific guidelines and resources
- specific forms for hemophilia
- specific forms for sickle cell disease.
For each segment, there are 2 types of forms— a transition-readiness assessment and a clinical summary.
The transition-readiness assessment should be completed by the patient. It assesses the patient’s readiness for the transition to adult care by evaluating the patient’s understanding of his or her condition and ability to manage medications, appointments, insurance, and medical privacy issues.
This assessment should be used by the adult care team to assess any remaining gaps in the patient’s self-care knowledge or additional issues that should be addressed to ensure optimal care.
The clinical summary is a medical record summary to be completed by the referring provider and the patient. The summary contains essential clinical information regarding the patient’s condition that is to be included in the patient’s medical record upon transfer to the adult practice.
More information on the ACP Pediatric to Adult Care Transitions Initiative is available on the ACP website. The forms for the ASH transitions toolkit are available in the “Hematology” section of the Condition-Specific Tools page.
FDA grants priority review for blinatumomab
and solution for infusion
Photo courtesy of Amgen
The US Food and Drug Administration (FDA) has accepted for priority review the supplemental biologics license application for blinatumomab (Blincyto) as a treatment for pediatric and adolescent patients with Philadelphia chromosome negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
To grant an application priority review, the FDA must believe the drug would provide a significant improvement in the treatment, diagnosis, or prevention of a serious condition.
The priority review designation means the FDA’s goal is to take action on an application within 6 months, rather than the 10 months typically taken for a standard review.
The Prescription Drug User Fee Act target action date for the supplemental biologics license application for blinatumomab is September 1, 2016.
About blinatumomab
Blinatumomab is a bispecific, CD19-directed, CD3 T-cell engager (BiTE®) antibody construct that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.
Blinatumomab was previously granted breakthrough therapy and priority review designations by the FDA and is now approved in the US for the treatment of adults with Ph- relapsed or refractory B-cell precursor ALL.
This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials.
Blinatumomab is marketed by Amgen as Blincyto. The full US prescribing information is available at www.BLINCYTO.com.
‘205 trial
The supplemental biologics license application for blinatumomab in pediatric and adolescent patients is based on data from the phase 1/2 '205 trial.
In this study, researchers evaluated blinatumomab in patients younger than 18 years of age. The patients had B-cell precursor ALL that was refractory, had relapsed at least twice, or relapsed after an allogeneic hematopoietic stem cell transplant.
Treatment in this study has been completed, and subjects are being monitored for long-term efficacy. The data is being submitted for publication.
Preliminary data were presented at the 2014 ASH Annual Meeting (abstract 3703).
and solution for infusion
Photo courtesy of Amgen
The US Food and Drug Administration (FDA) has accepted for priority review the supplemental biologics license application for blinatumomab (Blincyto) as a treatment for pediatric and adolescent patients with Philadelphia chromosome negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
To grant an application priority review, the FDA must believe the drug would provide a significant improvement in the treatment, diagnosis, or prevention of a serious condition.
The priority review designation means the FDA’s goal is to take action on an application within 6 months, rather than the 10 months typically taken for a standard review.
The Prescription Drug User Fee Act target action date for the supplemental biologics license application for blinatumomab is September 1, 2016.
About blinatumomab
Blinatumomab is a bispecific, CD19-directed, CD3 T-cell engager (BiTE®) antibody construct that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.
Blinatumomab was previously granted breakthrough therapy and priority review designations by the FDA and is now approved in the US for the treatment of adults with Ph- relapsed or refractory B-cell precursor ALL.
This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials.
Blinatumomab is marketed by Amgen as Blincyto. The full US prescribing information is available at www.BLINCYTO.com.
‘205 trial
The supplemental biologics license application for blinatumomab in pediatric and adolescent patients is based on data from the phase 1/2 '205 trial.
In this study, researchers evaluated blinatumomab in patients younger than 18 years of age. The patients had B-cell precursor ALL that was refractory, had relapsed at least twice, or relapsed after an allogeneic hematopoietic stem cell transplant.
Treatment in this study has been completed, and subjects are being monitored for long-term efficacy. The data is being submitted for publication.
Preliminary data were presented at the 2014 ASH Annual Meeting (abstract 3703).
and solution for infusion
Photo courtesy of Amgen
The US Food and Drug Administration (FDA) has accepted for priority review the supplemental biologics license application for blinatumomab (Blincyto) as a treatment for pediatric and adolescent patients with Philadelphia chromosome negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
To grant an application priority review, the FDA must believe the drug would provide a significant improvement in the treatment, diagnosis, or prevention of a serious condition.
The priority review designation means the FDA’s goal is to take action on an application within 6 months, rather than the 10 months typically taken for a standard review.
The Prescription Drug User Fee Act target action date for the supplemental biologics license application for blinatumomab is September 1, 2016.
About blinatumomab
Blinatumomab is a bispecific, CD19-directed, CD3 T-cell engager (BiTE®) antibody construct that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.
Blinatumomab was previously granted breakthrough therapy and priority review designations by the FDA and is now approved in the US for the treatment of adults with Ph- relapsed or refractory B-cell precursor ALL.
This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials.
Blinatumomab is marketed by Amgen as Blincyto. The full US prescribing information is available at www.BLINCYTO.com.
‘205 trial
The supplemental biologics license application for blinatumomab in pediatric and adolescent patients is based on data from the phase 1/2 '205 trial.
In this study, researchers evaluated blinatumomab in patients younger than 18 years of age. The patients had B-cell precursor ALL that was refractory, had relapsed at least twice, or relapsed after an allogeneic hematopoietic stem cell transplant.
