AACR Annual Meeting 2018

CHICAGO – A combination of an immunostimulatory IL-15-based agent, ALT-803, with a therapeutic monoclonal antibody (mAb) against CD20, was well tolerated and had clinical activity in patients with indolent non-Hodgkin lymphoma (iNHL), according to preliminary findings from a phase 1 study.

“The cancer immunotherapy breakthrough that happened several years ago continues year after year, with a plethora of different modalities of immunotherapy at our disposal,” Todd A. Fehniger, MD, PhD, said at the annual meeting of the American Association for Cancer Research.

Immunotherapy with anti-CD20 mAbs, alone or in combination with chemotherapy, is a standard therapy for iNHL patients. Since iNHL cells express CD20, targeting it with mAbs triggers antitumor responses via cell surface receptors resulting in a potent antibody-dependent cellular toxicity. However, response in patients is highly heterogeneous, with relapse within a few months in a subset of patients. In addition, chemotherapeutic combinations can be toxic and result in serious and long-term complications.

“Relapsed or refractory iNHL is not curable and treatment strategies without long-term complications are needed,” said Dr. Fehniger, associate professor of medicine at Washington University, St. Louis.

In an attempt to address this, Dr. Fehniger and his colleagues combined rituximab, an anti-CD20 antibody, with a relatively new IL-15 agonist immunostimulatory agent called ALT-803.

In the phase 1 trial, the researchers enrolled patients with indolent non-Hodgkin lymphoma who had relapsed after at least 1 prior to CD20 antibody containing therapy. The study was a standard 3+3 dose escalation design with rituximab administered by intravenous infusion, 375 mg/m² in four weekly doses, followed by a rest and four consolidation doses every 8 weeks for four cycles.

ALT-803 was administered concurrently at dose levels of 1 mcg/kg, 3 mcg/kg, and 6 mcg/kg IV followed by 6 mcg/kg, 10 mcg/kg, 15 mcg/kg, and 20 mcg/kg subcutaneously.

SOURCE: Fehniger TA et al. AACR Annual Meeting, Abstract CT146.

CHICAGO – A combination of an immunostimulatory IL-15-based agent, ALT-803, with a therapeutic monoclonal antibody (mAb) against CD20, was well tolerated and had clinical activity in patients with indolent non-Hodgkin lymphoma (iNHL), according to preliminary findings from a phase 1 study.

“The cancer immunotherapy breakthrough that happened several years ago continues year after year, with a plethora of different modalities of immunotherapy at our disposal,” Todd A. Fehniger, MD, PhD, said at the annual meeting of the American Association for Cancer Research.

Immunotherapy with anti-CD20 mAbs, alone or in combination with chemotherapy, is a standard therapy for iNHL patients. Since iNHL cells express CD20, targeting it with mAbs triggers antitumor responses via cell surface receptors resulting in a potent antibody-dependent cellular toxicity. However, response in patients is highly heterogeneous, with relapse within a few months in a subset of patients. In addition, chemotherapeutic combinations can be toxic and result in serious and long-term complications.

“Relapsed or refractory iNHL is not curable and treatment strategies without long-term complications are needed,” said Dr. Fehniger, associate professor of medicine at Washington University, St. Louis.

In an attempt to address this, Dr. Fehniger and his colleagues combined rituximab, an anti-CD20 antibody, with a relatively new IL-15 agonist immunostimulatory agent called ALT-803.

In the phase 1 trial, the researchers enrolled patients with indolent non-Hodgkin lymphoma who had relapsed after at least 1 prior to CD20 antibody containing therapy. The study was a standard 3+3 dose escalation design with rituximab administered by intravenous infusion, 375 mg/m² in four weekly doses, followed by a rest and four consolidation doses every 8 weeks for four cycles.

ALT-803 was administered concurrently at dose levels of 1 mcg/kg, 3 mcg/kg, and 6 mcg/kg IV followed by 6 mcg/kg, 10 mcg/kg, 15 mcg/kg, and 20 mcg/kg subcutaneously.

SOURCE: Fehniger TA et al. AACR Annual Meeting, Abstract CT146.

CHICAGO – A combination of an immunostimulatory IL-15-based agent, ALT-803, with a therapeutic monoclonal antibody (mAb) against CD20, was well tolerated and had clinical activity in patients with indolent non-Hodgkin lymphoma (iNHL), according to preliminary findings from a phase 1 study.

“The cancer immunotherapy breakthrough that happened several years ago continues year after year, with a plethora of different modalities of immunotherapy at our disposal,” Todd A. Fehniger, MD, PhD, said at the annual meeting of the American Association for Cancer Research.

Immunotherapy with anti-CD20 mAbs, alone or in combination with chemotherapy, is a standard therapy for iNHL patients. Since iNHL cells express CD20, targeting it with mAbs triggers antitumor responses via cell surface receptors resulting in a potent antibody-dependent cellular toxicity. However, response in patients is highly heterogeneous, with relapse within a few months in a subset of patients. In addition, chemotherapeutic combinations can be toxic and result in serious and long-term complications.

“Relapsed or refractory iNHL is not curable and treatment strategies without long-term complications are needed,” said Dr. Fehniger, associate professor of medicine at Washington University, St. Louis.

In an attempt to address this, Dr. Fehniger and his colleagues combined rituximab, an anti-CD20 antibody, with a relatively new IL-15 agonist immunostimulatory agent called ALT-803.

In the phase 1 trial, the researchers enrolled patients with indolent non-Hodgkin lymphoma who had relapsed after at least 1 prior to CD20 antibody containing therapy. The study was a standard 3+3 dose escalation design with rituximab administered by intravenous infusion, 375 mg/m² in four weekly doses, followed by a rest and four consolidation doses every 8 weeks for four cycles.

ALT-803 was administered concurrently at dose levels of 1 mcg/kg, 3 mcg/kg, and 6 mcg/kg IV followed by 6 mcg/kg, 10 mcg/kg, 15 mcg/kg, and 20 mcg/kg subcutaneously.

SOURCE: Fehniger TA et al. AACR Annual Meeting, Abstract CT146.

Mantle cell lymphoma

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.

Mantle cell lymphoma

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.

Mantle cell lymphoma

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.

Micrograph showing 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.

Micrograph showing 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.

Micrograph showing 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.

Photo by Petr Kratochvil

CHICAGO—Researchers have identified a link between habitual physical activity (PA) and mortality among cancer patients.

Engaging in regular PA, both pre- and post-diagnosis, was associated with a significantly lower risk of death for the entire population studied and for patients with 8 specific types of cancer.

However, the association was not significant for patients with other cancer types, including hematologic malignancies.

Rikki Cannioto, PhD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, and her colleagues presented these findings at the AACR Annual Meeting 2018 (abstract 5254*).

The researchers examined the association between habitual PA and outcomes in 5807 cancer patients enrolled in the Data Bank and BioRepository at Roswell Park between 2003 and 2016.

The population was 54.8% female and 93% white. The average age at diagnosis was 60.6 years.

The researchers looked at patterns of PA over time, from the decade before the cancer was diagnosed and continuing for up to 1 year after diagnosis.

Patients who engaged in regular, moderate- to vigorous-intensity PA (such as walking, running, aerobics, or other cardiovascular exercise) both before and after their diagnosis were considered habitually active, whereas those who did not exercise regularly were considered habitually inactive.

Overall, 52% of patients reported habitual activity, and 19% reported habitual inactivity. Twenty-three percent of patients said their activity level decreased after diagnosis, and 6% said their activity level increased.

Patients were followed through January 31, 2018. The median time to follow-up was 53 months, and 33.7% of patients (n=1956) died during the follow-up period.

