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Team identifies 5 subtypes of DLBCL
New research has revealed 5 genetic subtypes of diffuse large B-cell lymphoma (DLBCL).
Researchers identified a group of low-risk activated B-cell (ABC) DLBCLs, 2 subsets of germinal center B-cell (GCB) DLBCLs, a group of ABC/GCB-independent DLBCLs, and a group of ABC DLBCLs with genetic characteristics found in primary central nervous system lymphoma and testicular lymphoma.
The researchers believe these findings may have revealed new therapeutic targets for DLBCL, some of which could be inhibited by drugs that are already approved or under investigation in clinical trials.
Margaret Shipp, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and her colleagues conducted this research and reported the results in Nature Medicine.
The team performed genetic analyses on samples from 304 DLBCL patients and observed great genetic diversity. The median number of genetic driver alterations in individual tumors was 17.
The researchers integrated data on 3 types of genetic alterations—recurrent mutations, somatic copy number alterations, and structural variants—to define previously unappreciated DLBCL subtypes.
“Specific genes that were perturbed by mutations could also be altered by changes in gene copy numbers or by chromosomal rearrangements, underscoring the importance of evaluating all 3 types of genetic alterations,” Dr Shipp noted.
“Most importantly, we saw that there were 5 discrete types of DLBCL that were distinguished one from another on the basis of the specific types of genetic alterations that occurred in combination.”
The researchers classified these subtypes as clusters (C) 1 to 5.
C1 consisted of largely ABC-DLBCLs with genetic features of an extra-follicular, possibly marginal zone origin.
C2 included both ABC and GCB DLBCLs with biallelic inactivation of TP53, 9p21.3/CDKN2A, and associated genomic instability.
Most DLBCLs in C3 were of the GCB subtype and were characterized by BCL2 structural variants and alterations of PTEN and epigenetic enzymes.
C4 consisted largely of GCB DLBCLs with alterations in BCR/PI3K, JAK/STAT, and BRAF pathway components and multiple histones.
Most C5 DLBCLs were of the ABC subtype, and the researchers said the major components of the C5 signature—BCL2 gain, concordant MYD88L265P/CD79B mutations, and mutations of ETV6, PIM1, GRHPR, TBL1XR1, and BTG1—were similar to those observed in primary central nervous system and testicular lymphoma.
Dr Shipp and her colleagues also identified a sixth cluster of DLBCLs (dubbed C0) that “lacked defining genetic drivers.”
Finally, the team found that patients with C0, C1, and C4 DLBCLs had more favorable outcomes, while patients with C2, C3, and C5 DLBCLs had less favorable outcomes.
“We feel this research opens the door to a whole series of additional investigations to understand how the combinations of these genetic alterations work together, and then to use that information to benefit patients with targeted therapies,” Dr Shipp said.
She and her colleagues are now working on creating a clinical tool to identify these genetic signatures in patients. The team is also developing clinical trials that will match patients with given genetic signatures to targeted treatments.
Another group of researchers recently identified 4 genetic subtypes of DLBCL.
New research has revealed 5 genetic subtypes of diffuse large B-cell lymphoma (DLBCL).
Researchers identified a group of low-risk activated B-cell (ABC) DLBCLs, 2 subsets of germinal center B-cell (GCB) DLBCLs, a group of ABC/GCB-independent DLBCLs, and a group of ABC DLBCLs with genetic characteristics found in primary central nervous system lymphoma and testicular lymphoma.
The researchers believe these findings may have revealed new therapeutic targets for DLBCL, some of which could be inhibited by drugs that are already approved or under investigation in clinical trials.
Margaret Shipp, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and her colleagues conducted this research and reported the results in Nature Medicine.
The team performed genetic analyses on samples from 304 DLBCL patients and observed great genetic diversity. The median number of genetic driver alterations in individual tumors was 17.
The researchers integrated data on 3 types of genetic alterations—recurrent mutations, somatic copy number alterations, and structural variants—to define previously unappreciated DLBCL subtypes.
“Specific genes that were perturbed by mutations could also be altered by changes in gene copy numbers or by chromosomal rearrangements, underscoring the importance of evaluating all 3 types of genetic alterations,” Dr Shipp noted.
“Most importantly, we saw that there were 5 discrete types of DLBCL that were distinguished one from another on the basis of the specific types of genetic alterations that occurred in combination.”
The researchers classified these subtypes as clusters (C) 1 to 5.
C1 consisted of largely ABC-DLBCLs with genetic features of an extra-follicular, possibly marginal zone origin.
C2 included both ABC and GCB DLBCLs with biallelic inactivation of TP53, 9p21.3/CDKN2A, and associated genomic instability.
Most DLBCLs in C3 were of the GCB subtype and were characterized by BCL2 structural variants and alterations of PTEN and epigenetic enzymes.
C4 consisted largely of GCB DLBCLs with alterations in BCR/PI3K, JAK/STAT, and BRAF pathway components and multiple histones.
Most C5 DLBCLs were of the ABC subtype, and the researchers said the major components of the C5 signature—BCL2 gain, concordant MYD88L265P/CD79B mutations, and mutations of ETV6, PIM1, GRHPR, TBL1XR1, and BTG1—were similar to those observed in primary central nervous system and testicular lymphoma.
Dr Shipp and her colleagues also identified a sixth cluster of DLBCLs (dubbed C0) that “lacked defining genetic drivers.”
Finally, the team found that patients with C0, C1, and C4 DLBCLs had more favorable outcomes, while patients with C2, C3, and C5 DLBCLs had less favorable outcomes.
“We feel this research opens the door to a whole series of additional investigations to understand how the combinations of these genetic alterations work together, and then to use that information to benefit patients with targeted therapies,” Dr Shipp said.
She and her colleagues are now working on creating a clinical tool to identify these genetic signatures in patients. The team is also developing clinical trials that will match patients with given genetic signatures to targeted treatments.
Another group of researchers recently identified 4 genetic subtypes of DLBCL.
New research has revealed 5 genetic subtypes of diffuse large B-cell lymphoma (DLBCL).
Researchers identified a group of low-risk activated B-cell (ABC) DLBCLs, 2 subsets of germinal center B-cell (GCB) DLBCLs, a group of ABC/GCB-independent DLBCLs, and a group of ABC DLBCLs with genetic characteristics found in primary central nervous system lymphoma and testicular lymphoma.
The researchers believe these findings may have revealed new therapeutic targets for DLBCL, some of which could be inhibited by drugs that are already approved or under investigation in clinical trials.
Margaret Shipp, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and her colleagues conducted this research and reported the results in Nature Medicine.
The team performed genetic analyses on samples from 304 DLBCL patients and observed great genetic diversity. The median number of genetic driver alterations in individual tumors was 17.
The researchers integrated data on 3 types of genetic alterations—recurrent mutations, somatic copy number alterations, and structural variants—to define previously unappreciated DLBCL subtypes.
“Specific genes that were perturbed by mutations could also be altered by changes in gene copy numbers or by chromosomal rearrangements, underscoring the importance of evaluating all 3 types of genetic alterations,” Dr Shipp noted.
“Most importantly, we saw that there were 5 discrete types of DLBCL that were distinguished one from another on the basis of the specific types of genetic alterations that occurred in combination.”
The researchers classified these subtypes as clusters (C) 1 to 5.
C1 consisted of largely ABC-DLBCLs with genetic features of an extra-follicular, possibly marginal zone origin.
C2 included both ABC and GCB DLBCLs with biallelic inactivation of TP53, 9p21.3/CDKN2A, and associated genomic instability.
Most DLBCLs in C3 were of the GCB subtype and were characterized by BCL2 structural variants and alterations of PTEN and epigenetic enzymes.
C4 consisted largely of GCB DLBCLs with alterations in BCR/PI3K, JAK/STAT, and BRAF pathway components and multiple histones.
Most C5 DLBCLs were of the ABC subtype, and the researchers said the major components of the C5 signature—BCL2 gain, concordant MYD88L265P/CD79B mutations, and mutations of ETV6, PIM1, GRHPR, TBL1XR1, and BTG1—were similar to those observed in primary central nervous system and testicular lymphoma.
Dr Shipp and her colleagues also identified a sixth cluster of DLBCLs (dubbed C0) that “lacked defining genetic drivers.”
Finally, the team found that patients with C0, C1, and C4 DLBCLs had more favorable outcomes, while patients with C2, C3, and C5 DLBCLs had less favorable outcomes.
“We feel this research opens the door to a whole series of additional investigations to understand how the combinations of these genetic alterations work together, and then to use that information to benefit patients with targeted therapies,” Dr Shipp said.
She and her colleagues are now working on creating a clinical tool to identify these genetic signatures in patients. The team is also developing clinical trials that will match patients with given genetic signatures to targeted treatments.
Another group of researchers recently identified 4 genetic subtypes of DLBCL.
CHMP recommends approval for generic carmustine
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion of Carmustine Obvius, a generic version of Carmubris.