Treatment in this study has been completed, and subjects are being monitored for long-term efficacy. The data is being submitted for publication.
Preliminary data were presented at the 2014 ASH Annual Meeting (abstract 3703).
Drug produces similar results in older and younger ALL patients
Photo from MD Anderson
Data from two phase 2 studies suggests single-agent blinatumomab produces similar outcomes in adults with relapsed/refractory acute lymphoblastic leukemia (ALL), regardless of age.
Patients age 65 and older had similar hematologic response rates and relapse-free survival rates as patients younger than 65.
The incidence of grade 3 or higher adverse events (AEs) was similar between the age groups as well.
Older patients did have more serious AEs, however. And they had more neurologic events, but these were reversible.
Hagop M. Kantarjian, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues reported these results in Cancer. The research was funded by Amgen Inc., makers of blinatumomab.
Patients
The researchers examined 261 adults with relapsed/refractory ALL who were enrolled in 2 different studies. There were 36 patients who were 65 or older and 225 patients who were younger than 65. The median ages were 70 (range, 65-79) and 34 (range, 18-64), respectively.
Among the older patients, 14% had primary refractory disease, 67% had 1 prior relapse, 14% had 2 prior relapses, and 6% had 3 or more. Among the younger patients, 9% had primary refractory disease, 55% had 1 prior relapse, 26% had 2 prior relapses, and 10% had 3 or more.
The younger patients were more likely to have received an allogeneic hematopoietic stem cell transplant (allo-HSCT) than the older patients—37% and 11%, respectively.
But older patients were more likely to have mild renal impairment (42% vs 13%) or moderate renal impairment (22% vs 1%).
Treatment
All patients received blinatumomab, and stepwise dosing was used to reduce the risk of cytokine release syndrome. A treatment cycle consisted of 4 weeks of continuous intravenous infusions, followed by a 2-week treatment-free interval.
The patients received 2 initial cycles. If they achieved a complete remission (CR) or CR with partial hematologic recovery (CRh) at this point, they could receive an additional 3 cycles as consolidation, unless they were scheduled to receive an allo-HSCT.
Patients also received intrathecal prophylaxis with dexamethasone and/or steroids, cytarabine, and methotrexate. And patients with a high blast percentage at baseline received a pre-phase treatment with dexamethasone and/or cyclophosphamide.
Older patients received a median of 2 cycles of blinatumomab (range, 1-6), as did the younger patients (range, 1-7).
Response and survival
Fifty-six percent of the older patients (20/36) achieved a CR/CRh during the first 2 cycles of blinatumomab, as did 46% of the younger patients (46/225). There were 14 CRs among the older patients (39%) and 78 CRs among the younger patients (35%).
There were 12 complete minimal residual disease responses among older patients (60% of responders) and 73 among the younger patients (70% of responders).
Of the responders, 3 older patients (15%) and 61 younger patients (59%) went on to allo-HSCT. Most of the patients received a transplant while in remission. However, 1 of the older patients and 8 of the younger patients went to transplant after an initial response to blinatumomab that was followed by a relapse.
The median relapse-free survival was 7.4 months for both age groups. The median overall survival was 5.5 months for older patients and 7.6 months for younger patients.
Safety
All of the older patients had at least 1 AE, and all but 1 of the younger patients had at least 1 AE. Older patients had higher rates of peripheral edema (42% vs 24%), fatigue (28% vs 18%), and dizziness (25% vs 11%) of any grade.
The incidence of grade 3 or higher AEs was similar between the groups—86% in the older group and 80% in the younger group. The same was true for AEs leading to treatment discontinuation—22% and 19%, respectively.
However, there was a higher incidence of serious AEs in the older patients (72% vs 64%). Device-related infection and encephalopathy were more common among older patients than younger patients (both 11% vs 3%).
The incidence of cytokine release syndrome was higher in the older group than the younger group—19% and 10%, respectively.
Older patients also had more neurologic events of any grade (72% vs 48%) and more grade 3 or higher neurologic events (28% vs 13%). However, all neurologic events were reversed by temporarily or permanently discontinuing blinatumomab.
There were 7 fatal treatment-emergent AEs in the older adults, including pneumonia (n=3), B-cell lymphoma (n=1), and disease progression (n=3). None of the fatal AEs were considered treatment-related. And none of the patients who were in remission died during treatment with blinatumomab.
Photo from MD Anderson
Data from two phase 2 studies suggests single-agent blinatumomab produces similar outcomes in adults with relapsed/refractory acute lymphoblastic leukemia (ALL), regardless of age.
Patients age 65 and older had similar hematologic response rates and relapse-free survival rates as patients younger than 65.
The incidence of grade 3 or higher adverse events (AEs) was similar between the age groups as well.
Older patients did have more serious AEs, however. And they had more neurologic events, but these were reversible.
Hagop M. Kantarjian, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues reported these results in Cancer. The research was funded by Amgen Inc., makers of blinatumomab.
Patients
The researchers examined 261 adults with relapsed/refractory ALL who were enrolled in 2 different studies. There were 36 patients who were 65 or older and 225 patients who were younger than 65. The median ages were 70 (range, 65-79) and 34 (range, 18-64), respectively.
Among the older patients, 14% had primary refractory disease, 67% had 1 prior relapse, 14% had 2 prior relapses, and 6% had 3 or more. Among the younger patients, 9% had primary refractory disease, 55% had 1 prior relapse, 26% had 2 prior relapses, and 10% had 3 or more.
The younger patients were more likely to have received an allogeneic hematopoietic stem cell transplant (allo-HSCT) than the older patients—37% and 11%, respectively.