Results

The researchers found that patients who were active before and after diagnosis were 40% more likely to survive than those who were habitually inactive (P<0.001). Habitually inactive patients had a 66% increased risk of mortality compared to active patients.

The habitually active patients had a 37-month mean survival advantage over the inactive patients.

In addition, patients whose activity level increased after diagnosis had a 25% lower risk of death than patients who remained inactive after diagnosis.

The researchers observed a significant (P<0.05) association between habitual PA and decreased mortality in patients with breast, colon, prostate, bladder, endometrial, ovarian, esophageal, and skin cancers.

However, the association between PA and mortality was not significant for patients with hematologic malignancies (P=0.59) or kidney, liver, lung, pancreas, stomach, or “other” cancers.

The researchers said the associations between habitual PA and decreased mortality remained consistent regardless of a patient’s sex, tumor stage, smoking status, or body mass index.

“[W]hen it comes to exercise, something is better than nothing, but regular, weekly exercise seems to really make a difference,” Dr Cannioto said.

“In fact, patients who were physically active 3 or 4 days a week experienced an even greater benefit than those who exercised daily, and patients who had only 1 or 2 days of regular activity per week did nearly as well. This is particularly encouraging, as cancer patients and survivors can be overwhelmed by current physical activity recommendations.”

*Information in the abstract differs from the presentation.

Photo by Petr Kratochvil

CHICAGO—Researchers have identified a link between habitual physical activity (PA) and mortality among cancer patients.

Engaging in regular PA, both pre- and post-diagnosis, was associated with a significantly lower risk of death for the entire population studied and for patients with 8 specific types of cancer.

However, the association was not significant for patients with other cancer types, including hematologic malignancies.

Rikki Cannioto, PhD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, and her colleagues presented these findings at the AACR Annual Meeting 2018 (abstract 5254*).

The researchers examined the association between habitual PA and outcomes in 5807 cancer patients enrolled in the Data Bank and BioRepository at Roswell Park between 2003 and 2016.

The population was 54.8% female and 93% white. The average age at diagnosis was 60.6 years.

The researchers looked at patterns of PA over time, from the decade before the cancer was diagnosed and continuing for up to 1 year after diagnosis.

Patients who engaged in regular, moderate- to vigorous-intensity PA (such as walking, running, aerobics, or other cardiovascular exercise) both before and after their diagnosis were considered habitually active, whereas those who did not exercise regularly were considered habitually inactive.

Overall, 52% of patients reported habitual activity, and 19% reported habitual inactivity. Twenty-three percent of patients said their activity level decreased after diagnosis, and 6% said their activity level increased.

Patients were followed through January 31, 2018. The median time to follow-up was 53 months, and 33.7% of patients (n=1956) died during the follow-up period.

Results

The researchers found that patients who were active before and after diagnosis were 40% more likely to survive than those who were habitually inactive (P<0.001). Habitually inactive patients had a 66% increased risk of mortality compared to active patients.

The habitually active patients had a 37-month mean survival advantage over the inactive patients.

In addition, patients whose activity level increased after diagnosis had a 25% lower risk of death than patients who remained inactive after diagnosis.

The researchers observed a significant (P<0.05) association between habitual PA and decreased mortality in patients with breast, colon, prostate, bladder, endometrial, ovarian, esophageal, and skin cancers.

However, the association between PA and mortality was not significant for patients with hematologic malignancies (P=0.59) or kidney, liver, lung, pancreas, stomach, or “other” cancers.

The researchers said the associations between habitual PA and decreased mortality remained consistent regardless of a patient’s sex, tumor stage, smoking status, or body mass index.

“[W]hen it comes to exercise, something is better than nothing, but regular, weekly exercise seems to really make a difference,” Dr Cannioto said.

“In fact, patients who were physically active 3 or 4 days a week experienced an even greater benefit than those who exercised daily, and patients who had only 1 or 2 days of regular activity per week did nearly as well. This is particularly encouraging, as cancer patients and survivors can be overwhelmed by current physical activity recommendations.”

*Information in the abstract differs from the presentation.

Photo by Petr Kratochvil

CHICAGO—Researchers have identified a link between habitual physical activity (PA) and mortality among cancer patients.

Engaging in regular PA, both pre- and post-diagnosis, was associated with a significantly lower risk of death for the entire population studied and for patients with 8 specific types of cancer.

However, the association was not significant for patients with other cancer types, including hematologic malignancies.

Rikki Cannioto, PhD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, and her colleagues presented these findings at the AACR Annual Meeting 2018 (abstract 5254*).

The researchers examined the association between habitual PA and outcomes in 5807 cancer patients enrolled in the Data Bank and BioRepository at Roswell Park between 2003 and 2016.

The population was 54.8% female and 93% white. The average age at diagnosis was 60.6 years.

The researchers looked at patterns of PA over time, from the decade before the cancer was diagnosed and continuing for up to 1 year after diagnosis.

Patients who engaged in regular, moderate- to vigorous-intensity PA (such as walking, running, aerobics, or other cardiovascular exercise) both before and after their diagnosis were considered habitually active, whereas those who did not exercise regularly were considered habitually inactive.

Overall, 52% of patients reported habitual activity, and 19% reported habitual inactivity. Twenty-three percent of patients said their activity level decreased after diagnosis, and 6% said their activity level increased.

Patients were followed through January 31, 2018. The median time to follow-up was 53 months, and 33.7% of patients (n=1956) died during the follow-up period.

Results

The researchers found that patients who were active before and after diagnosis were 40% more likely to survive than those who were habitually inactive (P<0.001). Habitually inactive patients had a 66% increased risk of mortality compared to active patients.

The habitually active patients had a 37-month mean survival advantage over the inactive patients.

In addition, patients whose activity level increased after diagnosis had a 25% lower risk of death than patients who remained inactive after diagnosis.

The researchers observed a significant (P<0.05) association between habitual PA and decreased mortality in patients with breast, colon, prostate, bladder, endometrial, ovarian, esophageal, and skin cancers.

However, the association between PA and mortality was not significant for patients with hematologic malignancies (P=0.59) or kidney, liver, lung, pancreas, stomach, or “other” cancers.

The researchers said the associations between habitual PA and decreased mortality remained consistent regardless of a patient’s sex, tumor stage, smoking status, or body mass index.

“[W]hen it comes to exercise, something is better than nothing, but regular, weekly exercise seems to really make a difference,” Dr Cannioto said.

“In fact, patients who were physically active 3 or 4 days a week experienced an even greater benefit than those who exercised daily, and patients who had only 1 or 2 days of regular activity per week did nearly as well. This is particularly encouraging, as cancer patients and survivors can be overwhelmed by current physical activity recommendations.”

*Information in the abstract differs from the presentation.

CHICAGO – The intratumoral Toll-Like Receptor 9 (TLR-9) agonist, CMP-001, in combination with pembrolizumab in advanced melanoma patients, was well tolerated with a durable systemic clinical response, according to early results from an ongoing phase 1 trial.

Objective response rates on weekly (n = 56) and every 3 weeks schedules (n = 13) were 23% (13%-36%) and 15% (2%-45%) respectively, reported Mohammed M. Milhem, MBBS, of the University of Iowa, Iowa City.

For those dosed weekly at low dose (less than 5 mL) and high dose (5 mL or more), the ORR was 19% (n = 43, 95% confidence interval, 8%-33%) and 27% (n = 26, 95% CI, 12%-48%), respectively. Activity was demonstrated in subjects regardless of tumor burden, Dr. Milhem said at the annual meeting of the American Association for Cancer Research.

In this phase 1b study with a 3+3 design of dose escalation and expansion, the researchers enrolled patients with advanced melanoma who did not respond or had progressed resistant on prior anti-PD-1 monotherapy or in combination. CMP-001 was injected intratumorally in combination with pembrolizumab as per label intravenously.