The CHMP is recommending marketing authorization for Carmustine Obvius as second-line treatment for Hodgkin and non-Hodgkin lymphoma as well as to treat new or recurrent brain tumors, including glioblastoma, medulloblastoma, astrocytoma, and metastatic brain tumors.
The CHMP’s opinion on Carmustine Obvius will be reviewed by the European Commission (EC).
If the EC agrees with the CHMP’s recommendation, the commission will grant a centralized marketing authorization that will be valid in the European Union.
The EC typically makes a decision on a product within 67 days of the CHMP’s recommendation.
If approved, Carmustine Obvius will be available as a 100 mg powder and solvent for solution for infusion.
The active substance of Carmustine Obvius is carmustine, an alkylating antineoplastic agent of the nitrosourea type, which prevents DNA replication and transcription by alkylating reactive sites on nucleoproteins.
Carmustine Obvius is a generic of Carmubris, which has been authorized in the European Union since July 31, 1996.
Since Carmustine Obvius is administered intravenously and is 100% bioavailable, a bioequivalence study of the drug versus Carmubris was not required.
Carmustine Obvius is a product of Obvius Investment B.V.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion of Carmustine Obvius, a generic version of Carmubris.
The CHMP is recommending marketing authorization for Carmustine Obvius as second-line treatment for Hodgkin and non-Hodgkin lymphoma as well as to treat new or recurrent brain tumors, including glioblastoma, medulloblastoma, astrocytoma, and metastatic brain tumors.
The CHMP’s opinion on Carmustine Obvius will be reviewed by the European Commission (EC).
If the EC agrees with the CHMP’s recommendation, the commission will grant a centralized marketing authorization that will be valid in the European Union.
The EC typically makes a decision on a product within 67 days of the CHMP’s recommendation.
If approved, Carmustine Obvius will be available as a 100 mg powder and solvent for solution for infusion.
The active substance of Carmustine Obvius is carmustine, an alkylating antineoplastic agent of the nitrosourea type, which prevents DNA replication and transcription by alkylating reactive sites on nucleoproteins.
Carmustine Obvius is a generic of Carmubris, which has been authorized in the European Union since July 31, 1996.
Since Carmustine Obvius is administered intravenously and is 100% bioavailable, a bioequivalence study of the drug versus Carmubris was not required.
Carmustine Obvius is a product of Obvius Investment B.V.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion of Carmustine Obvius, a generic version of Carmubris.
The CHMP is recommending marketing authorization for Carmustine Obvius as second-line treatment for Hodgkin and non-Hodgkin lymphoma as well as to treat new or recurrent brain tumors, including glioblastoma, medulloblastoma, astrocytoma, and metastatic brain tumors.
The CHMP’s opinion on Carmustine Obvius will be reviewed by the European Commission (EC).
If the EC agrees with the CHMP’s recommendation, the commission will grant a centralized marketing authorization that will be valid in the European Union.
The EC typically makes a decision on a product within 67 days of the CHMP’s recommendation.
If approved, Carmustine Obvius will be available as a 100 mg powder and solvent for solution for infusion.
The active substance of Carmustine Obvius is carmustine, an alkylating antineoplastic agent of the nitrosourea type, which prevents DNA replication and transcription by alkylating reactive sites on nucleoproteins.
Carmustine Obvius is a generic of Carmubris, which has been authorized in the European Union since July 31, 1996.
Since Carmustine Obvius is administered intravenously and is 100% bioavailable, a bioequivalence study of the drug versus Carmubris was not required.
Carmustine Obvius is a product of Obvius Investment B.V.
Radioimmunoconjugate shows activity in NHL
CHICAGO—The radioimmunoconjugate 177Lu-NNV003 has demonstrated activity against non-Hodgkin lymphomas (NHLs).
Experiments showed that 177Lu-NNV003 can inhibit proliferation in mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL) cell lines.
177Lu-NNV003 also exhibited an antitumor effect and prolonged survival in mouse models of MCL, DLBCL, and CLL.
These results were presented at the AACR Annual Meeting 2018 (abstract 848).
This research was conducted by employees of Nordic Nanovector and other researchers. Nordic Nanovector is the company developing 177Lu-NNV003.
177Lu-NNV003 consists of a chimeric antibody targeting CD37 (NNV003) conjugated with p-SCN-Bn-DOTA, which chelates the β-emitting radionuclide lutetium-177.
The researchers found that 177Lu-NNV003 inhibited proliferation in all 3 NHL cell lines tested—MEC-2 (CLL), DOHH2 (DLBCL), and REC-1 (MCL). DOHH2 was the most radiosensitive cell line.
The unlabeled NNV003 antibody, on the other hand, did not exhibit an antiproliferative effect in these cell lines. However, NNV003 did induce antibody-dependent cellular cytotoxicity in MEC-2 and DOHH2 cells and antibody-dependent cellular phagocytosis in MEC-2 cells.
The researchers found that 177Lu-NNV003 targeted CD37-positive cells and demonstrated antitumor effects in mouse models of MCL, CLL, and DLBCL.
REC-1 model
177Lu-NNV003 prolonged survival in CB17 SCID mice injected with REC-1 cells and cured 50% to 60% of the mice.
Median survival times were 55 days in mice that received sodium chloride (NaCl), 85 days in mice that received NNV003 (0.167 mg/kg), and 61 days in mice that received 177Lu-IgG1 (100 MBq/kg).
On the other hand, mice treated with 177Lu-NNV003 had a median survival of 152 days (100 MBq/kg), or the median survival was not reached (50 MBq/kg).
The difference in survival was significant for 177Lu-NNV003 recipients compared to recipients of NaCl (P<0.001) or 177Lu-IgG1 (P<0.002).
MEC-2 model
177Lu-NNV003 also prolonged survival in NRG mice injected with MEC-2 cells.
The median survival was 21 days in mice that received NaCl, NNV003 (2 x 0.33 mg/kg), or 177Lu-IgG1 (200 MBq/kg).
However, mice treated with 177Lu-NNV003 had a median survival of 32 days (200 MBq/kg) or 29 days (2 x 200 MBq/kg).
The difference in survival was significant for 177Lu-NNV003 recipients compared to recipients of 177Lu-IgG1 (P<0.025) or 2 x NNV003 (P<0.02).
DOHH2 model
RAG-2 mice injected with DOHH2 cells had survival times surpassing 200 days after treatment with NNV003 or 177Lu-NNV003.
The median survival was not reached in mice that received NNV003 (at 2 or 30 mg/kg) or 177Lu-NNV003 (at 200, 300, or 400 MBq/kg). But the median survival was 46 days in mice that received NaCl and 47 days in mice that received 177Lu-IgG1 (300 MBq/kg).
The difference in survival was significant for recipients of NNV003 or 177Lu-NNV003 compared to recipients of 177Lu-IgG1 or NaCl (P<0.001 for all).
Toxicity and biodistribution
The researchers noted that the 177Lu-labeled antibodies caused transient hematologic toxicity in the mice.
In the MEC-2 and DOHH2 models, there was no redistribution of 177Lu-NNV003 in organs after initial uptake. (The researchers did not report on biodistribution in the REC-1 model.)
177Lu-NNV003 had low uptake in the liver, spleen, kidneys, and femur. The researchers said this suggests 177Lu-NNV003 is stable in vivo, as free lutetium-177 tends to accumulate in bones.
CHICAGO—The radioimmunoconjugate 177Lu-NNV003 has demonstrated activity against non-Hodgkin lymphomas (NHLs).
Experiments showed that 177Lu-NNV003 can inhibit proliferation in mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL) cell lines.
177Lu-NNV003 also exhibited an antitumor effect and prolonged survival in mouse models of MCL, DLBCL, and CLL.
These results were presented at the AACR Annual Meeting 2018 (abstract 848).
This research was conducted by employees of Nordic Nanovector and other researchers. Nordic Nanovector is the company developing 177Lu-NNV003.
177Lu-NNV003 consists of a chimeric antibody targeting CD37 (NNV003) conjugated with p-SCN-Bn-DOTA, which chelates the β-emitting radionuclide lutetium-177.
The researchers found that 177Lu-NNV003 inhibited proliferation in all 3 NHL cell lines tested—MEC-2 (CLL), DOHH2 (DLBCL), and REC-1 (MCL). DOHH2 was the most radiosensitive cell line.
The unlabeled NNV003 antibody, on the other hand, did not exhibit an antiproliferative effect in these cell lines. However, NNV003 did induce antibody-dependent cellular cytotoxicity in MEC-2 and DOHH2 cells and antibody-dependent cellular phagocytosis in MEC-2 cells.
The researchers found that 177Lu-NNV003 targeted CD37-positive cells and demonstrated antitumor effects in mouse models of MCL, CLL, and DLBCL.
REC-1 model
177Lu-NNV003 prolonged survival in CB17 SCID mice injected with REC-1 cells and cured 50% to 60% of the mice.