But older patients were more likely to have mild renal impairment (42% vs 13%) or moderate renal impairment (22% vs 1%).
Treatment
All patients received blinatumomab, and stepwise dosing was used to reduce the risk of cytokine release syndrome. A treatment cycle consisted of 4 weeks of continuous intravenous infusions, followed by a 2-week treatment-free interval.
The patients received 2 initial cycles. If they achieved a complete remission (CR) or CR with partial hematologic recovery (CRh) at this point, they could receive an additional 3 cycles as consolidation, unless they were scheduled to receive an allo-HSCT.
Patients also received intrathecal prophylaxis with dexamethasone and/or steroids, cytarabine, and methotrexate. And patients with a high blast percentage at baseline received a pre-phase treatment with dexamethasone and/or cyclophosphamide.
Older patients received a median of 2 cycles of blinatumomab (range, 1-6), as did the younger patients (range, 1-7).
Response and survival
Fifty-six percent of the older patients (20/36) achieved a CR/CRh during the first 2 cycles of blinatumomab, as did 46% of the younger patients (46/225). There were 14 CRs among the older patients (39%) and 78 CRs among the younger patients (35%).
There were 12 complete minimal residual disease responses among older patients (60% of responders) and 73 among the younger patients (70% of responders).
Of the responders, 3 older patients (15%) and 61 younger patients (59%) went on to allo-HSCT. Most of the patients received a transplant while in remission. However, 1 of the older patients and 8 of the younger patients went to transplant after an initial response to blinatumomab that was followed by a relapse.
The median relapse-free survival was 7.4 months for both age groups. The median overall survival was 5.5 months for older patients and 7.6 months for younger patients.
Safety
All of the older patients had at least 1 AE, and all but 1 of the younger patients had at least 1 AE. Older patients had higher rates of peripheral edema (42% vs 24%), fatigue (28% vs 18%), and dizziness (25% vs 11%) of any grade.
The incidence of grade 3 or higher AEs was similar between the groups—86% in the older group and 80% in the younger group. The same was true for AEs leading to treatment discontinuation—22% and 19%, respectively.
However, there was a higher incidence of serious AEs in the older patients (72% vs 64%). Device-related infection and encephalopathy were more common among older patients than younger patients (both 11% vs 3%).
The incidence of cytokine release syndrome was higher in the older group than the younger group—19% and 10%, respectively.
Older patients also had more neurologic events of any grade (72% vs 48%) and more grade 3 or higher neurologic events (28% vs 13%). However, all neurologic events were reversed by temporarily or permanently discontinuing blinatumomab.
There were 7 fatal treatment-emergent AEs in the older adults, including pneumonia (n=3), B-cell lymphoma (n=1), and disease progression (n=3). None of the fatal AEs were considered treatment-related. And none of the patients who were in remission died during treatment with blinatumomab.
Photo from MD Anderson
Data from two phase 2 studies suggests single-agent blinatumomab produces similar outcomes in adults with relapsed/refractory acute lymphoblastic leukemia (ALL), regardless of age.
Patients age 65 and older had similar hematologic response rates and relapse-free survival rates as patients younger than 65.
The incidence of grade 3 or higher adverse events (AEs) was similar between the age groups as well.
Older patients did have more serious AEs, however. And they had more neurologic events, but these were reversible.
Hagop M. Kantarjian, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues reported these results in Cancer. The research was funded by Amgen Inc., makers of blinatumomab.
Patients
The researchers examined 261 adults with relapsed/refractory ALL who were enrolled in 2 different studies. There were 36 patients who were 65 or older and 225 patients who were younger than 65. The median ages were 70 (range, 65-79) and 34 (range, 18-64), respectively.
Among the older patients, 14% had primary refractory disease, 67% had 1 prior relapse, 14% had 2 prior relapses, and 6% had 3 or more. Among the younger patients, 9% had primary refractory disease, 55% had 1 prior relapse, 26% had 2 prior relapses, and 10% had 3 or more.
The younger patients were more likely to have received an allogeneic hematopoietic stem cell transplant (allo-HSCT) than the older patients—37% and 11%, respectively.
But older patients were more likely to have mild renal impairment (42% vs 13%) or moderate renal impairment (22% vs 1%).
Treatment
All patients received blinatumomab, and stepwise dosing was used to reduce the risk of cytokine release syndrome. A treatment cycle consisted of 4 weeks of continuous intravenous infusions, followed by a 2-week treatment-free interval.
The patients received 2 initial cycles. If they achieved a complete remission (CR) or CR with partial hematologic recovery (CRh) at this point, they could receive an additional 3 cycles as consolidation, unless they were scheduled to receive an allo-HSCT.
Patients also received intrathecal prophylaxis with dexamethasone and/or steroids, cytarabine, and methotrexate. And patients with a high blast percentage at baseline received a pre-phase treatment with dexamethasone and/or cyclophosphamide.
Older patients received a median of 2 cycles of blinatumomab (range, 1-6), as did the younger patients (range, 1-7).
Response and survival
Fifty-six percent of the older patients (20/36) achieved a CR/CRh during the first 2 cycles of blinatumomab, as did 46% of the younger patients (46/225). There were 14 CRs among the older patients (39%) and 78 CRs among the younger patients (35%).
There were 12 complete minimal residual disease responses among older patients (60% of responders) and 73 among the younger patients (70% of responders).
Of the responders, 3 older patients (15%) and 61 younger patients (59%) went on to allo-HSCT. Most of the patients received a transplant while in remission. However, 1 of the older patients and 8 of the younger patients went to transplant after an initial response to blinatumomab that was followed by a relapse.