The study drug CMP-001 has two components, a 30-mer CpG-A DNA oligonucleotide and a nonvirulent virus-like particle (VLP). The CpG-A DNA is packaged within the VLP that protects it from degradation and also allows TLR9 receptor uptake. CpG-A DNA acts as a TLR9 agonist by binding to it, thereby activating plasmacytoid dendritic cells (pDCs) within the tumor microenvironment. The activation results in secretion of large amounts of type 1 interferon and Th1 chemokines, changing the microenvironment from a “cold/desert-like” immune suppressed state to a “hot” antitumor inflamed state, Dr. Milhem said.

“The T cells thus generated can mediate tumor rejection both in the injected and noninjected tumor,” he said. Two CMP-001 schedules were evaluated, weekly for 7 weeks or weekly for 2 weeks, followed thereafter by every 3 weeks until discontinuation (due to progression, toxicity, investigator decision, or withdrawal of consent). Scans were done every 12 weeks and tumor response was assessed by RECIST v1.1.

The CMP-001 dose escalation scheme ranged from 1 mg to 10 mg. The maximum tolerated dose was not reached and the dose of 5 mg/weekly plus pembrolizumab was used for the dose expansion phase. It was up to the investigator to increase the dose to 10 mg since maximum tolerated dose was not reached. The key inclusion criteria were metastatic or unresectable melanoma; in the dose escalation phase prior best response to anti-PD1-based therapy was disease progression or stable disease. In the dose expansion phase, patients who had progressed on anti-PD1 based therapy were allowed regardless of best response. There was no restriction on the number of prior lines of therapy.

A total of 69 subjects were treated, 44 subjects from dose escalation and 25 in the expansion phase (ongoing). Two subjects discontinued because of treatment-related adverse events. The rest of the patients had a manageable toxicity profile consisting predominantly of fever, nausea/vomiting, hypotension and rigors. Severe grade 3/4 treatment-related adverse events were reported in more than 1 subject, with hypotension (n = 9, 13%) being the most prominent AE, followed by anemia (n = 2, 3%), chills (n = 2, 3%), and hypertension (n = 2, 3%). Hypotension was manageable by responsive fluid resuscitation and in some patients required stress dose steroids. Most of these side effects occurred 1-4 hours after the CMP-001 injection.

Of the 18 responders, 1 progressed, 2 withdrew consent, and 13 remain on study with 2 subjects maintaining their response though week 72. The median duration of response was not reached. Regression of noninjected tumors occurred in cutaneous, nodal, hepatic, and splenic metastases.

“CMP-001 plus pembrolizumab induced systemic antitumor activity, and not just local efficacy since both injected and noninjected target lesions changed from baseline per RECIST,” Dr. Milhem said. Not only did the responders show a rapid reduction in target lesions from baseline, but also a durable tumor regression as usually seen with other immunotherapeutics.

Immunohistochemical analysis of tumor biopsies demonstrated increase in CD8 (greater than fivefold) and PD-L1 expression, 5 weeks after therapy in a subset of patients with pre- and posttreatment biopsies. Transcriptional analysis by RNA-seq revealed induction of T cell inflamed gene signature, notably significant upregulation of TLR, and IFN-responsive genes.

It would be interesting to further investigate how this combination therapy compares with other strategies in a similar clinical scenario, such as oncolytic virus, other TLR ligands or means of APC activation, discussant Jedd Wolchok, MD, PhD, pointed out. Understanding resistance mechanisms at an individual patient level and optimal patient selection for this combination therapy remains a challenge, he said.

Dr. Milhem had no financial relationships to disclose.

SOURCE: Milhem MD et al. AACR Annual Meeting Abstract CT144.

CHICAGO – The intratumoral Toll-Like Receptor 9 (TLR-9) agonist, CMP-001, in combination with pembrolizumab in advanced melanoma patients, was well tolerated with a durable systemic clinical response, according to early results from an ongoing phase 1 trial.

Objective response rates on weekly (n = 56) and every 3 weeks schedules (n = 13) were 23% (13%-36%) and 15% (2%-45%) respectively, reported Mohammed M. Milhem, MBBS, of the University of Iowa, Iowa City.

For those dosed weekly at low dose (less than 5 mL) and high dose (5 mL or more), the ORR was 19% (n = 43, 95% confidence interval, 8%-33%) and 27% (n = 26, 95% CI, 12%-48%), respectively. Activity was demonstrated in subjects regardless of tumor burden, Dr. Milhem said at the annual meeting of the American Association for Cancer Research.

In this phase 1b study with a 3+3 design of dose escalation and expansion, the researchers enrolled patients with advanced melanoma who did not respond or had progressed resistant on prior anti-PD-1 monotherapy or in combination. CMP-001 was injected intratumorally in combination with pembrolizumab as per label intravenously.

The study drug CMP-001 has two components, a 30-mer CpG-A DNA oligonucleotide and a nonvirulent virus-like particle (VLP). The CpG-A DNA is packaged within the VLP that protects it from degradation and also allows TLR9 receptor uptake. CpG-A DNA acts as a TLR9 agonist by binding to it, thereby activating plasmacytoid dendritic cells (pDCs) within the tumor microenvironment. The activation results in secretion of large amounts of type 1 interferon and Th1 chemokines, changing the microenvironment from a “cold/desert-like” immune suppressed state to a “hot” antitumor inflamed state, Dr. Milhem said.

“The T cells thus generated can mediate tumor rejection both in the injected and noninjected tumor,” he said. Two CMP-001 schedules were evaluated, weekly for 7 weeks or weekly for 2 weeks, followed thereafter by every 3 weeks until discontinuation (due to progression, toxicity, investigator decision, or withdrawal of consent). Scans were done every 12 weeks and tumor response was assessed by RECIST v1.1.

The CMP-001 dose escalation scheme ranged from 1 mg to 10 mg. The maximum tolerated dose was not reached and the dose of 5 mg/weekly plus pembrolizumab was used for the dose expansion phase. It was up to the investigator to increase the dose to 10 mg since maximum tolerated dose was not reached. The key inclusion criteria were metastatic or unresectable melanoma; in the dose escalation phase prior best response to anti-PD1-based therapy was disease progression or stable disease. In the dose expansion phase, patients who had progressed on anti-PD1 based therapy were allowed regardless of best response. There was no restriction on the number of prior lines of therapy.

A total of 69 subjects were treated, 44 subjects from dose escalation and 25 in the expansion phase (ongoing). Two subjects discontinued because of treatment-related adverse events. The rest of the patients had a manageable toxicity profile consisting predominantly of fever, nausea/vomiting, hypotension and rigors. Severe grade 3/4 treatment-related adverse events were reported in more than 1 subject, with hypotension (n = 9, 13%) being the most prominent AE, followed by anemia (n = 2, 3%), chills (n = 2, 3%), and hypertension (n = 2, 3%). Hypotension was manageable by responsive fluid resuscitation and in some patients required stress dose steroids. Most of these side effects occurred 1-4 hours after the CMP-001 injection.

Of the 18 responders, 1 progressed, 2 withdrew consent, and 13 remain on study with 2 subjects maintaining their response though week 72. The median duration of response was not reached. Regression of noninjected tumors occurred in cutaneous, nodal, hepatic, and splenic metastases.

“CMP-001 plus pembrolizumab induced systemic antitumor activity, and not just local efficacy since both injected and noninjected target lesions changed from baseline per RECIST,” Dr. Milhem said. Not only did the responders show a rapid reduction in target lesions from baseline, but also a durable tumor regression as usually seen with other immunotherapeutics.