Median survival times were 55 days in mice that received sodium chloride (NaCl), 85 days in mice that received NNV003 (0.167 mg/kg), and 61 days in mice that received 177Lu-IgG1 (100 MBq/kg).
On the other hand, mice treated with 177Lu-NNV003 had a median survival of 152 days (100 MBq/kg), or the median survival was not reached (50 MBq/kg).
The difference in survival was significant for 177Lu-NNV003 recipients compared to recipients of NaCl (P<0.001) or 177Lu-IgG1 (P<0.002).
MEC-2 model
177Lu-NNV003 also prolonged survival in NRG mice injected with MEC-2 cells.
The median survival was 21 days in mice that received NaCl, NNV003 (2 x 0.33 mg/kg), or 177Lu-IgG1 (200 MBq/kg).
However, mice treated with 177Lu-NNV003 had a median survival of 32 days (200 MBq/kg) or 29 days (2 x 200 MBq/kg).
The difference in survival was significant for 177Lu-NNV003 recipients compared to recipients of 177Lu-IgG1 (P<0.025) or 2 x NNV003 (P<0.02).
DOHH2 model
RAG-2 mice injected with DOHH2 cells had survival times surpassing 200 days after treatment with NNV003 or 177Lu-NNV003.
The median survival was not reached in mice that received NNV003 (at 2 or 30 mg/kg) or 177Lu-NNV003 (at 200, 300, or 400 MBq/kg). But the median survival was 46 days in mice that received NaCl and 47 days in mice that received 177Lu-IgG1 (300 MBq/kg).
The difference in survival was significant for recipients of NNV003 or 177Lu-NNV003 compared to recipients of 177Lu-IgG1 or NaCl (P<0.001 for all).
Toxicity and biodistribution
The researchers noted that the 177Lu-labeled antibodies caused transient hematologic toxicity in the mice.
In the MEC-2 and DOHH2 models, there was no redistribution of 177Lu-NNV003 in organs after initial uptake. (The researchers did not report on biodistribution in the REC-1 model.)
177Lu-NNV003 had low uptake in the liver, spleen, kidneys, and femur. The researchers said this suggests 177Lu-NNV003 is stable in vivo, as free lutetium-177 tends to accumulate in bones.
CHICAGO—The radioimmunoconjugate 177Lu-NNV003 has demonstrated activity against non-Hodgkin lymphomas (NHLs).
Experiments showed that 177Lu-NNV003 can inhibit proliferation in mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL) cell lines.
177Lu-NNV003 also exhibited an antitumor effect and prolonged survival in mouse models of MCL, DLBCL, and CLL.
These results were presented at the AACR Annual Meeting 2018 (abstract 848).
This research was conducted by employees of Nordic Nanovector and other researchers. Nordic Nanovector is the company developing 177Lu-NNV003.
177Lu-NNV003 consists of a chimeric antibody targeting CD37 (NNV003) conjugated with p-SCN-Bn-DOTA, which chelates the β-emitting radionuclide lutetium-177.
The researchers found that 177Lu-NNV003 inhibited proliferation in all 3 NHL cell lines tested—MEC-2 (CLL), DOHH2 (DLBCL), and REC-1 (MCL). DOHH2 was the most radiosensitive cell line.
The unlabeled NNV003 antibody, on the other hand, did not exhibit an antiproliferative effect in these cell lines. However, NNV003 did induce antibody-dependent cellular cytotoxicity in MEC-2 and DOHH2 cells and antibody-dependent cellular phagocytosis in MEC-2 cells.
The researchers found that 177Lu-NNV003 targeted CD37-positive cells and demonstrated antitumor effects in mouse models of MCL, CLL, and DLBCL.
REC-1 model
177Lu-NNV003 prolonged survival in CB17 SCID mice injected with REC-1 cells and cured 50% to 60% of the mice.
Median survival times were 55 days in mice that received sodium chloride (NaCl), 85 days in mice that received NNV003 (0.167 mg/kg), and 61 days in mice that received 177Lu-IgG1 (100 MBq/kg).
On the other hand, mice treated with 177Lu-NNV003 had a median survival of 152 days (100 MBq/kg), or the median survival was not reached (50 MBq/kg).
The difference in survival was significant for 177Lu-NNV003 recipients compared to recipients of NaCl (P<0.001) or 177Lu-IgG1 (P<0.002).
MEC-2 model
177Lu-NNV003 also prolonged survival in NRG mice injected with MEC-2 cells.
The median survival was 21 days in mice that received NaCl, NNV003 (2 x 0.33 mg/kg), or 177Lu-IgG1 (200 MBq/kg).
However, mice treated with 177Lu-NNV003 had a median survival of 32 days (200 MBq/kg) or 29 days (2 x 200 MBq/kg).
The difference in survival was significant for 177Lu-NNV003 recipients compared to recipients of 177Lu-IgG1 (P<0.025) or 2 x NNV003 (P<0.02).
DOHH2 model
RAG-2 mice injected with DOHH2 cells had survival times surpassing 200 days after treatment with NNV003 or 177Lu-NNV003.
The median survival was not reached in mice that received NNV003 (at 2 or 30 mg/kg) or 177Lu-NNV003 (at 200, 300, or 400 MBq/kg). But the median survival was 46 days in mice that received NaCl and 47 days in mice that received 177Lu-IgG1 (300 MBq/kg).
The difference in survival was significant for recipients of NNV003 or 177Lu-NNV003 compared to recipients of 177Lu-IgG1 or NaCl (P<0.001 for all).
Toxicity and biodistribution
The researchers noted that the 177Lu-labeled antibodies caused transient hematologic toxicity in the mice.
In the MEC-2 and DOHH2 models, there was no redistribution of 177Lu-NNV003 in organs after initial uptake. (The researchers did not report on biodistribution in the REC-1 model.)
177Lu-NNV003 had low uptake in the liver, spleen, kidneys, and femur. The researchers said this suggests 177Lu-NNV003 is stable in vivo, as free lutetium-177 tends to accumulate in bones.
CDK inhibitor synergizes with venetoclax in CLL
CHICAGO—Researchers have reported “strong synergy” between the CDK2/9 inhibitor CYC065 and the Bcl-2 inhibitor venetoclax in chronic lymphocytic leukemia (CLL).
Experiments indicated that CYC065 and venetoclax target parallel mechanisms that promote survival in CLL cells, working together to induce apoptosis.
The drugs demonstrated synergy even in CLL samples that are inherently resistant to each drug alone.
William Plunkett, PhD, of The University of Texas MD Anderson Cancer Center in Houston, Texas, and his colleagues reported these findings at the AACR Annual Meeting 2018 (abstract 3905).
This research was supported by Cyclacel Pharmaceuticals, Inc., the company developing CYC065.
The researchers explained that CYC065 depletes Mcl-1 to induce apoptosis in CLL cells, while venetoclax induces apoptosis via inhibition of Bcl-2. However, upregulation of Mcl-1 is associated with resistance to venetoclax.
Therefore, the researchers theorized that combining CYC065 and venetoclax would serve to target 2 mechanisms that promote survival in CLL cells.
Experiments showed that CYC065 and venetoclax combined synergistically in CLL samples with or without 17p deletion. However, the researchers observed heterogeneity in response across samples.
The team said both drugs appeared to be less potent in some del(17p) samples. However, they also observed “great synergy” in del(17p) samples that were resistant to CYC065 or venetoclax alone.
The researchers noted differences in the kinetics of cell death in response to each drug and said this is consistent with the drugs’ different mechanisms of action.
Maximal cell death was reached at 6 to 8 hours with venetoclax but took at least 24 hours with CYC065.
The researchers also assessed the reversibility of CYC065 and venetoclax. They incubated CLL cells with each drug alone and in combination, then washed and incubated cells in drug-free media.
The team observed no additional cell death after the removal of CYC065, venetoclax, or the combination. They said this suggests an “adequate exposure time” is needed to maximize the induction of apoptosis with these drugs.
“[T]he combination of CYC065 and venetoclax is strongly synergistic in primary CLL cells from patients, including those with 17p deletions,” said Spiro Rombotis, president and chief executive officer of Cyclacel.
“In addition, the combination was active in 2 CLL samples which were resistant to either agent alone. These findings support the hypothesis that dual targeting of the Mcl-1- and Bcl-2-dependent mechanisms could induce synergistic cell death by apoptosis.”
Based on these results, Cyclacel is planning a trial of CYC065 and venetoclax in patients with relapsed/refractory CLL.
CHICAGO—Researchers have reported “strong synergy” between the CDK2/9 inhibitor CYC065 and the Bcl-2 inhibitor venetoclax in chronic lymphocytic leukemia (CLL).
Experiments indicated that CYC065 and venetoclax target parallel mechanisms that promote survival in CLL cells, working together to induce apoptosis.
The drugs demonstrated synergy even in CLL samples that are inherently resistant to each drug alone.
William Plunkett, PhD, of The University of Texas MD Anderson Cancer Center in Houston, Texas, and his colleagues reported these findings at the AACR Annual Meeting 2018 (abstract 3905).