The median relapse-free survival was 7.4 months for both age groups. The median overall survival was 5.5 months for older patients and 7.6 months for younger patients.
Safety
All of the older patients had at least 1 AE, and all but 1 of the younger patients had at least 1 AE. Older patients had higher rates of peripheral edema (42% vs 24%), fatigue (28% vs 18%), and dizziness (25% vs 11%) of any grade.
The incidence of grade 3 or higher AEs was similar between the groups—86% in the older group and 80% in the younger group. The same was true for AEs leading to treatment discontinuation—22% and 19%, respectively.
However, there was a higher incidence of serious AEs in the older patients (72% vs 64%). Device-related infection and encephalopathy were more common among older patients than younger patients (both 11% vs 3%).
The incidence of cytokine release syndrome was higher in the older group than the younger group—19% and 10%, respectively.
Older patients also had more neurologic events of any grade (72% vs 48%) and more grade 3 or higher neurologic events (28% vs 13%). However, all neurologic events were reversed by temporarily or permanently discontinuing blinatumomab.
There were 7 fatal treatment-emergent AEs in the older adults, including pneumonia (n=3), B-cell lymphoma (n=1), and disease progression (n=3). None of the fatal AEs were considered treatment-related. And none of the patients who were in remission died during treatment with blinatumomab.
CAR T-cell therapy granted orphan designation
The US Food and Drug Administration (FDA) has granted orphan drug designation for the chimeric antigen receptor (CAR) T-cell therapy KTE-C19 as a treatment for several hematologic malignancies.
This includes primary mediastinal B-cell lymphoma (PMBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), acute lymphoblastic leukemia (ALL), and chronic lymphocytic leukemia (CLL).
KTE-C19 previously received orphan designation from the FDA for the treatment of diffuse large B-cell lymphoma (DLBCL).
The FDA grants orphan designation to drugs and biologics 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.
KTE-C19 also has breakthrough therapy designation from the FDA as a treatment for DLBCL, PMBCL, and transformed FL.
About KTE-C19
KTE-C19 is an investigational therapy in which a patient’s T cells are genetically modified to express a CAR designed to target CD19. The product is being developed by Kite Pharma, Inc.
In a study published in the Journal of Clinical Oncology, researchers evaluated KTE-C19 in 15 patients with advanced B-cell malignancies.
The patients received a conditioning regimen of cyclophosphamide and fludarabine, followed 1 day later by a single infusion of KTE-C19. The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.
Thirteen patients were evaluable for response. The overall response rate was 92%. Eight patients achieved a complete response (CR), and 4 had a partial response (PR).
Of the 7 patients with DLBCL, 4 achieved a CR, 2 achieved a PR, and 1 had stable disease. Three of the CRs were ongoing at the time of publication, with the duration ranging from 9 months to 22 months.
Of the 4 patients with CLL, 3 had a CR, and 1 had a PR. All 3 CRs were ongoing at the time of publication, with the duration ranging from 14 months to 23 months.
Among the 2 patients with indolent lymphomas, 1 achieved a CR, and 1 had a PR. The duration of the CR was 11 months at the time of publication.
KTE-C19 elicited a number of adverse events, including fever, hypotension, delirium, and other neurologic toxicities. All but 2 patients experienced grade 3/4 adverse events.
Three patients developed unexpected neurologic abnormalities. One patient experienced aphasia and right-sided facial paresis. One patient developed aphasia, confusion, and severe, generalized myoclonus. And 1 patient had aphasia, confusion, hemifacial spasms, apraxia, and gait disturbances.
KTE-C19 is currently under investigation in a phase 2 trial of refractory DLBCL, PMBCL, and transformed FL (ZUMA-1), a phase 2 trial of relapsed/refractory MCL (ZUMA-2), a phase 1/2 trial of relapsed/refractory adult ALL (ZUMA-3), and a phase 1/2 trial of relapsed/refractory pediatric ALL (ZUMA-4).
Results from ZUMA-1 were recently presented at the 2016 AACR Annual Meeting (abstract CT135).
The US Food and Drug Administration (FDA) has granted orphan drug designation for the chimeric antigen receptor (CAR) T-cell therapy KTE-C19 as a treatment for several hematologic malignancies.
This includes primary mediastinal B-cell lymphoma (PMBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), acute lymphoblastic leukemia (ALL), and chronic lymphocytic leukemia (CLL).
KTE-C19 previously received orphan designation from the FDA for the treatment of diffuse large B-cell lymphoma (DLBCL).
The FDA grants orphan designation to drugs and biologics 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.
KTE-C19 also has breakthrough therapy designation from the FDA as a treatment for DLBCL, PMBCL, and transformed FL.
About KTE-C19
KTE-C19 is an investigational therapy in which a patient’s T cells are genetically modified to express a CAR designed to target CD19. The product is being developed by Kite Pharma, Inc.
In a study published in the Journal of Clinical Oncology, researchers evaluated KTE-C19 in 15 patients with advanced B-cell malignancies.
The patients received a conditioning regimen of cyclophosphamide and fludarabine, followed 1 day later by a single infusion of KTE-C19. The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.
Thirteen patients were evaluable for response. The overall response rate was 92%. Eight patients achieved a complete response (CR), and 4 had a partial response (PR).
Of the 7 patients with DLBCL, 4 achieved a CR, 2 achieved a PR, and 1 had stable disease. Three of the CRs were ongoing at the time of publication, with the duration ranging from 9 months to 22 months.
Of the 4 patients with CLL, 3 had a CR, and 1 had a PR. All 3 CRs were ongoing at the time of publication, with the duration ranging from 14 months to 23 months.