Immunohistochemical analysis of tumor biopsies demonstrated increase in CD8 (greater than fivefold) and PD-L1 expression, 5 weeks after therapy in a subset of patients with pre- and posttreatment biopsies. Transcriptional analysis by RNA-seq revealed induction of T cell inflamed gene signature, notably significant upregulation of TLR, and IFN-responsive genes.

It would be interesting to further investigate how this combination therapy compares with other strategies in a similar clinical scenario, such as oncolytic virus, other TLR ligands or means of APC activation, discussant Jedd Wolchok, MD, PhD, pointed out. Understanding resistance mechanisms at an individual patient level and optimal patient selection for this combination therapy remains a challenge, he said.

Dr. Milhem had no financial relationships to disclose.

SOURCE: Milhem MD et al. AACR Annual Meeting Abstract CT144.

CHICAGO – The intratumoral Toll-Like Receptor 9 (TLR-9) agonist, CMP-001, in combination with pembrolizumab in advanced melanoma patients, was well tolerated with a durable systemic clinical response, according to early results from an ongoing phase 1 trial.

Objective response rates on weekly (n = 56) and every 3 weeks schedules (n = 13) were 23% (13%-36%) and 15% (2%-45%) respectively, reported Mohammed M. Milhem, MBBS, of the University of Iowa, Iowa City.

For those dosed weekly at low dose (less than 5 mL) and high dose (5 mL or more), the ORR was 19% (n = 43, 95% confidence interval, 8%-33%) and 27% (n = 26, 95% CI, 12%-48%), respectively. Activity was demonstrated in subjects regardless of tumor burden, Dr. Milhem said at the annual meeting of the American Association for Cancer Research.

In this phase 1b study with a 3+3 design of dose escalation and expansion, the researchers enrolled patients with advanced melanoma who did not respond or had progressed resistant on prior anti-PD-1 monotherapy or in combination. CMP-001 was injected intratumorally in combination with pembrolizumab as per label intravenously.

The study drug CMP-001 has two components, a 30-mer CpG-A DNA oligonucleotide and a nonvirulent virus-like particle (VLP). The CpG-A DNA is packaged within the VLP that protects it from degradation and also allows TLR9 receptor uptake. CpG-A DNA acts as a TLR9 agonist by binding to it, thereby activating plasmacytoid dendritic cells (pDCs) within the tumor microenvironment. The activation results in secretion of large amounts of type 1 interferon and Th1 chemokines, changing the microenvironment from a “cold/desert-like” immune suppressed state to a “hot” antitumor inflamed state, Dr. Milhem said.

“The T cells thus generated can mediate tumor rejection both in the injected and noninjected tumor,” he said. Two CMP-001 schedules were evaluated, weekly for 7 weeks or weekly for 2 weeks, followed thereafter by every 3 weeks until discontinuation (due to progression, toxicity, investigator decision, or withdrawal of consent). Scans were done every 12 weeks and tumor response was assessed by RECIST v1.1.

The CMP-001 dose escalation scheme ranged from 1 mg to 10 mg. The maximum tolerated dose was not reached and the dose of 5 mg/weekly plus pembrolizumab was used for the dose expansion phase. It was up to the investigator to increase the dose to 10 mg since maximum tolerated dose was not reached. The key inclusion criteria were metastatic or unresectable melanoma; in the dose escalation phase prior best response to anti-PD1-based therapy was disease progression or stable disease. In the dose expansion phase, patients who had progressed on anti-PD1 based therapy were allowed regardless of best response. There was no restriction on the number of prior lines of therapy.

A total of 69 subjects were treated, 44 subjects from dose escalation and 25 in the expansion phase (ongoing). Two subjects discontinued because of treatment-related adverse events. The rest of the patients had a manageable toxicity profile consisting predominantly of fever, nausea/vomiting, hypotension and rigors. Severe grade 3/4 treatment-related adverse events were reported in more than 1 subject, with hypotension (n = 9, 13%) being the most prominent AE, followed by anemia (n = 2, 3%), chills (n = 2, 3%), and hypertension (n = 2, 3%). Hypotension was manageable by responsive fluid resuscitation and in some patients required stress dose steroids. Most of these side effects occurred 1-4 hours after the CMP-001 injection.

Of the 18 responders, 1 progressed, 2 withdrew consent, and 13 remain on study with 2 subjects maintaining their response though week 72. The median duration of response was not reached. Regression of noninjected tumors occurred in cutaneous, nodal, hepatic, and splenic metastases.

“CMP-001 plus pembrolizumab induced systemic antitumor activity, and not just local efficacy since both injected and noninjected target lesions changed from baseline per RECIST,” Dr. Milhem said. Not only did the responders show a rapid reduction in target lesions from baseline, but also a durable tumor regression as usually seen with other immunotherapeutics.

Immunohistochemical analysis of tumor biopsies demonstrated increase in CD8 (greater than fivefold) and PD-L1 expression, 5 weeks after therapy in a subset of patients with pre- and posttreatment biopsies. Transcriptional analysis by RNA-seq revealed induction of T cell inflamed gene signature, notably significant upregulation of TLR, and IFN-responsive genes.

It would be interesting to further investigate how this combination therapy compares with other strategies in a similar clinical scenario, such as oncolytic virus, other TLR ligands or means of APC activation, discussant Jedd Wolchok, MD, PhD, pointed out. Understanding resistance mechanisms at an individual patient level and optimal patient selection for this combination therapy remains a challenge, he said.

Dr. Milhem had no financial relationships to disclose.

SOURCE: Milhem MD et al. AACR Annual Meeting Abstract CT144.

multiple myeloma

CHICAGO—Early phase 1 results suggest a chimeric antigen receptor (CAR) T-cell therapy can induce tumor regression in heavily pretreated patients with multiple myeloma (MM).

The therapy, P-BCMA-101, has only been tested in 3 patients in the lowest dose cohort.

However, signs of efficacy have been seen in all 3 patients, including a lasting partial response in 1 patient.

There have been no dose-limiting toxicities, and none of the patients have developed cytokine release syndrome (CRS).

“The results from the first cohort of the phase 1 P-BCMA-101 study have surpassed historical benchmarks of safety and efficacy in multiple myeloma at this dose level and give us confidence to move ahead into additional dose cohorts,” said Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics, Inc.

Dr Ostertag and his colleagues presented these results at the AACR Annual Meeting 2018 (abstract CT130). The trial is sponsored by Poseida Therapeutics, Inc.

The trial is enrolling patients with relapsed/refractory MM who have received a proteasome inhibitor and immunomodulatory agent.

Conditioning consists of standard cyclophosphamide (300 mg/m²) and fludarabine (30 mg/m²) on days -5 to -3. Patients then receive a single dose of P-BCMA-101 on day 0.

The trial has a 3+3 dose-escalation design, with up to 6 dose levels. The first dose level is 0.75 x 10⁶ P-BCMA-101 cells/kg.

The 3 patients who have received this dose had 6 to 9 prior therapies.

Patient 1

The first patient was a 54-year-old female with lambda light chain MM. She had t(11;14), del13q14, and 11q23(x3).

Before she received P-BCMA-101, the patient had an increase in free light chains (FLCs) to 3290 mg/L, which caused renal failure. She was treated with cyclophosphamide/prednisone and plasmapheresis bridging therapy before proceeding to P-BCMA-101.

The patient achieved a partial response 2 weeks after receiving P-BCMA-101, and this has persisted through week 12.  She had a maximal reduction in urine M-protein of 92% and a reduction in plasma FLCs of 79%.

The patient did not experience any adverse events (AEs) considered related to P-BCMA-101.

Patient 2

The second patient was a 50-year-old female with oligosecretory kappa light chain MM and plasmacytomas. She had del17p (TP53) and 11q13(x3).