This research was supported by Cyclacel Pharmaceuticals, Inc., the company developing CYC065.
The researchers explained that CYC065 depletes Mcl-1 to induce apoptosis in CLL cells, while venetoclax induces apoptosis via inhibition of Bcl-2. However, upregulation of Mcl-1 is associated with resistance to venetoclax.
Therefore, the researchers theorized that combining CYC065 and venetoclax would serve to target 2 mechanisms that promote survival in CLL cells.
Experiments showed that CYC065 and venetoclax combined synergistically in CLL samples with or without 17p deletion. However, the researchers observed heterogeneity in response across samples.
The team said both drugs appeared to be less potent in some del(17p) samples. However, they also observed “great synergy” in del(17p) samples that were resistant to CYC065 or venetoclax alone.
The researchers noted differences in the kinetics of cell death in response to each drug and said this is consistent with the drugs’ different mechanisms of action.
Maximal cell death was reached at 6 to 8 hours with venetoclax but took at least 24 hours with CYC065.
The researchers also assessed the reversibility of CYC065 and venetoclax. They incubated CLL cells with each drug alone and in combination, then washed and incubated cells in drug-free media.
The team observed no additional cell death after the removal of CYC065, venetoclax, or the combination. They said this suggests an “adequate exposure time” is needed to maximize the induction of apoptosis with these drugs.
“[T]he combination of CYC065 and venetoclax is strongly synergistic in primary CLL cells from patients, including those with 17p deletions,” said Spiro Rombotis, president and chief executive officer of Cyclacel.
“In addition, the combination was active in 2 CLL samples which were resistant to either agent alone. These findings support the hypothesis that dual targeting of the Mcl-1- and Bcl-2-dependent mechanisms could induce synergistic cell death by apoptosis.”
Based on these results, Cyclacel is planning a trial of CYC065 and venetoclax in patients with relapsed/refractory CLL.
CHICAGO—Researchers have reported “strong synergy” between the CDK2/9 inhibitor CYC065 and the Bcl-2 inhibitor venetoclax in chronic lymphocytic leukemia (CLL).
Experiments indicated that CYC065 and venetoclax target parallel mechanisms that promote survival in CLL cells, working together to induce apoptosis.
The drugs demonstrated synergy even in CLL samples that are inherently resistant to each drug alone.
William Plunkett, PhD, of The University of Texas MD Anderson Cancer Center in Houston, Texas, and his colleagues reported these findings at the AACR Annual Meeting 2018 (abstract 3905).
This research was supported by Cyclacel Pharmaceuticals, Inc., the company developing CYC065.
The researchers explained that CYC065 depletes Mcl-1 to induce apoptosis in CLL cells, while venetoclax induces apoptosis via inhibition of Bcl-2. However, upregulation of Mcl-1 is associated with resistance to venetoclax.
Therefore, the researchers theorized that combining CYC065 and venetoclax would serve to target 2 mechanisms that promote survival in CLL cells.
Experiments showed that CYC065 and venetoclax combined synergistically in CLL samples with or without 17p deletion. However, the researchers observed heterogeneity in response across samples.
The team said both drugs appeared to be less potent in some del(17p) samples. However, they also observed “great synergy” in del(17p) samples that were resistant to CYC065 or venetoclax alone.
The researchers noted differences in the kinetics of cell death in response to each drug and said this is consistent with the drugs’ different mechanisms of action.
Maximal cell death was reached at 6 to 8 hours with venetoclax but took at least 24 hours with CYC065.
The researchers also assessed the reversibility of CYC065 and venetoclax. They incubated CLL cells with each drug alone and in combination, then washed and incubated cells in drug-free media.
The team observed no additional cell death after the removal of CYC065, venetoclax, or the combination. They said this suggests an “adequate exposure time” is needed to maximize the induction of apoptosis with these drugs.
“[T]he combination of CYC065 and venetoclax is strongly synergistic in primary CLL cells from patients, including those with 17p deletions,” said Spiro Rombotis, president and chief executive officer of Cyclacel.
“In addition, the combination was active in 2 CLL samples which were resistant to either agent alone. These findings support the hypothesis that dual targeting of the Mcl-1- and Bcl-2-dependent mechanisms could induce synergistic cell death by apoptosis.”
Based on these results, Cyclacel is planning a trial of CYC065 and venetoclax in patients with relapsed/refractory CLL.
FDA places partial hold on trials after secondary lymphoma
The drugmaker after a pediatric patient developed a secondary T-cell lymphoma.
The Food and Drug Administration had issued a partial clinical hold in April on new enrollment of any patients with genetically defined solid tumors and hematologic malignancies. Patients already enrolled who have not had disease progression can continue to receive tazemetostat.
Tazemetostat is a first-in-class EZH2 inhibitor being studied as monotherapy in phase 1 and 2 trials for certain molecularly defined solid tumors, follicular lymphoma and diffuse large B-cell lymphoma, mesothelioma, and in combination studies of DLBCL and non–small cell lung cancer.
Epizyme is currently working to update informed consent, the investigator’s brochure, and study protocols, the company said in a statement.
The drugmaker after a pediatric patient developed a secondary T-cell lymphoma.
The Food and Drug Administration had issued a partial clinical hold in April on new enrollment of any patients with genetically defined solid tumors and hematologic malignancies. Patients already enrolled who have not had disease progression can continue to receive tazemetostat.
Tazemetostat is a first-in-class EZH2 inhibitor being studied as monotherapy in phase 1 and 2 trials for certain molecularly defined solid tumors, follicular lymphoma and diffuse large B-cell lymphoma, mesothelioma, and in combination studies of DLBCL and non–small cell lung cancer.
Epizyme is currently working to update informed consent, the investigator’s brochure, and study protocols, the company said in a statement.
The drugmaker after a pediatric patient developed a secondary T-cell lymphoma.
The Food and Drug Administration had issued a partial clinical hold in April on new enrollment of any patients with genetically defined solid tumors and hematologic malignancies. Patients already enrolled who have not had disease progression can continue to receive tazemetostat.
Tazemetostat is a first-in-class EZH2 inhibitor being studied as monotherapy in phase 1 and 2 trials for certain molecularly defined solid tumors, follicular lymphoma and diffuse large B-cell lymphoma, mesothelioma, and in combination studies of DLBCL and non–small cell lung cancer.
Epizyme is currently working to update informed consent, the investigator’s brochure, and study protocols, the company said in a statement.
FDA places tazemetostat trials on partial hold
The US Food and Drug Administration (FDA) has placed a partial hold on clinical trials of tazemetostat, an EZH2 inhibitor being developed to treat solid tumors and lymphomas.
The hold has halted enrollment in US-based trials of tazemetostat, but study subjects who have not experienced disease progression may continue to receive the drug.
The hold is due to an adverse event observed in a pediatric patient on a phase 1 study of tazemetostat.
The patient, who had advanced poorly differentiated chordoma, developed a secondary T-cell lymphoma while taking tazemetostat.
The patient had been on study for approximately 15 months and had achieved a confirmed partial response. Now, the patient has discontinued tazemetostat and is being treated for T-cell lymphoma.
More than 750 patients have been treated with tazemetostat to date, and this is the only case of secondary lymphoma that has been observed, according to Epizyme, Inc., the company developing tazemetostat.
The company also noted that doses of tazemetostat explored in its phase 1 pediatric study are higher than those used in the phase 2 adult studies.
Epizyme has begun taking steps to address the hold on tazemetostat trials—updating the informed consent, investigator’s brochure, and study protocols.
The company will need to confirm alignment with the FDA in order to resume US enrollment.
“We are working expeditiously with clinical trial investigators and regulatory authorities to initiate the appropriate steps to resume enrollment,” said Robert Bazemore, president and chief executive officer of Epizyme.
“Epizyme, along with our global investigator community, has been very encouraged by the clinical responses and tolerability of tazemetostat observed in pediatric and adult patients with hematological malignancies and solid tumors enrolled in our trials. We remain encouraged by the potential of tazemetostat to address the unmet needs of many patients living with cancer.”
The US Food and Drug Administration (FDA) has placed a partial hold on clinical trials of tazemetostat, an EZH2 inhibitor being developed to treat solid tumors and lymphomas.
The hold has halted enrollment in US-based trials of tazemetostat, but study subjects who have not experienced disease progression may continue to receive the drug.
The hold is due to an adverse event observed in a pediatric patient on a phase 1 study of tazemetostat.
The patient, who had advanced poorly differentiated chordoma, developed a secondary T-cell lymphoma while taking tazemetostat.
The patient had been on study for approximately 15 months and had achieved a confirmed partial response. Now, the patient has discontinued tazemetostat and is being treated for T-cell lymphoma.
More than 750 patients have been treated with tazemetostat to date, and this is the only case of secondary lymphoma that has been observed, according to Epizyme, Inc., the company developing tazemetostat.
The company also noted that doses of tazemetostat explored in its phase 1 pediatric study are higher than those used in the phase 2 adult studies.