Among the 2 patients with indolent lymphomas, 1 achieved a CR, and 1 had a PR. The duration of the CR was 11 months at the time of publication.
KTE-C19 elicited a number of adverse events, including fever, hypotension, delirium, and other neurologic toxicities. All but 2 patients experienced grade 3/4 adverse events.
Three patients developed unexpected neurologic abnormalities. One patient experienced aphasia and right-sided facial paresis. One patient developed aphasia, confusion, and severe, generalized myoclonus. And 1 patient had aphasia, confusion, hemifacial spasms, apraxia, and gait disturbances.
KTE-C19 is currently under investigation in a phase 2 trial of refractory DLBCL, PMBCL, and transformed FL (ZUMA-1), a phase 2 trial of relapsed/refractory MCL (ZUMA-2), a phase 1/2 trial of relapsed/refractory adult ALL (ZUMA-3), and a phase 1/2 trial of relapsed/refractory pediatric ALL (ZUMA-4).
Results from ZUMA-1 were recently presented at the 2016 AACR Annual Meeting (abstract CT135).
The US Food and Drug Administration (FDA) has granted orphan drug designation for the chimeric antigen receptor (CAR) T-cell therapy KTE-C19 as a treatment for several hematologic malignancies.
This includes primary mediastinal B-cell lymphoma (PMBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), acute lymphoblastic leukemia (ALL), and chronic lymphocytic leukemia (CLL).
KTE-C19 previously received orphan designation from the FDA for the treatment of diffuse large B-cell lymphoma (DLBCL).
The FDA grants orphan designation to drugs and biologics 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.
KTE-C19 also has breakthrough therapy designation from the FDA as a treatment for DLBCL, PMBCL, and transformed FL.
About KTE-C19
KTE-C19 is an investigational therapy in which a patient’s T cells are genetically modified to express a CAR designed to target CD19. The product is being developed by Kite Pharma, Inc.
In a study published in the Journal of Clinical Oncology, researchers evaluated KTE-C19 in 15 patients with advanced B-cell malignancies.
The patients received a conditioning regimen of cyclophosphamide and fludarabine, followed 1 day later by a single infusion of KTE-C19. The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.
Thirteen patients were evaluable for response. The overall response rate was 92%. Eight patients achieved a complete response (CR), and 4 had a partial response (PR).
Of the 7 patients with DLBCL, 4 achieved a CR, 2 achieved a PR, and 1 had stable disease. Three of the CRs were ongoing at the time of publication, with the duration ranging from 9 months to 22 months.
Of the 4 patients with CLL, 3 had a CR, and 1 had a PR. All 3 CRs were ongoing at the time of publication, with the duration ranging from 14 months to 23 months.
Among the 2 patients with indolent lymphomas, 1 achieved a CR, and 1 had a PR. The duration of the CR was 11 months at the time of publication.
KTE-C19 elicited a number of adverse events, including fever, hypotension, delirium, and other neurologic toxicities. All but 2 patients experienced grade 3/4 adverse events.
Three patients developed unexpected neurologic abnormalities. One patient experienced aphasia and right-sided facial paresis. One patient developed aphasia, confusion, and severe, generalized myoclonus. And 1 patient had aphasia, confusion, hemifacial spasms, apraxia, and gait disturbances.
KTE-C19 is currently under investigation in a phase 2 trial of refractory DLBCL, PMBCL, and transformed FL (ZUMA-1), a phase 2 trial of relapsed/refractory MCL (ZUMA-2), a phase 1/2 trial of relapsed/refractory adult ALL (ZUMA-3), and a phase 1/2 trial of relapsed/refractory pediatric ALL (ZUMA-4).
Results from ZUMA-1 were recently presented at the 2016 AACR Annual Meeting (abstract CT135).
On the road to harnessing CRISPR gene editing to treat cancer
CRISPR technology, a simple, yet incredibly powerful tool for genetic engineering, is not only allowing cancer researchers to screen for drug targets more efficiently, but is also opening the door for direct cancer treatment through gene interference or activation.
“The pace at which this technology is developing is astounding and almost every cancer research lab is now using some version of it in their studies,” Dr. Scott A. Armstrong, director of Memorial Sloan Kettering Leukemia Center, New York, said in an interview.
Ancient defense mechanism
While the term CRISPR is now synonymous with the editing of human genes, it actually refers to a sort of primitive immune system used by bacteria for billions of years. CRISPR is an acronym for Clustered Regularly Interspaced Short Palindromic Repeats, but the complex terminology belies an elegantly simple mechanism by which bacterial cells destroy invading pathogens.
The bacterial genome contains regions with short repetitive stretches of DNA that are separated by spacers. Researchers made the startling discovery that the spacers are often composed of bits of foreign DNA and it transpired that bacteria use it as a molecular memory of prior infection.
When the same pathogen is encountered again, the stretches of repeats and spacers are transcribed to form CRISPR RNAs (crRNA). Together with a transactivating RNA (tracrRNA), it forms a kind of GPS system for a series of CRISPR-associated (Cas) proteins that function like molecular scissors, destroying the target DNA sequence in the invader’s genome.
There are three CRISPR systems – type I, II, and III – that are associated with different sets of Cas proteins and each employ unique methods for achieving the same ultimate function. The type II system that pairs with Cas9 has received the most attention.
Cut and paste gene editing
The discovery that CRISPR could be exploited as a tool for genetic manipulation in mammalian cells sparked a revolution in the genome editing field. “The CRISPR-Cas9 system has been adapted to specifically edit the genomes of mammalian cells, allowing one to make targeted changes to almost any gene,” Dr. Armstrong said.