Due to enlarging plasmacytomas, the patient was treated with DT-PACE (dexamethasone plus thalidomide with cisplatin, doxorubicin, cyclophosphamide, and etoposide) before receiving P-BCMA-101.

Her bone plasmacytomas resolved to below background within 4 to 8 weeks of P-BCMA-101 administration, but 1 new non-bone lesion appeared months later.

AEs considered at least possibly related to treatment in this patient included grade 2-4 neutropenia as well as grade 3-4 thrombocytopenia.

Patient 3

The third patient was a 65-year-old female with lambda light chain MM and del13q14.

Her urine M-protein and FLCs briefly dipped and rose after she received bridging therapy with lenalidomide and dexamethasone, but they decreased at 4 weeks after P-BCMA-101 administration, which corresponded with P-BCMA-101 expansion in the peripheral blood.

AEs considered at least possibly related to treatment included easy bruising (grade 1), fatigue (grade 2), febrile neutropenia (grade 3), hypogammaglobinemia (grade 2), neutropenia (grade 2-3), and thrombocytopenia (grade 3-4).

“The lack of cytokine release syndrome in any of the 3 patients, in spite of marked efficacy, is unprecedented at this dose, which we believe is attributable to multiple differentiated aspects of our technology, resulting in a highly purified CAR T product with a high percentage of cells with a T stem cell memory phenotype,” Dr Ostertag said.

In addition to a lack of CRS, there were no dose-limiting toxicities. Therefore, the dose has been escalated to 2 x 10⁶ P-BCMA-101+ CAR T cells/kg for the next patient cohort. The first patient has been treated at this dose level, with no CRS yet reported.

About P-BCMA-101

P-BCMA-101 employs a B-cell maturation antigen-specific Centyrin™ fused to a second-generation CAR scaffold (a CARTyrin) rather than a single-chain variable fragment (scFv).

Centyrins have similar binding affinities as scFvs but are said to be potentially less immunogenic than scFvs, more stable at the cell surface, and resistant to antigen/ligand-independent tonic signaling.

P-BCMA-101 is engineered using PiggyBac™, a transposon-based system requiring only mRNA and plasmid DNA (no virus).

The increased cargo capacity of PiggyBac allows for the incorporation of a safety switch and a selectable gene. The safety switch can be activated to enable depletion in case AEs occur. And the selectable gene allows for enrichment of CAR+ cells.

multiple myeloma

CHICAGO—Early phase 1 results suggest a chimeric antigen receptor (CAR) T-cell therapy can induce tumor regression in heavily pretreated patients with multiple myeloma (MM).

The therapy, P-BCMA-101, has only been tested in 3 patients in the lowest dose cohort.

However, signs of efficacy have been seen in all 3 patients, including a lasting partial response in 1 patient.

There have been no dose-limiting toxicities, and none of the patients have developed cytokine release syndrome (CRS).

“The results from the first cohort of the phase 1 P-BCMA-101 study have surpassed historical benchmarks of safety and efficacy in multiple myeloma at this dose level and give us confidence to move ahead into additional dose cohorts,” said Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics, Inc.

Dr Ostertag and his colleagues presented these results at the AACR Annual Meeting 2018 (abstract CT130). The trial is sponsored by Poseida Therapeutics, Inc.

The trial is enrolling patients with relapsed/refractory MM who have received a proteasome inhibitor and immunomodulatory agent.

Conditioning consists of standard cyclophosphamide (300 mg/m²) and fludarabine (30 mg/m²) on days -5 to -3. Patients then receive a single dose of P-BCMA-101 on day 0.

The trial has a 3+3 dose-escalation design, with up to 6 dose levels. The first dose level is 0.75 x 10⁶ P-BCMA-101 cells/kg.

The 3 patients who have received this dose had 6 to 9 prior therapies.

Patient 1

The first patient was a 54-year-old female with lambda light chain MM. She had t(11;14), del13q14, and 11q23(x3).

Before she received P-BCMA-101, the patient had an increase in free light chains (FLCs) to 3290 mg/L, which caused renal failure. She was treated with cyclophosphamide/prednisone and plasmapheresis bridging therapy before proceeding to P-BCMA-101.

The patient achieved a partial response 2 weeks after receiving P-BCMA-101, and this has persisted through week 12.  She had a maximal reduction in urine M-protein of 92% and a reduction in plasma FLCs of 79%.

The patient did not experience any adverse events (AEs) considered related to P-BCMA-101.

Patient 2

The second patient was a 50-year-old female with oligosecretory kappa light chain MM and plasmacytomas. She had del17p (TP53) and 11q13(x3).

Due to enlarging plasmacytomas, the patient was treated with DT-PACE (dexamethasone plus thalidomide with cisplatin, doxorubicin, cyclophosphamide, and etoposide) before receiving P-BCMA-101.

Her bone plasmacytomas resolved to below background within 4 to 8 weeks of P-BCMA-101 administration, but 1 new non-bone lesion appeared months later.

AEs considered at least possibly related to treatment in this patient included grade 2-4 neutropenia as well as grade 3-4 thrombocytopenia.

Patient 3

The third patient was a 65-year-old female with lambda light chain MM and del13q14.

Her urine M-protein and FLCs briefly dipped and rose after she received bridging therapy with lenalidomide and dexamethasone, but they decreased at 4 weeks after P-BCMA-101 administration, which corresponded with P-BCMA-101 expansion in the peripheral blood.

AEs considered at least possibly related to treatment included easy bruising (grade 1), fatigue (grade 2), febrile neutropenia (grade 3), hypogammaglobinemia (grade 2), neutropenia (grade 2-3), and thrombocytopenia (grade 3-4).

“The lack of cytokine release syndrome in any of the 3 patients, in spite of marked efficacy, is unprecedented at this dose, which we believe is attributable to multiple differentiated aspects of our technology, resulting in a highly purified CAR T product with a high percentage of cells with a T stem cell memory phenotype,” Dr Ostertag said.

In addition to a lack of CRS, there were no dose-limiting toxicities. Therefore, the dose has been escalated to 2 x 10⁶ P-BCMA-101+ CAR T cells/kg for the next patient cohort. The first patient has been treated at this dose level, with no CRS yet reported.

About P-BCMA-101

P-BCMA-101 employs a B-cell maturation antigen-specific Centyrin™ fused to a second-generation CAR scaffold (a CARTyrin) rather than a single-chain variable fragment (scFv).

Centyrins have similar binding affinities as scFvs but are said to be potentially less immunogenic than scFvs, more stable at the cell surface, and resistant to antigen/ligand-independent tonic signaling.

P-BCMA-101 is engineered using PiggyBac™, a transposon-based system requiring only mRNA and plasmid DNA (no virus).

The increased cargo capacity of PiggyBac allows for the incorporation of a safety switch and a selectable gene. The safety switch can be activated to enable depletion in case AEs occur. And the selectable gene allows for enrichment of CAR+ cells.

multiple myeloma

CHICAGO—Early phase 1 results suggest a chimeric antigen receptor (CAR) T-cell therapy can induce tumor regression in heavily pretreated patients with multiple myeloma (MM).

The therapy, P-BCMA-101, has only been tested in 3 patients in the lowest dose cohort.

However, signs of efficacy have been seen in all 3 patients, including a lasting partial response in 1 patient.

There have been no dose-limiting toxicities, and none of the patients have developed cytokine release syndrome (CRS).

“The results from the first cohort of the phase 1 P-BCMA-101 study have surpassed historical benchmarks of safety and efficacy in multiple myeloma at this dose level and give us confidence to move ahead into additional dose cohorts,” said Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics, Inc.

Dr Ostertag and his colleagues presented these results at the AACR Annual Meeting 2018 (abstract CT130). The trial is sponsored by Poseida Therapeutics, Inc.