Epizyme has begun taking steps to address the hold on tazemetostat trials—updating the informed consent, investigator’s brochure, and study protocols.
The company will need to confirm alignment with the FDA in order to resume US enrollment.
“We are working expeditiously with clinical trial investigators and regulatory authorities to initiate the appropriate steps to resume enrollment,” said Robert Bazemore, president and chief executive officer of Epizyme.
“Epizyme, along with our global investigator community, has been very encouraged by the clinical responses and tolerability of tazemetostat observed in pediatric and adult patients with hematological malignancies and solid tumors enrolled in our trials. We remain encouraged by the potential of tazemetostat to address the unmet needs of many patients living with cancer.”
The US Food and Drug Administration (FDA) has placed a partial hold on clinical trials of tazemetostat, an EZH2 inhibitor being developed to treat solid tumors and lymphomas.
The hold has halted enrollment in US-based trials of tazemetostat, but study subjects who have not experienced disease progression may continue to receive the drug.
The hold is due to an adverse event observed in a pediatric patient on a phase 1 study of tazemetostat.
The patient, who had advanced poorly differentiated chordoma, developed a secondary T-cell lymphoma while taking tazemetostat.
The patient had been on study for approximately 15 months and had achieved a confirmed partial response. Now, the patient has discontinued tazemetostat and is being treated for T-cell lymphoma.
More than 750 patients have been treated with tazemetostat to date, and this is the only case of secondary lymphoma that has been observed, according to Epizyme, Inc., the company developing tazemetostat.
The company also noted that doses of tazemetostat explored in its phase 1 pediatric study are higher than those used in the phase 2 adult studies.
Epizyme has begun taking steps to address the hold on tazemetostat trials—updating the informed consent, investigator’s brochure, and study protocols.
The company will need to confirm alignment with the FDA in order to resume US enrollment.
“We are working expeditiously with clinical trial investigators and regulatory authorities to initiate the appropriate steps to resume enrollment,” said Robert Bazemore, president and chief executive officer of Epizyme.
“Epizyme, along with our global investigator community, has been very encouraged by the clinical responses and tolerability of tazemetostat observed in pediatric and adult patients with hematological malignancies and solid tumors enrolled in our trials. We remain encouraged by the potential of tazemetostat to address the unmet needs of many patients living with cancer.”
Art education benefits blood cancer patients
New research suggests a bedside visual art intervention (BVAI) can reduce pain and anxiety in inpatients with hematologic malignancies, including those undergoing transplant.
The BVAI involved an educator teaching patients art technique one-on-one for approximately 30 minutes.
After a single session, patients had significant improvements in positive mood and pain scores, as well as decreases in negative mood and anxiety.
Alexandra P. Wolanskyj, MD, of Mayo Clinic in Rochester, Minnesota, and her colleagues reported these results in the European Journal of Cancer Care.
The study included 21 patients, 19 of them female. Their median age was 53.5 (range, 19-75). Six patients were undergoing hematopoietic stem cell transplant.
The patients had multiple myeloma (n=5), acute myeloid leukemia (n=5), non-Hodgkin lymphoma (n=3), Hodgkin lymphoma (n=2), acute lymphoblastic leukemia (n=1), chronic lymphocytic leukemia (n=1), amyloidosis (n=1), Gardner-Diamond syndrome (n=1), myelodysplastic syndrome (n=1), and Waldenstrom’s macroglobulinemia (n=1).
Nearly half of patients had relapsed disease (47.6%), 23.8% had active and new disease, 19.0% had active disease with primary resistance on chemotherapy, and 9.5% of patients were in remission.
Intervention
The researchers recruited an educator from a community art center to teach art at the patients’ bedsides. Sessions were intended to be about 30 minutes. However, patients could stop at any time or continue beyond 30 minutes.
Patients and their families could make art or just observe. Materials used included watercolors, oil pastels, colored pencils, and clay (all non-toxic and odorless). The materials were left with patients so they could continue to use them after the sessions.
Results
The researchers assessed patients’ pain, anxiety, and mood at baseline and after the patients had a session with the art educator.
After the BVAI, patients had a significant decrease in pain, according to the Visual Analog Scale (VAS). The 14 patients who reported any pain at baseline had a mean reduction in VAS score of 1.5, or a 35.1% reduction in pain (P=0.017).
Patients had a 21.6% reduction in anxiety after the BVAI. Among the 20 patients who completed this assessment, there was a mean 9.2-point decrease in State-Trait Anxiety Inventory (STAI) score (P=0.001).
In addition, patients had a significant increase in positive mood and a significant decrease in negative mood after the BVAI. Mood was assessed in 20 patients using the Positive and Negative Affect Schedule (PANAS) scale.
Positive mood increased 14.6% (P=0.003), and negative mood decreased 18.0% (P=0.015) after the BVAI. Patients’ mean PANAS scores increased 4.6 points for positive mood and decreased 3.3 points for negative mood.
All 21 patients completed a questionnaire on the BVAI. All but 1 patient (95%) said the intervention was positive overall, and 85% of patients (n=18) said they would be interested in participating in future art-based interventions.
The researchers said these results suggest experiences provided by artists in the community may be an adjunct to conventional treatments in patients with cancer-related mood symptoms and pain.
New research suggests a bedside visual art intervention (BVAI) can reduce pain and anxiety in inpatients with hematologic malignancies, including those undergoing transplant.
The BVAI involved an educator teaching patients art technique one-on-one for approximately 30 minutes.
After a single session, patients had significant improvements in positive mood and pain scores, as well as decreases in negative mood and anxiety.
Alexandra P. Wolanskyj, MD, of Mayo Clinic in Rochester, Minnesota, and her colleagues reported these results in the European Journal of Cancer Care.
The study included 21 patients, 19 of them female. Their median age was 53.5 (range, 19-75). Six patients were undergoing hematopoietic stem cell transplant.
The patients had multiple myeloma (n=5), acute myeloid leukemia (n=5), non-Hodgkin lymphoma (n=3), Hodgkin lymphoma (n=2), acute lymphoblastic leukemia (n=1), chronic lymphocytic leukemia (n=1), amyloidosis (n=1), Gardner-Diamond syndrome (n=1), myelodysplastic syndrome (n=1), and Waldenstrom’s macroglobulinemia (n=1).
Nearly half of patients had relapsed disease (47.6%), 23.8% had active and new disease, 19.0% had active disease with primary resistance on chemotherapy, and 9.5% of patients were in remission.
Intervention
The researchers recruited an educator from a community art center to teach art at the patients’ bedsides. Sessions were intended to be about 30 minutes. However, patients could stop at any time or continue beyond 30 minutes.
Patients and their families could make art or just observe. Materials used included watercolors, oil pastels, colored pencils, and clay (all non-toxic and odorless). The materials were left with patients so they could continue to use them after the sessions.
Results
The researchers assessed patients’ pain, anxiety, and mood at baseline and after the patients had a session with the art educator.
After the BVAI, patients had a significant decrease in pain, according to the Visual Analog Scale (VAS). The 14 patients who reported any pain at baseline had a mean reduction in VAS score of 1.5, or a 35.1% reduction in pain (P=0.017).
Patients had a 21.6% reduction in anxiety after the BVAI. Among the 20 patients who completed this assessment, there was a mean 9.2-point decrease in State-Trait Anxiety Inventory (STAI) score (P=0.001).
In addition, patients had a significant increase in positive mood and a significant decrease in negative mood after the BVAI. Mood was assessed in 20 patients using the Positive and Negative Affect Schedule (PANAS) scale.
Positive mood increased 14.6% (P=0.003), and negative mood decreased 18.0% (P=0.015) after the BVAI. Patients’ mean PANAS scores increased 4.6 points for positive mood and decreased 3.3 points for negative mood.
All 21 patients completed a questionnaire on the BVAI. All but 1 patient (95%) said the intervention was positive overall, and 85% of patients (n=18) said they would be interested in participating in future art-based interventions.
The researchers said these results suggest experiences provided by artists in the community may be an adjunct to conventional treatments in patients with cancer-related mood symptoms and pain.
New research suggests a bedside visual art intervention (BVAI) can reduce pain and anxiety in inpatients with hematologic malignancies, including those undergoing transplant.
The BVAI involved an educator teaching patients art technique one-on-one for approximately 30 minutes.
After a single session, patients had significant improvements in positive mood and pain scores, as well as decreases in negative mood and anxiety.
Alexandra P. Wolanskyj, MD, of Mayo Clinic in Rochester, Minnesota, and her colleagues reported these results in the European Journal of Cancer Care.
The study included 21 patients, 19 of them female. Their median age was 53.5 (range, 19-75). Six patients were undergoing hematopoietic stem cell transplant.
The patients had multiple myeloma (n=5), acute myeloid leukemia (n=5), non-Hodgkin lymphoma (n=3), Hodgkin lymphoma (n=2), acute lymphoblastic leukemia (n=1), chronic lymphocytic leukemia (n=1), amyloidosis (n=1), Gardner-Diamond syndrome (n=1), myelodysplastic syndrome (n=1), and Waldenstrom’s macroglobulinemia (n=1).