The use of CRISPR-Cas9 as a genome editing tool is simplified by joining the crRNA and tracrRNA together so they are transcribed in a single guide RNA (gRNA). The GPS coordinates of the gRNA can be preprogrammed to target a gene of interest, specifically directing the co-transcribed Cas9 protein to cut at that location, and introducing a double-strand break (DSB) in the DNA. Cells employ a number of different mechanisms to repair DSBs and these can then be exploited for genome editing purposes, allowing researchers to introduce changes to the DNA as it is repaired.
The CRISPR-Cas9 system excels in its simplicity – allowing alterations to be made to the genome much more easily, quickly, and cheaply than ever before, plagued by far fewer off-target effects. It also allows researchers to examine the function of multiple genes at once, where before they were mostly limited to a single gene.
“Cancer genomics has identified a large number of genes that are mutated in human cancer,” Tyler Jacks, Ph.D., director of the Koch Institute for Integrative Cancer Research at MIT, Boston, said in an interview. “CRISPR allows us to study these genes in cancer cells and in whole animals much more efficiently than the methods that were in use just a few years ago.”
But the potential of the CRISPR-Cas9 system doesn’t stop there. “At the moment, a particularly exciting application is the use of this approach to inactive genes in very specific fashion to assess the function of a given protein in a cancer cell, which should speed the identification of proteins that are important for cancer cells and thus potentially aid drug discovery efforts,” Dr. Armstrong said.
CRISPR at AACR
The latest developments in the use of the CRISPR-Cas9 system were highlighted at the annual meeting of the American Association of Cancer Research. Dr. David Sabatini, professor of biology at MIT, Boston, described his own lab’s method for using CRISPR-Cas9 to seek out the essential genes involved in different types of cancers. In a study recently published in Science, he and his colleagues employed this method in chronic myelogenous leukemia and Burkitt’s lymphoma cell lines. The gRNA library targeted just over 18,000 genes and roughly 10% of these proved to be essential. Mostly, these genes were linked to key cellular processes (Science 2015;350[6264]:1096-1101).
Dr. Christopher Vakoc of Cold Spring Harbor (N.Y.) Laboratory, presented a slightly different kind of CRISPR screen for drug targets. Most commonly, CRISPR introduces edits at the start of the gene, which may or may not change the DNA enough to produce a nonfunctional protein. Dr. Vakoc’s lab has developed a system that instead edits functional protein domains, which present ideal drug targets. Mutated domains can be identified that are essential for cancer cell survival and small molecule inhibitors designed that bind to them to kill cancer cells.
The technique has already been used to identify such a domain on the BRD4 protein and inhibitors that bind to this domain had significant antitumor activity in leukemia, Dr. Vakoc reported. A screen targeting 192 chromatin regulatory domains expressed in mouse acute myeloid leukemia cells was subsequently performed and identified 25 domains that impacted survival, 6 that are already being therapeutically targeted, and 19 novel potential targets.
Another development in CRISPR-Cas9 technology creates an inactive version of the Cas9 enzyme, one that has lost the ability to cut DNA. Though it seems counterintuitive, this has opened up a wealth of new possible uses. Jonathan S. Weissman, Ph.D., professor of cellular and molecular pharmacology, University of California, San Francisco, part of the group to develop this ‘dead’ Cas9 (dCas9), published a description of the use of two new tools dubbed CRISPR interference and CRISPR activation (Cell 2013;152[5]:1173-83).
Essentially, by fusing dCas9 with different proteins, such as epigenetic modifiers or transcriptional activators or repressors, it can be used as a delivery system to fine-tune gene expression, instead of editing the gene sequence.
Treating cancer?
Ultimately, CRISPR-Cas9 could be used to treat cancers by cutting out defective genes and replacing them with a wild-type version, or by repairing mutations, though for the time being this is theoretical. Studies have suggested it is possible with other types of diseases, however.
“It is not clear exactly how the CRISPR system would be used to directly treat cancer, but the discoveries that come from its use will likely lead to new ways to treat cancer,” said Dr Armstrong.
Dr Jacks highlighted the technical challenges that will need to be overcome first. “In principle, CRISPR-based genome editing could be used to correct cancer-causing mutations in tumors in vivo or to inactivate activated cancer genes,” he said. “At this point, however, we lack the technology necessary to deliver the CRISPR system to all cancer cells in the body. Improvements in this so-called ‘delivery problem’ may allow CRISPR to become a powerful anticancer therapy strategy.”
CRISPR technology, a simple, yet incredibly powerful tool for genetic engineering, is not only allowing cancer researchers to screen for drug targets more efficiently, but is also opening the door for direct cancer treatment through gene interference or activation.
“The pace at which this technology is developing is astounding and almost every cancer research lab is now using some version of it in their studies,” Dr. Scott A. Armstrong, director of Memorial Sloan Kettering Leukemia Center, New York, said in an interview.
Ancient defense mechanism
While the term CRISPR is now synonymous with the editing of human genes, it actually refers to a sort of primitive immune system used by bacteria for billions of years. CRISPR is an acronym for Clustered Regularly Interspaced Short Palindromic Repeats, but the complex terminology belies an elegantly simple mechanism by which bacterial cells destroy invading pathogens.
The bacterial genome contains regions with short repetitive stretches of DNA that are separated by spacers. Researchers made the startling discovery that the spacers are often composed of bits of foreign DNA and it transpired that bacteria use it as a molecular memory of prior infection.
When the same pathogen is encountered again, the stretches of repeats and spacers are transcribed to form CRISPR RNAs (crRNA). Together with a transactivating RNA (tracrRNA), it forms a kind of GPS system for a series of CRISPR-associated (Cas) proteins that function like molecular scissors, destroying the target DNA sequence in the invader’s genome.
