Early results favor combo IL-15/anti-CD20 in indolent NHL

 

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.

 

In total, 21 patients were treated: 16 patients had follicular lymphoma, four patients had marginal zone lymphoma, and one patient had small lymphocytic lymphoma. The median prior therapies received was two (range: 1-18) and five patients were treated who were refractory to prior anti-CD20 MAb therapy.

ALT-803 was well tolerated with no dose limiting toxicities or grade 4 or 5 adverse events. No patients discontinued ALT-803 and the recommended phase 2 dose was 20 mcg/kg subcutaneously. Grade 3 adverse events, regardless of attribution to ALT-803, included transient hypertension (14%), anemia (5%), nausea (5%), chills (5%), fever (5%), neutropenia (5%), and hyperglycemia (5%).

“Patients who received [subcutaneous] ALT-803 developed a unique injection site rash reaction that peaked 7-10 days later but resolved typically within 14 days. It was self-limited and resolved on its own,” Dr. Fehniger said.

At the time of the presentation, the best overall response rate was achieved in 11 of 21 patients (52%), with 9 complete responders (43%), and 2 partial responders (10%).

 

Of the 12 patients treated with ALT-803 subcutaneously, 11 patients had either stable disease, or partial or complete responses. All 11 patients remained on study and were in consolidation or follow-up and have not relapsed, Dr. Fehniger reported.

Among the five rituximab-refractory patients, the researchers observed one complete response, two patients with stable disease (45% and 36% tumor volume decrease), and two patients with partial disease. The durability of the responses can only be understood with longer follow-up, Dr. Fehniger said.

The peripheral blood of the patients was analyzed via flow cytometry and mass cytometry. Over the duration of four weekly doses, there was an increase in percentage (sixfold, P less than .001) and absolute number (10-fold, P less than .001) of natural killer cells at the 15-mcg/kg and 20-mcg/kg subcutaneous dose levels of ALT-803.

These results suggest that further studies of ALT-803 with other therapeutic targeting mAbs, or other immunotherapy modalities, are warranted, the researchers concluded.

Dr. Fehniger reported research funding from Altor BioScience.

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.

 

In total, 21 patients were treated: 16 patients had follicular lymphoma, four patients had marginal zone lymphoma, and one patient had small lymphocytic lymphoma. The median prior therapies received was two (range: 1-18) and five patients were treated who were refractory to prior anti-CD20 MAb therapy.

ALT-803 was well tolerated with no dose limiting toxicities or grade 4 or 5 adverse events. No patients discontinued ALT-803 and the recommended phase 2 dose was 20 mcg/kg subcutaneously. Grade 3 adverse events, regardless of attribution to ALT-803, included transient hypertension (14%), anemia (5%), nausea (5%), chills (5%), fever (5%), neutropenia (5%), and hyperglycemia (5%).

“Patients who received [subcutaneous] ALT-803 developed a unique injection site rash reaction that peaked 7-10 days later but resolved typically within 14 days. It was self-limited and resolved on its own,” Dr. Fehniger said.

At the time of the presentation, the best overall response rate was achieved in 11 of 21 patients (52%), with 9 complete responders (43%), and 2 partial responders (10%).

 

Of the 12 patients treated with ALT-803 subcutaneously, 11 patients had either stable disease, or partial or complete responses. All 11 patients remained on study and were in consolidation or follow-up and have not relapsed, Dr. Fehniger reported.

Among the five rituximab-refractory patients, the researchers observed one complete response, two patients with stable disease (45% and 36% tumor volume decrease), and two patients with partial disease. The durability of the responses can only be understood with longer follow-up, Dr. Fehniger said.

The peripheral blood of the patients was analyzed via flow cytometry and mass cytometry. Over the duration of four weekly doses, there was an increase in percentage (sixfold, P less than .001) and absolute number (10-fold, P less than .001) of natural killer cells at the 15-mcg/kg and 20-mcg/kg subcutaneous dose levels of ALT-803.

These results suggest that further studies of ALT-803 with other therapeutic targeting mAbs, or other immunotherapy modalities, are warranted, the researchers concluded.

Dr. Fehniger reported research funding from Altor BioScience.

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.

 

In total, 21 patients were treated: 16 patients had follicular lymphoma, four patients had marginal zone lymphoma, and one patient had small lymphocytic lymphoma. The median prior therapies received was two (range: 1-18) and five patients were treated who were refractory to prior anti-CD20 MAb therapy.

ALT-803 was well tolerated with no dose limiting toxicities or grade 4 or 5 adverse events. No patients discontinued ALT-803 and the recommended phase 2 dose was 20 mcg/kg subcutaneously. Grade 3 adverse events, regardless of attribution to ALT-803, included transient hypertension (14%), anemia (5%), nausea (5%), chills (5%), fever (5%), neutropenia (5%), and hyperglycemia (5%).

“Patients who received [subcutaneous] ALT-803 developed a unique injection site rash reaction that peaked 7-10 days later but resolved typically within 14 days. It was self-limited and resolved on its own,” Dr. Fehniger said.

At the time of the presentation, the best overall response rate was achieved in 11 of 21 patients (52%), with 9 complete responders (43%), and 2 partial responders (10%).

 

Of the 12 patients treated with ALT-803 subcutaneously, 11 patients had either stable disease, or partial or complete responses. All 11 patients remained on study and were in consolidation or follow-up and have not relapsed, Dr. Fehniger reported.

Among the five rituximab-refractory patients, the researchers observed one complete response, two patients with stable disease (45% and 36% tumor volume decrease), and two patients with partial disease. The durability of the responses can only be understood with longer follow-up, Dr. Fehniger said.

The peripheral blood of the patients was analyzed via flow cytometry and mass cytometry. Over the duration of four weekly doses, there was an increase in percentage (sixfold, P less than .001) and absolute number (10-fold, P less than .001) of natural killer cells at the 15-mcg/kg and 20-mcg/kg subcutaneous dose levels of ALT-803.

These results suggest that further studies of ALT-803 with other therapeutic targeting mAbs, or other immunotherapy modalities, are warranted, the researchers concluded.

Dr. Fehniger reported research funding from Altor BioScience.

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