Nearly half of patients had relapsed disease (47.6%), 23.8% had active and new disease, 19.0% had active disease with primary resistance on chemotherapy, and 9.5% of patients were in remission.
Intervention
The researchers recruited an educator from a community art center to teach art at the patients’ bedsides. Sessions were intended to be about 30 minutes. However, patients could stop at any time or continue beyond 30 minutes.
Patients and their families could make art or just observe. Materials used included watercolors, oil pastels, colored pencils, and clay (all non-toxic and odorless). The materials were left with patients so they could continue to use them after the sessions.
Results
The researchers assessed patients’ pain, anxiety, and mood at baseline and after the patients had a session with the art educator.
After the BVAI, patients had a significant decrease in pain, according to the Visual Analog Scale (VAS). The 14 patients who reported any pain at baseline had a mean reduction in VAS score of 1.5, or a 35.1% reduction in pain (P=0.017).
Patients had a 21.6% reduction in anxiety after the BVAI. Among the 20 patients who completed this assessment, there was a mean 9.2-point decrease in State-Trait Anxiety Inventory (STAI) score (P=0.001).
In addition, patients had a significant increase in positive mood and a significant decrease in negative mood after the BVAI. Mood was assessed in 20 patients using the Positive and Negative Affect Schedule (PANAS) scale.
Positive mood increased 14.6% (P=0.003), and negative mood decreased 18.0% (P=0.015) after the BVAI. Patients’ mean PANAS scores increased 4.6 points for positive mood and decreased 3.3 points for negative mood.
All 21 patients completed a questionnaire on the BVAI. All but 1 patient (95%) said the intervention was positive overall, and 85% of patients (n=18) said they would be interested in participating in future art-based interventions.
The researchers said these results suggest experiences provided by artists in the community may be an adjunct to conventional treatments in patients with cancer-related mood symptoms and pain.
Inhibitor outperforms rivals in leukemia, lymphoma
CHICAGO—Preclinical research suggests the pan-FLT3/pan-BTK inhibitor CG’806 is more effective than other kinase inhibitors in fighting certain hematologic malignancies.
In one study, CG’806 proved more potent than comparator drugs in primary samples of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL).
In another study, CG’806 demonstrated greater cytotoxicity than comparators in a range of malignant B cell lines.
Data from both studies were presented at the AACR Annual Meeting 2018 (abstracts 791 and 794).
The research was supported by Aptose Biosciences, Inc., the company developing CG’806.
CG’806 is a small molecule that inhibits wild-type (WT) FLT3, as well as FLT3 housing the ITD mutation or with point mutations in the tyrosine kinase domain (TKD, including D835G, D835Y, D835H) or in the gatekeeper region (F691L). CG’806 also inhibits BTK-WT and BTK-C481S.
Stephen E. Kurtz, PhD, of Oregon Health & Science University in Portland, and his colleagues presented results with CG’806 in primary patient samples.
The team found that CG’806 demonstrated greater potency against AML samples relative to other FLT3 inhibitors.
Median IC50 values in 188 AML patient samples were 0.0765 µM for CG’806, 0.125 µM for gilteritinib, 0.199 µM for quizartinib, 0.551 µM for dovitinib, 2.25 µM for midostaurin, 2.93 µM for sorafenib, and 5.01 µM for crenolanib.
The researchers said CG’806 sensitivity was enhanced in FLT3-ITD and FLT3-TKD positive cases.
In CLL patient samples, CG’806 exhibited greater potency and a greater range of activity than the BTK inhibitor ibrutinib. Across 95 CLL samples, the median IC50 values were 0.114 µM for CG’806 and 4.09 µM for ibrutinib.
The researchers said this greater potency of CG’806 may be due to the activity of CG’806 on CSF1R, which has been identified as a therapeutic target in CLL.
“The clinical benefit of current FLT3 inhibitors in AML is transient, as resistance develops after several months of treatment,” Dr Kurtz noted. “Similarly, ibrutinib . . . is limited by acquired resistance as well as refractory disease and tolerance challenges. As a pan-FLT3/pan-BTK inhibitor . . ., CG’806 offers important potential to address these limitations.”
Hongying Zhang, MD, PhD, of Aptose Biosciences, and her colleagues presented results with CG’806 in malignant B-cell and AML cell lines.
The researchers found that CG’806 inhibited FLT3-ITD signaling and induced apoptosis more effectively than quizartinib in FLT3-ITD AML cells (MV4-11). The team noted that CG’806 caused G0/G1 cell-cycle arrest in the cells.
CG’806 also exhibited greater cytotoxic activity than quizartinib in FLT3-WT AML cell lines (KG-1 and NOMO-1).
In addition, CG’806 was more potent than quizartinib, gilteritinib, and crenolanib in Ba/F3 cells transfected with FLT3-WT, ITD, D835Y, and ITD-F691. CG’806 was more potent than quizartinib and crenolanib—but not gilteritinib—in Ba/F3 cells transfected with FLT3-ITD-D835Y.
The researchers said they found that CG’806 inhibits BTK, AURK, and downstream signals in FLT3-WT AML cells.
The team also found that CG’806 decreased BTK phosphorylation in all tested cell lines of B-cell malignancies. This included acute lymphoblastic leukemia, mantle cell lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma cell lines.
Across all cell lines, CG’806 killed malignant B cells more effectively than ibrutinib. And CG’806 was “equally potent” against WT and C481S-mutant BTK, according to the researchers.
The team also said CG’806 inhibited AURK and induced polyploidy in B-cell malignancies.
“[C]G’806 has demonstrated the ability to kill a broad range of AML and B-cell malignancies through inhibition of multiple oncogenic pathways,” said William G. Rice, PhD, chairman and chief executive officer of Aptose.
“These studies are critical for understanding how to develop and position CG’806 as we prepare for clinical development in these challenging hematologic malignancies.”
CHICAGO—Preclinical research suggests the pan-FLT3/pan-BTK inhibitor CG’806 is more effective than other kinase inhibitors in fighting certain hematologic malignancies.
In one study, CG’806 proved more potent than comparator drugs in primary samples of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL).
In another study, CG’806 demonstrated greater cytotoxicity than comparators in a range of malignant B cell lines.
Data from both studies were presented at the AACR Annual Meeting 2018 (abstracts 791 and 794).
The research was supported by Aptose Biosciences, Inc., the company developing CG’806.
CG’806 is a small molecule that inhibits wild-type (WT) FLT3, as well as FLT3 housing the ITD mutation or with point mutations in the tyrosine kinase domain (TKD, including D835G, D835Y, D835H) or in the gatekeeper region (F691L). CG’806 also inhibits BTK-WT and BTK-C481S.
Stephen E. Kurtz, PhD, of Oregon Health & Science University in Portland, and his colleagues presented results with CG’806 in primary patient samples.
The team found that CG’806 demonstrated greater potency against AML samples relative to other FLT3 inhibitors.
Median IC50 values in 188 AML patient samples were 0.0765 µM for CG’806, 0.125 µM for gilteritinib, 0.199 µM for quizartinib, 0.551 µM for dovitinib, 2.25 µM for midostaurin, 2.93 µM for sorafenib, and 5.01 µM for crenolanib.
The researchers said CG’806 sensitivity was enhanced in FLT3-ITD and FLT3-TKD positive cases.
In CLL patient samples, CG’806 exhibited greater potency and a greater range of activity than the BTK inhibitor ibrutinib. Across 95 CLL samples, the median IC50 values were 0.114 µM for CG’806 and 4.09 µM for ibrutinib.
The researchers said this greater potency of CG’806 may be due to the activity of CG’806 on CSF1R, which has been identified as a therapeutic target in CLL.
“The clinical benefit of current FLT3 inhibitors in AML is transient, as resistance develops after several months of treatment,” Dr Kurtz noted. “Similarly, ibrutinib . . . is limited by acquired resistance as well as refractory disease and tolerance challenges. As a pan-FLT3/pan-BTK inhibitor . . ., CG’806 offers important potential to address these limitations.”
Hongying Zhang, MD, PhD, of Aptose Biosciences, and her colleagues presented results with CG’806 in malignant B-cell and AML cell lines.
The researchers found that CG’806 inhibited FLT3-ITD signaling and induced apoptosis more effectively than quizartinib in FLT3-ITD AML cells (MV4-11). The team noted that CG’806 caused G0/G1 cell-cycle arrest in the cells.
CG’806 also exhibited greater cytotoxic activity than quizartinib in FLT3-WT AML cell lines (KG-1 and NOMO-1).
In addition, CG’806 was more potent than quizartinib, gilteritinib, and crenolanib in Ba/F3 cells transfected with FLT3-WT, ITD, D835Y, and ITD-F691. CG’806 was more potent than quizartinib and crenolanib—but not gilteritinib—in Ba/F3 cells transfected with FLT3-ITD-D835Y.