The trial is enrolling patients with relapsed/refractory MM who have received a proteasome inhibitor and immunomodulatory agent.

Conditioning consists of standard cyclophosphamide (300 mg/m²) and fludarabine (30 mg/m²) on days -5 to -3. Patients then receive a single dose of P-BCMA-101 on day 0.

The trial has a 3+3 dose-escalation design, with up to 6 dose levels. The first dose level is 0.75 x 10⁶ P-BCMA-101 cells/kg.

The 3 patients who have received this dose had 6 to 9 prior therapies.

Patient 1

The first patient was a 54-year-old female with lambda light chain MM. She had t(11;14), del13q14, and 11q23(x3).

Before she received P-BCMA-101, the patient had an increase in free light chains (FLCs) to 3290 mg/L, which caused renal failure. She was treated with cyclophosphamide/prednisone and plasmapheresis bridging therapy before proceeding to P-BCMA-101.

The patient achieved a partial response 2 weeks after receiving P-BCMA-101, and this has persisted through week 12.  She had a maximal reduction in urine M-protein of 92% and a reduction in plasma FLCs of 79%.

The patient did not experience any adverse events (AEs) considered related to P-BCMA-101.

Patient 2

The second patient was a 50-year-old female with oligosecretory kappa light chain MM and plasmacytomas. She had del17p (TP53) and 11q13(x3).

Due to enlarging plasmacytomas, the patient was treated with DT-PACE (dexamethasone plus thalidomide with cisplatin, doxorubicin, cyclophosphamide, and etoposide) before receiving P-BCMA-101.

Her bone plasmacytomas resolved to below background within 4 to 8 weeks of P-BCMA-101 administration, but 1 new non-bone lesion appeared months later.

AEs considered at least possibly related to treatment in this patient included grade 2-4 neutropenia as well as grade 3-4 thrombocytopenia.

Patient 3

The third patient was a 65-year-old female with lambda light chain MM and del13q14.

Her urine M-protein and FLCs briefly dipped and rose after she received bridging therapy with lenalidomide and dexamethasone, but they decreased at 4 weeks after P-BCMA-101 administration, which corresponded with P-BCMA-101 expansion in the peripheral blood.

AEs considered at least possibly related to treatment included easy bruising (grade 1), fatigue (grade 2), febrile neutropenia (grade 3), hypogammaglobinemia (grade 2), neutropenia (grade 2-3), and thrombocytopenia (grade 3-4).

“The lack of cytokine release syndrome in any of the 3 patients, in spite of marked efficacy, is unprecedented at this dose, which we believe is attributable to multiple differentiated aspects of our technology, resulting in a highly purified CAR T product with a high percentage of cells with a T stem cell memory phenotype,” Dr Ostertag said.

In addition to a lack of CRS, there were no dose-limiting toxicities. Therefore, the dose has been escalated to 2 x 10⁶ P-BCMA-101+ CAR T cells/kg for the next patient cohort. The first patient has been treated at this dose level, with no CRS yet reported.

About P-BCMA-101

P-BCMA-101 employs a B-cell maturation antigen-specific Centyrin™ fused to a second-generation CAR scaffold (a CARTyrin) rather than a single-chain variable fragment (scFv).

Centyrins have similar binding affinities as scFvs but are said to be potentially less immunogenic than scFvs, more stable at the cell surface, and resistant to antigen/ligand-independent tonic signaling.

P-BCMA-101 is engineered using PiggyBac™, a transposon-based system requiring only mRNA and plasmid DNA (no virus).

The increased cargo capacity of PiggyBac allows for the incorporation of a safety switch and a selectable gene. The safety switch can be activated to enable depletion in case AEs occur. And the selectable gene allows for enrichment of CAR+ cells.

Photo by Aaron Logan

CHICAGO—A BET inhibitor can have potent and long-lasting effects against leukemia and multiple myeloma (MM), according to researchers.

The inhibitor, TG-1601 (or CK-103), exhibited cytotoxicity in MM and leukemia cell lines but did not affect the growth of normal cell lines.

TG-1601 also reduced tumor volume in mouse models of MM and acute myeloid leukemia (AML), and drug holidays had little impact on this activity.

Furthermore, researchers observed enduring MYC inhibition in mice treated with TG-1601.

This research was presented at the AACR Annual Meeting 2018 (abstract 5790).

The work was conducted by researchers from TG Therapeutics and Checkpoint Therapeutics—the companies developing TG-1601—as well as Jubilant Biosys.

In vitro activity

Researchers assessed the cytotoxic activity of TG-1601 in leukemia, MM, and normal cell lines by incubating the cells with increasing concentrations of the drug for 72 hours.

The results suggested TG-1601 inhibits MM and leukemia cell growth, as all EC₅₀ values were below 100 nM.

In the leukemia cell lines, EC₅₀ values were 35 nM (Jurkat), 31 nM (HEL92.1.7), 24 nM (CCRF-CEM and MV4-11), and 18 nM (OCI-AML3).

In the MM cell lines, EC₅₀ values were 85 nM (RPMI8226), 32 nM (KMS28PE), 24 nM (KMS28BM), 21 nM (MOLP8), and 15 nM (MM1s).

In the normal cell lines (Beas2B and WT9-12), cell growth wasn’t inhibited more than 50% with TG-1601 at 10 μM.

In vivo activity

For their MM model, researchers used mice inoculated with MM1 cells. The mice received TG-1601 at 10 mg/kg twice a day.

At day 17 after treatment initiation, there was a 70% reduction in tumor volume. During a week-long drug holiday, tumors did not grow back as fast in TG-1601-treated mice as they did in vehicle control mice.

For their AML model, researchers used mice inoculated with MV4-11 cells. The mice received TG-1601 as a single dose of 20 mg/kg/day—continuously or with 2, 3, or 4 days off per week—or at 10 mg/kg twice a day.

At day 15, 100% of mice that received the drug at 10 mg/kg twice a day were tumor-free. Mice that received the single 20 mg/kg dose had a 94% reduction in tumor volume.

The reduction in tumor volume was 91% in mice with the 2-day drug holiday, 78% in those with the 3-day holiday, and 82% in those with the 4-day holiday.

The researchers also found that TG-1601 had synergistic antitumor activity with an anti-PD-1 antibody in a mouse model of melanoma.

Pharmacodynamic activity

In the MV4-11 cell line, TG-1601 induced “rapid” downregulation of MYC and BCL2 and an increase of p21 mRNA, according to the researchers.

The team also assessed MYC expression in mice with MV4-11 tumors. They said MYC levels rapidly decreased in the tumors and were undetectable at 3 hours after a single dose of TG-1601.

The researchers noted that, at 24 hours after dosing, TG-1601 was cleared from the tumor. However, MYC levels remained below 40% their initial level.

The team said this suggests a long-lasting effect of TG-1601 that may be attributed to its enhanced binding affinity.

“These data demonstrate [TG-1601’s] potential to be a novel BET inhibitor that potently inhibits MYC expression,” said James F. Oliviero, president and chief executive officer of Checkpoint Therapeutics.

“We believe the preclinical data presented today provides encouraging evidence to support the development of [TG-1601] as an anticancer agent, alone and in combination with our anti-PD-L1 antibody, and look forward to the advancement of [TG-1601] into a first-in-human phase 1 trial expected to commence later this year.”

Photo by Aaron Logan

CHICAGO—A BET inhibitor can have potent and long-lasting effects against leukemia and multiple myeloma (MM), according to researchers.

The inhibitor, TG-1601 (or CK-103), exhibited cytotoxicity in MM and leukemia cell lines but did not affect the growth of normal cell lines.

TG-1601 also reduced tumor volume in mouse models of MM and acute myeloid leukemia (AML), and drug holidays had little impact on this activity.