There are three CRISPR systems – type I, II, and III – that are associated with different sets of Cas proteins and each employ unique methods for achieving the same ultimate function. The type II system that pairs with Cas9 has received the most attention.
Cut and paste gene editing
The discovery that CRISPR could be exploited as a tool for genetic manipulation in mammalian cells sparked a revolution in the genome editing field. “The CRISPR-Cas9 system has been adapted to specifically edit the genomes of mammalian cells, allowing one to make targeted changes to almost any gene,” Dr. Armstrong said.
The use of CRISPR-Cas9 as a genome editing tool is simplified by joining the crRNA and tracrRNA together so they are transcribed in a single guide RNA (gRNA). The GPS coordinates of the gRNA can be preprogrammed to target a gene of interest, specifically directing the co-transcribed Cas9 protein to cut at that location, and introducing a double-strand break (DSB) in the DNA. Cells employ a number of different mechanisms to repair DSBs and these can then be exploited for genome editing purposes, allowing researchers to introduce changes to the DNA as it is repaired.
The CRISPR-Cas9 system excels in its simplicity – allowing alterations to be made to the genome much more easily, quickly, and cheaply than ever before, plagued by far fewer off-target effects. It also allows researchers to examine the function of multiple genes at once, where before they were mostly limited to a single gene.
“Cancer genomics has identified a large number of genes that are mutated in human cancer,” Tyler Jacks, Ph.D., director of the Koch Institute for Integrative Cancer Research at MIT, Boston, said in an interview. “CRISPR allows us to study these genes in cancer cells and in whole animals much more efficiently than the methods that were in use just a few years ago.”
But the potential of the CRISPR-Cas9 system doesn’t stop there. “At the moment, a particularly exciting application is the use of this approach to inactive genes in very specific fashion to assess the function of a given protein in a cancer cell, which should speed the identification of proteins that are important for cancer cells and thus potentially aid drug discovery efforts,” Dr. Armstrong said.
CRISPR at AACR
The latest developments in the use of the CRISPR-Cas9 system were highlighted at the annual meeting of the American Association of Cancer Research. Dr. David Sabatini, professor of biology at MIT, Boston, described his own lab’s method for using CRISPR-Cas9 to seek out the essential genes involved in different types of cancers. In a study recently published in Science, he and his colleagues employed this method in chronic myelogenous leukemia and Burkitt’s lymphoma cell lines. The gRNA library targeted just over 18,000 genes and roughly 10% of these proved to be essential. Mostly, these genes were linked to key cellular processes (Science 2015;350[6264]:1096-1101).
Dr. Christopher Vakoc of Cold Spring Harbor (N.Y.) Laboratory, presented a slightly different kind of CRISPR screen for drug targets. Most commonly, CRISPR introduces edits at the start of the gene, which may or may not change the DNA enough to produce a nonfunctional protein. Dr. Vakoc’s lab has developed a system that instead edits functional protein domains, which present ideal drug targets. Mutated domains can be identified that are essential for cancer cell survival and small molecule inhibitors designed that bind to them to kill cancer cells.
The technique has already been used to identify such a domain on the BRD4 protein and inhibitors that bind to this domain had significant antitumor activity in leukemia, Dr. Vakoc reported. A screen targeting 192 chromatin regulatory domains expressed in mouse acute myeloid leukemia cells was subsequently performed and identified 25 domains that impacted survival, 6 that are already being therapeutically targeted, and 19 novel potential targets.
Another development in CRISPR-Cas9 technology creates an inactive version of the Cas9 enzyme, one that has lost the ability to cut DNA. Though it seems counterintuitive, this has opened up a wealth of new possible uses. Jonathan S. Weissman, Ph.D., professor of cellular and molecular pharmacology, University of California, San Francisco, part of the group to develop this ‘dead’ Cas9 (dCas9), published a description of the use of two new tools dubbed CRISPR interference and CRISPR activation (Cell 2013;152[5]:1173-83).
Essentially, by fusing dCas9 with different proteins, such as epigenetic modifiers or transcriptional activators or repressors, it can be used as a delivery system to fine-tune gene expression, instead of editing the gene sequence.
Treating cancer?
Ultimately, CRISPR-Cas9 could be used to treat cancers by cutting out defective genes and replacing them with a wild-type version, or by repairing mutations, though for the time being this is theoretical. Studies have suggested it is possible with other types of diseases, however.
“It is not clear exactly how the CRISPR system would be used to directly treat cancer, but the discoveries that come from its use will likely lead to new ways to treat cancer,” said Dr Armstrong.
Dr Jacks highlighted the technical challenges that will need to be overcome first. “In principle, CRISPR-based genome editing could be used to correct cancer-causing mutations in tumors in vivo or to inactivate activated cancer genes,” he said. “At this point, however, we lack the technology necessary to deliver the CRISPR system to all cancer cells in the body. Improvements in this so-called ‘delivery problem’ may allow CRISPR to become a powerful anticancer therapy strategy.”
CRISPR technology, a simple, yet incredibly powerful tool for genetic engineering, is not only allowing cancer researchers to screen for drug targets more efficiently, but is also opening the door for direct cancer treatment through gene interference or activation.
“The pace at which this technology is developing is astounding and almost every cancer research lab is now using some version of it in their studies,” Dr. Scott A. Armstrong, director of Memorial Sloan Kettering Leukemia Center, New York, said in an interview.
Ancient defense mechanism
While the term CRISPR is now synonymous with the editing of human genes, it actually refers to a sort of primitive immune system used by bacteria for billions of years. CRISPR is an acronym for Clustered Regularly Interspaced Short Palindromic Repeats, but the complex terminology belies an elegantly simple mechanism by which bacterial cells destroy invading pathogens.