The researchers said they found that CG’806 inhibits BTK, AURK, and downstream signals in FLT3-WT AML cells.
The team also found that CG’806 decreased BTK phosphorylation in all tested cell lines of B-cell malignancies. This included acute lymphoblastic leukemia, mantle cell lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma cell lines.
Across all cell lines, CG’806 killed malignant B cells more effectively than ibrutinib. And CG’806 was “equally potent” against WT and C481S-mutant BTK, according to the researchers.
The team also said CG’806 inhibited AURK and induced polyploidy in B-cell malignancies.
“[C]G’806 has demonstrated the ability to kill a broad range of AML and B-cell malignancies through inhibition of multiple oncogenic pathways,” said William G. Rice, PhD, chairman and chief executive officer of Aptose.
“These studies are critical for understanding how to develop and position CG’806 as we prepare for clinical development in these challenging hematologic malignancies.”
CHICAGO—Preclinical research suggests the pan-FLT3/pan-BTK inhibitor CG’806 is more effective than other kinase inhibitors in fighting certain hematologic malignancies.
In one study, CG’806 proved more potent than comparator drugs in primary samples of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL).
In another study, CG’806 demonstrated greater cytotoxicity than comparators in a range of malignant B cell lines.
Data from both studies were presented at the AACR Annual Meeting 2018 (abstracts 791 and 794).
The research was supported by Aptose Biosciences, Inc., the company developing CG’806.
CG’806 is a small molecule that inhibits wild-type (WT) FLT3, as well as FLT3 housing the ITD mutation or with point mutations in the tyrosine kinase domain (TKD, including D835G, D835Y, D835H) or in the gatekeeper region (F691L). CG’806 also inhibits BTK-WT and BTK-C481S.
Stephen E. Kurtz, PhD, of Oregon Health & Science University in Portland, and his colleagues presented results with CG’806 in primary patient samples.
The team found that CG’806 demonstrated greater potency against AML samples relative to other FLT3 inhibitors.
Median IC50 values in 188 AML patient samples were 0.0765 µM for CG’806, 0.125 µM for gilteritinib, 0.199 µM for quizartinib, 0.551 µM for dovitinib, 2.25 µM for midostaurin, 2.93 µM for sorafenib, and 5.01 µM for crenolanib.
The researchers said CG’806 sensitivity was enhanced in FLT3-ITD and FLT3-TKD positive cases.
In CLL patient samples, CG’806 exhibited greater potency and a greater range of activity than the BTK inhibitor ibrutinib. Across 95 CLL samples, the median IC50 values were 0.114 µM for CG’806 and 4.09 µM for ibrutinib.
The researchers said this greater potency of CG’806 may be due to the activity of CG’806 on CSF1R, which has been identified as a therapeutic target in CLL.
“The clinical benefit of current FLT3 inhibitors in AML is transient, as resistance develops after several months of treatment,” Dr Kurtz noted. “Similarly, ibrutinib . . . is limited by acquired resistance as well as refractory disease and tolerance challenges. As a pan-FLT3/pan-BTK inhibitor . . ., CG’806 offers important potential to address these limitations.”
Hongying Zhang, MD, PhD, of Aptose Biosciences, and her colleagues presented results with CG’806 in malignant B-cell and AML cell lines.
The researchers found that CG’806 inhibited FLT3-ITD signaling and induced apoptosis more effectively than quizartinib in FLT3-ITD AML cells (MV4-11). The team noted that CG’806 caused G0/G1 cell-cycle arrest in the cells.
CG’806 also exhibited greater cytotoxic activity than quizartinib in FLT3-WT AML cell lines (KG-1 and NOMO-1).
In addition, CG’806 was more potent than quizartinib, gilteritinib, and crenolanib in Ba/F3 cells transfected with FLT3-WT, ITD, D835Y, and ITD-F691. CG’806 was more potent than quizartinib and crenolanib—but not gilteritinib—in Ba/F3 cells transfected with FLT3-ITD-D835Y.
The researchers said they found that CG’806 inhibits BTK, AURK, and downstream signals in FLT3-WT AML cells.
The team also found that CG’806 decreased BTK phosphorylation in all tested cell lines of B-cell malignancies. This included acute lymphoblastic leukemia, mantle cell lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma cell lines.
Across all cell lines, CG’806 killed malignant B cells more effectively than ibrutinib. And CG’806 was “equally potent” against WT and C481S-mutant BTK, according to the researchers.
The team also said CG’806 inhibited AURK and induced polyploidy in B-cell malignancies.
“[C]G’806 has demonstrated the ability to kill a broad range of AML and B-cell malignancies through inhibition of multiple oncogenic pathways,” said William G. Rice, PhD, chairman and chief executive officer of Aptose.
“These studies are critical for understanding how to develop and position CG’806 as we prepare for clinical development in these challenging hematologic malignancies.”
Team uses iPSCs to create ‘universal’ CAR T cells
CHICAGO—Researchers have used induced pluripotent stem cells (iPSCs) to create a “universal” chimeric antigen receptor (CAR) T-cell therapy known as FT819.
The team says FT819 has the potential to be mass-produced, stored, and made readily available for cancer patients.
In in vitro experiments, FT819 demonstrated activity against leukemia and lymphoma.
These results were presented at the AACR Annual Meeting 2018 (abstract LB-108).
The research was conducted by employees of Fate Therapeutics, Inc., the company developing FT819, as well as Memorial Sloan-Kettering Cancer Center.
About FT819
FT819 is produced from a master iPSC line generated using T cells from healthy donors.
“A master iPSC line has unlimited capacity to self-renew and can be banked and renewably used,” said Bob Valamehr, PhD, vice-president of cancer immunotherapy at Fate Therapeutics, Inc.
“We started with cells from a healthy donor rather than the patient, created a master cell line, and used the master cell line to produce large quantities of ‘universal’ CAR19 T cells that are not patient-restricted. These first-of-kind CAR19 T cells, called FT819, can be packaged, stored, and made readily available for treatment of a large number of patients.”
FT819 has 2 targeting receptors—a CAR targeting CD19-positive tumor cells and a CD16 Fc receptor that can engage other therapies (such as tumor antigen-targeting monoclonal antibodies) to overcome antigen escape.
The master iPSC line used for the production of FT819 is engineered in a one-time event to insert a CD19 CAR into the T-cell receptor α constant (TRAC) locus. This is done to eliminate T-cell receptor expression and reduce the likelihood of graft-versus-host disease.
Previous research showed that targeting a CAR to the TRAC locus results in uniform CAR expression and enhances T-cell potency. In fact, TRAC-CAR T cells outperformed conventionally generated CAR T cells by preventing T-cell exhaustion in a mouse model of acute lymphoblastic leukemia.
In vitro experiments
With the current work, the researchers found that FT819 displayed an efficient cytotoxic T-cell response when challenged with CD19-positive tumor cells. FT819 produced cytokines (IFN-gamma, TNF-alpha, and IL-2) and mediators of cell death (CD107a/b, perforin, and granzyme B).
FT819 was also target-specific, attacking only CD19-positive tumor cells and sparing CD19-negative tumor cells in experiments with Raji (Burkitt lymphoma) and Nalm-6 (B-cell acute lymphoblastic leukemia) cell lines.
The researchers said they observed consistent antigen-specific cytotoxicity against Nalm-6 cells with FT819 but variability in antigen-specific cytotoxicity with conventional CAR T cells.
In addition, when combined with rituximab, FT819 elicited antibody-dependent cell-mediated cytotoxicity against CD19-negative, CD20-positive tumor cells.
“Through the development of FT819, we believe there is significant opportunity to lower the cost of CAR T-cell manufacture, enhance the quality of the product, and create a readily available supply of a more efficacious product to reach more patients in need,” Dr Valamehr said.
CHICAGO—Researchers have used induced pluripotent stem cells (iPSCs) to create a “universal” chimeric antigen receptor (CAR) T-cell therapy known as FT819.
The team says FT819 has the potential to be mass-produced, stored, and made readily available for cancer patients.
In in vitro experiments, FT819 demonstrated activity against leukemia and lymphoma.
These results were presented at the AACR Annual Meeting 2018 (abstract LB-108).
The research was conducted by employees of Fate Therapeutics, Inc., the company developing FT819, as well as Memorial Sloan-Kettering Cancer Center.
About FT819
FT819 is produced from a master iPSC line generated using T cells from healthy donors.
“A master iPSC line has unlimited capacity to self-renew and can be banked and renewably used,” said Bob Valamehr, PhD, vice-president of cancer immunotherapy at Fate Therapeutics, Inc.
“We started with cells from a healthy donor rather than the patient, created a master cell line, and used the master cell line to produce large quantities of ‘universal’ CAR19 T cells that are not patient-restricted. These first-of-kind CAR19 T cells, called FT819, can be packaged, stored, and made readily available for treatment of a large number of patients.”