Furthermore, researchers observed enduring MYC inhibition in mice treated with TG-1601.

This research was presented at the AACR Annual Meeting 2018 (abstract 5790).

The work was conducted by researchers from TG Therapeutics and Checkpoint Therapeutics—the companies developing TG-1601—as well as Jubilant Biosys.

In vitro activity

Researchers assessed the cytotoxic activity of TG-1601 in leukemia, MM, and normal cell lines by incubating the cells with increasing concentrations of the drug for 72 hours.

The results suggested TG-1601 inhibits MM and leukemia cell growth, as all EC₅₀ values were below 100 nM.

In the leukemia cell lines, EC₅₀ values were 35 nM (Jurkat), 31 nM (HEL92.1.7), 24 nM (CCRF-CEM and MV4-11), and 18 nM (OCI-AML3).

In the MM cell lines, EC₅₀ values were 85 nM (RPMI8226), 32 nM (KMS28PE), 24 nM (KMS28BM), 21 nM (MOLP8), and 15 nM (MM1s).

In the normal cell lines (Beas2B and WT9-12), cell growth wasn’t inhibited more than 50% with TG-1601 at 10 μM.

In vivo activity

For their MM model, researchers used mice inoculated with MM1 cells. The mice received TG-1601 at 10 mg/kg twice a day.

At day 17 after treatment initiation, there was a 70% reduction in tumor volume. During a week-long drug holiday, tumors did not grow back as fast in TG-1601-treated mice as they did in vehicle control mice.

For their AML model, researchers used mice inoculated with MV4-11 cells. The mice received TG-1601 as a single dose of 20 mg/kg/day—continuously or with 2, 3, or 4 days off per week—or at 10 mg/kg twice a day.

At day 15, 100% of mice that received the drug at 10 mg/kg twice a day were tumor-free. Mice that received the single 20 mg/kg dose had a 94% reduction in tumor volume.

The reduction in tumor volume was 91% in mice with the 2-day drug holiday, 78% in those with the 3-day holiday, and 82% in those with the 4-day holiday.

The researchers also found that TG-1601 had synergistic antitumor activity with an anti-PD-1 antibody in a mouse model of melanoma.

Pharmacodynamic activity

In the MV4-11 cell line, TG-1601 induced “rapid” downregulation of MYC and BCL2 and an increase of p21 mRNA, according to the researchers.

The team also assessed MYC expression in mice with MV4-11 tumors. They said MYC levels rapidly decreased in the tumors and were undetectable at 3 hours after a single dose of TG-1601.

The researchers noted that, at 24 hours after dosing, TG-1601 was cleared from the tumor. However, MYC levels remained below 40% their initial level.

The team said this suggests a long-lasting effect of TG-1601 that may be attributed to its enhanced binding affinity.

“These data demonstrate [TG-1601’s] potential to be a novel BET inhibitor that potently inhibits MYC expression,” said James F. Oliviero, president and chief executive officer of Checkpoint Therapeutics.

“We believe the preclinical data presented today provides encouraging evidence to support the development of [TG-1601] as an anticancer agent, alone and in combination with our anti-PD-L1 antibody, and look forward to the advancement of [TG-1601] into a first-in-human phase 1 trial expected to commence later this year.”

Photo by Aaron Logan

CHICAGO—A BET inhibitor can have potent and long-lasting effects against leukemia and multiple myeloma (MM), according to researchers.

The inhibitor, TG-1601 (or CK-103), exhibited cytotoxicity in MM and leukemia cell lines but did not affect the growth of normal cell lines.

TG-1601 also reduced tumor volume in mouse models of MM and acute myeloid leukemia (AML), and drug holidays had little impact on this activity.

Furthermore, researchers observed enduring MYC inhibition in mice treated with TG-1601.

This research was presented at the AACR Annual Meeting 2018 (abstract 5790).

The work was conducted by researchers from TG Therapeutics and Checkpoint Therapeutics—the companies developing TG-1601—as well as Jubilant Biosys.

In vitro activity

Researchers assessed the cytotoxic activity of TG-1601 in leukemia, MM, and normal cell lines by incubating the cells with increasing concentrations of the drug for 72 hours.

The results suggested TG-1601 inhibits MM and leukemia cell growth, as all EC₅₀ values were below 100 nM.

In the leukemia cell lines, EC₅₀ values were 35 nM (Jurkat), 31 nM (HEL92.1.7), 24 nM (CCRF-CEM and MV4-11), and 18 nM (OCI-AML3).

In the MM cell lines, EC₅₀ values were 85 nM (RPMI8226), 32 nM (KMS28PE), 24 nM (KMS28BM), 21 nM (MOLP8), and 15 nM (MM1s).

In the normal cell lines (Beas2B and WT9-12), cell growth wasn’t inhibited more than 50% with TG-1601 at 10 μM.

In vivo activity

For their MM model, researchers used mice inoculated with MM1 cells. The mice received TG-1601 at 10 mg/kg twice a day.

At day 17 after treatment initiation, there was a 70% reduction in tumor volume. During a week-long drug holiday, tumors did not grow back as fast in TG-1601-treated mice as they did in vehicle control mice.

For their AML model, researchers used mice inoculated with MV4-11 cells. The mice received TG-1601 as a single dose of 20 mg/kg/day—continuously or with 2, 3, or 4 days off per week—or at 10 mg/kg twice a day.

At day 15, 100% of mice that received the drug at 10 mg/kg twice a day were tumor-free. Mice that received the single 20 mg/kg dose had a 94% reduction in tumor volume.

The reduction in tumor volume was 91% in mice with the 2-day drug holiday, 78% in those with the 3-day holiday, and 82% in those with the 4-day holiday.

The researchers also found that TG-1601 had synergistic antitumor activity with an anti-PD-1 antibody in a mouse model of melanoma.

Pharmacodynamic activity

In the MV4-11 cell line, TG-1601 induced “rapid” downregulation of MYC and BCL2 and an increase of p21 mRNA, according to the researchers.

The team also assessed MYC expression in mice with MV4-11 tumors. They said MYC levels rapidly decreased in the tumors and were undetectable at 3 hours after a single dose of TG-1601.

The researchers noted that, at 24 hours after dosing, TG-1601 was cleared from the tumor. However, MYC levels remained below 40% their initial level.

The team said this suggests a long-lasting effect of TG-1601 that may be attributed to its enhanced binding affinity.

“These data demonstrate [TG-1601’s] potential to be a novel BET inhibitor that potently inhibits MYC expression,” said James F. Oliviero, president and chief executive officer of Checkpoint Therapeutics.

“We believe the preclinical data presented today provides encouraging evidence to support the development of [TG-1601] as an anticancer agent, alone and in combination with our anti-PD-L1 antibody, and look forward to the advancement of [TG-1601] into a first-in-human phase 1 trial expected to commence later this year.”

Photo by Rhoda Baer

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.

Abstract 791

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.”

Abstract 794

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.”

Photo by Rhoda Baer

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.

Abstract 791

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.”

Abstract 794

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.”

Photo by Rhoda Baer

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.

Abstract 791

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.”

Abstract 794

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.”

Image by James Thomson

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.

Image by James Thomson

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.

Image by James Thomson

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.

Henrique Orlandi Mourao

CHICAGO—The bispecific antibody APVO436 has demonstrated robust T-cell activation with limited cytokine release in acute myeloid leukemia (AML), according to researchers.

APVO436 binds CD123 and CD3 to redirect T-cell cytotoxicity against CD123-expressing tumor cells.

Researchers found that APVO436 induced T-cell cytotoxicity in AML cells in vitro and in mouse models.