The bacterial genome contains regions with short repetitive stretches of DNA that are separated by spacers. Researchers made the startling discovery that the spacers are often composed of bits of foreign DNA and it transpired that bacteria use it as a molecular memory of prior infection.
When the same pathogen is encountered again, the stretches of repeats and spacers are transcribed to form CRISPR RNAs (crRNA). Together with a transactivating RNA (tracrRNA), it forms a kind of GPS system for a series of CRISPR-associated (Cas) proteins that function like molecular scissors, destroying the target DNA sequence in the invader’s genome.
There are three CRISPR systems – type I, II, and III – that are associated with different sets of Cas proteins and each employ unique methods for achieving the same ultimate function. The type II system that pairs with Cas9 has received the most attention.
Cut and paste gene editing
The discovery that CRISPR could be exploited as a tool for genetic manipulation in mammalian cells sparked a revolution in the genome editing field. “The CRISPR-Cas9 system has been adapted to specifically edit the genomes of mammalian cells, allowing one to make targeted changes to almost any gene,” Dr. Armstrong said.
The use of CRISPR-Cas9 as a genome editing tool is simplified by joining the crRNA and tracrRNA together so they are transcribed in a single guide RNA (gRNA). The GPS coordinates of the gRNA can be preprogrammed to target a gene of interest, specifically directing the co-transcribed Cas9 protein to cut at that location, and introducing a double-strand break (DSB) in the DNA. Cells employ a number of different mechanisms to repair DSBs and these can then be exploited for genome editing purposes, allowing researchers to introduce changes to the DNA as it is repaired.
The CRISPR-Cas9 system excels in its simplicity – allowing alterations to be made to the genome much more easily, quickly, and cheaply than ever before, plagued by far fewer off-target effects. It also allows researchers to examine the function of multiple genes at once, where before they were mostly limited to a single gene.
“Cancer genomics has identified a large number of genes that are mutated in human cancer,” Tyler Jacks, Ph.D., director of the Koch Institute for Integrative Cancer Research at MIT, Boston, said in an interview. “CRISPR allows us to study these genes in cancer cells and in whole animals much more efficiently than the methods that were in use just a few years ago.”
But the potential of the CRISPR-Cas9 system doesn’t stop there. “At the moment, a particularly exciting application is the use of this approach to inactive genes in very specific fashion to assess the function of a given protein in a cancer cell, which should speed the identification of proteins that are important for cancer cells and thus potentially aid drug discovery efforts,” Dr. Armstrong said.
CRISPR at AACR
The latest developments in the use of the CRISPR-Cas9 system were highlighted at the annual meeting of the American Association of Cancer Research. Dr. David Sabatini, professor of biology at MIT, Boston, described his own lab’s method for using CRISPR-Cas9 to seek out the essential genes involved in different types of cancers. In a study recently published in Science, he and his colleagues employed this method in chronic myelogenous leukemia and Burkitt’s lymphoma cell lines. The gRNA library targeted just over 18,000 genes and roughly 10% of these proved to be essential. Mostly, these genes were linked to key cellular processes (Science 2015;350[6264]:1096-1101).
Dr. Christopher Vakoc of Cold Spring Harbor (N.Y.) Laboratory, presented a slightly different kind of CRISPR screen for drug targets. Most commonly, CRISPR introduces edits at the start of the gene, which may or may not change the DNA enough to produce a nonfunctional protein. Dr. Vakoc’s lab has developed a system that instead edits functional protein domains, which present ideal drug targets. Mutated domains can be identified that are essential for cancer cell survival and small molecule inhibitors designed that bind to them to kill cancer cells.
The technique has already been used to identify such a domain on the BRD4 protein and inhibitors that bind to this domain had significant antitumor activity in leukemia, Dr. Vakoc reported. A screen targeting 192 chromatin regulatory domains expressed in mouse acute myeloid leukemia cells was subsequently performed and identified 25 domains that impacted survival, 6 that are already being therapeutically targeted, and 19 novel potential targets.
Another development in CRISPR-Cas9 technology creates an inactive version of the Cas9 enzyme, one that has lost the ability to cut DNA. Though it seems counterintuitive, this has opened up a wealth of new possible uses. Jonathan S. Weissman, Ph.D., professor of cellular and molecular pharmacology, University of California, San Francisco, part of the group to develop this ‘dead’ Cas9 (dCas9), published a description of the use of two new tools dubbed CRISPR interference and CRISPR activation (Cell 2013;152[5]:1173-83).
Essentially, by fusing dCas9 with different proteins, such as epigenetic modifiers or transcriptional activators or repressors, it can be used as a delivery system to fine-tune gene expression, instead of editing the gene sequence.
Treating cancer?
Ultimately, CRISPR-Cas9 could be used to treat cancers by cutting out defective genes and replacing them with a wild-type version, or by repairing mutations, though for the time being this is theoretical. Studies have suggested it is possible with other types of diseases, however.
“It is not clear exactly how the CRISPR system would be used to directly treat cancer, but the discoveries that come from its use will likely lead to new ways to treat cancer,” said Dr Armstrong.
Dr Jacks highlighted the technical challenges that will need to be overcome first. “In principle, CRISPR-based genome editing could be used to correct cancer-causing mutations in tumors in vivo or to inactivate activated cancer genes,” he said. “At this point, however, we lack the technology necessary to deliver the CRISPR system to all cancer cells in the body. Improvements in this so-called ‘delivery problem’ may allow CRISPR to become a powerful anticancer therapy strategy.”