FT819 has 2 targeting receptors—a CAR targeting CD19-positive tumor cells and a CD16 Fc receptor that can engage other therapies (such as tumor antigen-targeting monoclonal antibodies) to overcome antigen escape.
The master iPSC line used for the production of FT819 is engineered in a one-time event to insert a CD19 CAR into the T-cell receptor α constant (TRAC) locus. This is done to eliminate T-cell receptor expression and reduce the likelihood of graft-versus-host disease.
Previous research showed that targeting a CAR to the TRAC locus results in uniform CAR expression and enhances T-cell potency. In fact, TRAC-CAR T cells outperformed conventionally generated CAR T cells by preventing T-cell exhaustion in a mouse model of acute lymphoblastic leukemia.
In vitro experiments
With the current work, the researchers found that FT819 displayed an efficient cytotoxic T-cell response when challenged with CD19-positive tumor cells. FT819 produced cytokines (IFN-gamma, TNF-alpha, and IL-2) and mediators of cell death (CD107a/b, perforin, and granzyme B).
FT819 was also target-specific, attacking only CD19-positive tumor cells and sparing CD19-negative tumor cells in experiments with Raji (Burkitt lymphoma) and Nalm-6 (B-cell acute lymphoblastic leukemia) cell lines.
The researchers said they observed consistent antigen-specific cytotoxicity against Nalm-6 cells with FT819 but variability in antigen-specific cytotoxicity with conventional CAR T cells.
In addition, when combined with rituximab, FT819 elicited antibody-dependent cell-mediated cytotoxicity against CD19-negative, CD20-positive tumor cells.
“Through the development of FT819, we believe there is significant opportunity to lower the cost of CAR T-cell manufacture, enhance the quality of the product, and create a readily available supply of a more efficacious product to reach more patients in need,” Dr Valamehr said.
CHICAGO—Researchers have used induced pluripotent stem cells (iPSCs) to create a “universal” chimeric antigen receptor (CAR) T-cell therapy known as FT819.
The team says FT819 has the potential to be mass-produced, stored, and made readily available for cancer patients.
In in vitro experiments, FT819 demonstrated activity against leukemia and lymphoma.
These results were presented at the AACR Annual Meeting 2018 (abstract LB-108).
The research was conducted by employees of Fate Therapeutics, Inc., the company developing FT819, as well as Memorial Sloan-Kettering Cancer Center.
About FT819
FT819 is produced from a master iPSC line generated using T cells from healthy donors.
“A master iPSC line has unlimited capacity to self-renew and can be banked and renewably used,” said Bob Valamehr, PhD, vice-president of cancer immunotherapy at Fate Therapeutics, Inc.
“We started with cells from a healthy donor rather than the patient, created a master cell line, and used the master cell line to produce large quantities of ‘universal’ CAR19 T cells that are not patient-restricted. These first-of-kind CAR19 T cells, called FT819, can be packaged, stored, and made readily available for treatment of a large number of patients.”
FT819 has 2 targeting receptors—a CAR targeting CD19-positive tumor cells and a CD16 Fc receptor that can engage other therapies (such as tumor antigen-targeting monoclonal antibodies) to overcome antigen escape.
The master iPSC line used for the production of FT819 is engineered in a one-time event to insert a CD19 CAR into the T-cell receptor α constant (TRAC) locus. This is done to eliminate T-cell receptor expression and reduce the likelihood of graft-versus-host disease.
Previous research showed that targeting a CAR to the TRAC locus results in uniform CAR expression and enhances T-cell potency. In fact, TRAC-CAR T cells outperformed conventionally generated CAR T cells by preventing T-cell exhaustion in a mouse model of acute lymphoblastic leukemia.
In vitro experiments
With the current work, the researchers found that FT819 displayed an efficient cytotoxic T-cell response when challenged with CD19-positive tumor cells. FT819 produced cytokines (IFN-gamma, TNF-alpha, and IL-2) and mediators of cell death (CD107a/b, perforin, and granzyme B).
FT819 was also target-specific, attacking only CD19-positive tumor cells and sparing CD19-negative tumor cells in experiments with Raji (Burkitt lymphoma) and Nalm-6 (B-cell acute lymphoblastic leukemia) cell lines.
The researchers said they observed consistent antigen-specific cytotoxicity against Nalm-6 cells with FT819 but variability in antigen-specific cytotoxicity with conventional CAR T cells.
In addition, when combined with rituximab, FT819 elicited antibody-dependent cell-mediated cytotoxicity against CD19-negative, CD20-positive tumor cells.
“Through the development of FT819, we believe there is significant opportunity to lower the cost of CAR T-cell manufacture, enhance the quality of the product, and create a readily available supply of a more efficacious product to reach more patients in need,” Dr Valamehr said.
PDPK1 could be novel target in MCL
Researchers may have found a new therapeutic approach for treating mantle cell lymphoma (MCL) by targeting 3-phosphoinositide-dependent protein kinase 1 (PDPK1).
Saori Maegawa and colleagues at Kyoto Prefectural University of Medicine in Japan, evaluated PDPK1 activity in patient-derived primary B-cell lymphoma cells by immunohistochemical staining of p-PDPK1Ser241 (p-PDPK1) in tissue specimens from seven patients with MCL, six patients with diffuse large B-cell lymphoma, and five patients with follicular lymphoma. All specimens were biopsied at initial diagnosis, before starting treatment.
“Our study showed that PDPK1 inhibition caused inactivation of RSK2-NTKD, as well as the decrease of total RSK2 protein, but not of AKT, in MCL-derived cells,” the researchers wrote in Experimental Hematology. “This implies that RSK2 activity is mainly regulated by PDPK1 at both the transcriptional expression and post-translational levels, but AKT activity is regulated by a signaling pathway that does not interact with a PDPK1-mediated pathway in MCL.”
If a PDPK1 inhibitor is pursued as clinical target, the researchers said careful monitoring for hyperglycemia may be required since impaired glucose metabolism is commonly seen with AKT inhibitors. Future research in MCL could also be directed toward the targeting of RSK2-NTKD, the researchers wrote.
SOURCE: Maegawa S et al. Exp Hematol. 2018 Mar;59:72-81.e2.
Researchers may have found a new therapeutic approach for treating mantle cell lymphoma (MCL) by targeting 3-phosphoinositide-dependent protein kinase 1 (PDPK1).
Saori Maegawa and colleagues at Kyoto Prefectural University of Medicine in Japan, evaluated PDPK1 activity in patient-derived primary B-cell lymphoma cells by immunohistochemical staining of p-PDPK1Ser241 (p-PDPK1) in tissue specimens from seven patients with MCL, six patients with diffuse large B-cell lymphoma, and five patients with follicular lymphoma. All specimens were biopsied at initial diagnosis, before starting treatment.
“Our study showed that PDPK1 inhibition caused inactivation of RSK2-NTKD, as well as the decrease of total RSK2 protein, but not of AKT, in MCL-derived cells,” the researchers wrote in Experimental Hematology. “This implies that RSK2 activity is mainly regulated by PDPK1 at both the transcriptional expression and post-translational levels, but AKT activity is regulated by a signaling pathway that does not interact with a PDPK1-mediated pathway in MCL.”
If a PDPK1 inhibitor is pursued as clinical target, the researchers said careful monitoring for hyperglycemia may be required since impaired glucose metabolism is commonly seen with AKT inhibitors. Future research in MCL could also be directed toward the targeting of RSK2-NTKD, the researchers wrote.
SOURCE: Maegawa S et al. Exp Hematol. 2018 Mar;59:72-81.e2.
Researchers may have found a new therapeutic approach for treating mantle cell lymphoma (MCL) by targeting 3-phosphoinositide-dependent protein kinase 1 (PDPK1).
Saori Maegawa and colleagues at Kyoto Prefectural University of Medicine in Japan, evaluated PDPK1 activity in patient-derived primary B-cell lymphoma cells by immunohistochemical staining of p-PDPK1Ser241 (p-PDPK1) in tissue specimens from seven patients with MCL, six patients with diffuse large B-cell lymphoma, and five patients with follicular lymphoma. All specimens were biopsied at initial diagnosis, before starting treatment.
“Our study showed that PDPK1 inhibition caused inactivation of RSK2-NTKD, as well as the decrease of total RSK2 protein, but not of AKT, in MCL-derived cells,” the researchers wrote in Experimental Hematology. “This implies that RSK2 activity is mainly regulated by PDPK1 at both the transcriptional expression and post-translational levels, but AKT activity is regulated by a signaling pathway that does not interact with a PDPK1-mediated pathway in MCL.”
If a PDPK1 inhibitor is pursued as clinical target, the researchers said careful monitoring for hyperglycemia may be required since impaired glucose metabolism is commonly seen with AKT inhibitors. Future research in MCL could also be directed toward the targeting of RSK2-NTKD, the researchers wrote.
SOURCE: Maegawa S et al. Exp Hematol. 2018 Mar;59:72-81.e2.
FROM EXPERIMENTAL HEMATOLOGY