In addition, levels of several cytokines were lower in experiments with APVO436 than in experiments with a comparator antibody.

These findings were presented in a poster at the AACR Annual Meeting 2018 (abstract 1786).

The research was conducted by employees of Aptevo Therapeutics Inc., the company developing APVO436.

“We are especially excited about these latest data for APVO436, which continue to show robust T-cell engagement and cytotoxic activity with reduced levels of cytokine release,” said Jane Gross, PhD, senior vice president and chief scientific officer for Aptevo.

Dr Gross and her colleagues found that APVO436 binds human CD123 and CD3-expressing cells and has “potent” target-specific activity against CD123-expressing AML cell lines (Molm-13 and KG-1a).

In addition, APVO436 induced endogenous T-cell activation and proliferation, accompanied by depletion of CD123-expressing cells, in samples from AML patients and healthy donors.

T cells from these cultures (both AML and non-AML) were expanded and co-cultured with Molm-13 cells and APVO436 or a control antibody. Again, the researchers observed “potent” cytotoxic activity in the presence of APVO436.

Dr Gross and her colleagues also tested APVO436, co-administered with human T cells, in mice with established disseminated Molm-13 tumors. The treatment resulted in a “rapid and significant” reduction in skeletal tumor burden.

Finally, the team compared APVO436 with an Aptevo-generated version of MGD006, a CD123 x CD3 dual-affinity re-targeting molecule being developed by Macrogenics, Inc.

The researchers took purified T cells from healthy donors and cultured them with Molm-13 cells, as well as APVO436, Aptevo’s version of MGD006, and a control antibody.

Both APVO436 and Aptevo’s version of MGD006 were effective at stimulating a tumor-directed immune response, inducing comparable levels of T-cell activation, proliferation, and cytotoxicity.

However, APVO436 induced lower levels of several cytokines—including IFNγ, IL-2, IL-6, and TNFα.

“Importantly, IFNγ, IL-6, and TNFα are considered to be the most relevant cytokines responsible for dosing toxicities observed in clinical studies with T-cell engaging molecules, which suggests that APVO436 could offer the potential for reduced toxicities compared to other CD123 x CD3 T-cell engagers at comparable or higher doses,” Dr Gross said.

She added that Aptevo is planning to launch a phase 1 trial of APVO436 in patients with AML and myelodysplastic syndromes later this year.

Henrique Orlandi Mourao

CHICAGO—The bispecific antibody APVO436 has demonstrated robust T-cell activation with limited cytokine release in acute myeloid leukemia (AML), according to researchers.

APVO436 binds CD123 and CD3 to redirect T-cell cytotoxicity against CD123-expressing tumor cells.

Researchers found that APVO436 induced T-cell cytotoxicity in AML cells in vitro and in mouse models.

In addition, levels of several cytokines were lower in experiments with APVO436 than in experiments with a comparator antibody.

These findings were presented in a poster at the AACR Annual Meeting 2018 (abstract 1786).

The research was conducted by employees of Aptevo Therapeutics Inc., the company developing APVO436.

“We are especially excited about these latest data for APVO436, which continue to show robust T-cell engagement and cytotoxic activity with reduced levels of cytokine release,” said Jane Gross, PhD, senior vice president and chief scientific officer for Aptevo.

Dr Gross and her colleagues found that APVO436 binds human CD123 and CD3-expressing cells and has “potent” target-specific activity against CD123-expressing AML cell lines (Molm-13 and KG-1a).

In addition, APVO436 induced endogenous T-cell activation and proliferation, accompanied by depletion of CD123-expressing cells, in samples from AML patients and healthy donors.

T cells from these cultures (both AML and non-AML) were expanded and co-cultured with Molm-13 cells and APVO436 or a control antibody. Again, the researchers observed “potent” cytotoxic activity in the presence of APVO436.

Dr Gross and her colleagues also tested APVO436, co-administered with human T cells, in mice with established disseminated Molm-13 tumors. The treatment resulted in a “rapid and significant” reduction in skeletal tumor burden.

Finally, the team compared APVO436 with an Aptevo-generated version of MGD006, a CD123 x CD3 dual-affinity re-targeting molecule being developed by Macrogenics, Inc.

The researchers took purified T cells from healthy donors and cultured them with Molm-13 cells, as well as APVO436, Aptevo’s version of MGD006, and a control antibody.

Both APVO436 and Aptevo’s version of MGD006 were effective at stimulating a tumor-directed immune response, inducing comparable levels of T-cell activation, proliferation, and cytotoxicity.

However, APVO436 induced lower levels of several cytokines—including IFNγ, IL-2, IL-6, and TNFα.

“Importantly, IFNγ, IL-6, and TNFα are considered to be the most relevant cytokines responsible for dosing toxicities observed in clinical studies with T-cell engaging molecules, which suggests that APVO436 could offer the potential for reduced toxicities compared to other CD123 x CD3 T-cell engagers at comparable or higher doses,” Dr Gross said.

She added that Aptevo is planning to launch a phase 1 trial of APVO436 in patients with AML and myelodysplastic syndromes later this year.

Henrique Orlandi Mourao

CHICAGO—The bispecific antibody APVO436 has demonstrated robust T-cell activation with limited cytokine release in acute myeloid leukemia (AML), according to researchers.

APVO436 binds CD123 and CD3 to redirect T-cell cytotoxicity against CD123-expressing tumor cells.

Researchers found that APVO436 induced T-cell cytotoxicity in AML cells in vitro and in mouse models.

In addition, levels of several cytokines were lower in experiments with APVO436 than in experiments with a comparator antibody.

These findings were presented in a poster at the AACR Annual Meeting 2018 (abstract 1786).

The research was conducted by employees of Aptevo Therapeutics Inc., the company developing APVO436.

“We are especially excited about these latest data for APVO436, which continue to show robust T-cell engagement and cytotoxic activity with reduced levels of cytokine release,” said Jane Gross, PhD, senior vice president and chief scientific officer for Aptevo.

Dr Gross and her colleagues found that APVO436 binds human CD123 and CD3-expressing cells and has “potent” target-specific activity against CD123-expressing AML cell lines (Molm-13 and KG-1a).

In addition, APVO436 induced endogenous T-cell activation and proliferation, accompanied by depletion of CD123-expressing cells, in samples from AML patients and healthy donors.

T cells from these cultures (both AML and non-AML) were expanded and co-cultured with Molm-13 cells and APVO436 or a control antibody. Again, the researchers observed “potent” cytotoxic activity in the presence of APVO436.

Dr Gross and her colleagues also tested APVO436, co-administered with human T cells, in mice with established disseminated Molm-13 tumors. The treatment resulted in a “rapid and significant” reduction in skeletal tumor burden.

Finally, the team compared APVO436 with an Aptevo-generated version of MGD006, a CD123 x CD3 dual-affinity re-targeting molecule being developed by Macrogenics, Inc.

The researchers took purified T cells from healthy donors and cultured them with Molm-13 cells, as well as APVO436, Aptevo’s version of MGD006, and a control antibody.

Both APVO436 and Aptevo’s version of MGD006 were effective at stimulating a tumor-directed immune response, inducing comparable levels of T-cell activation, proliferation, and cytotoxicity.

However, APVO436 induced lower levels of several cytokines—including IFNγ, IL-2, IL-6, and TNFα.

“Importantly, IFNγ, IL-6, and TNFα are considered to be the most relevant cytokines responsible for dosing toxicities observed in clinical studies with T-cell engaging molecules, which suggests that APVO436 could offer the potential for reduced toxicities compared to other CD123 x CD3 T-cell engagers at comparable or higher doses,” Dr Gross said.

She added that Aptevo is planning to launch a phase 1 trial of APVO436 in patients with AML and myelodysplastic syndromes later this year.