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HOUSTON – Neutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) may be an effective strategy not only to manage toxicities associated with chimeric antigen receptor (CAR) T-cell therapy, but also to enhance CAR-T cell function, an investigator reported at the Transplantation & Cellular Therapy Meetings.
The GM-CSF targeted monoclonal antibody lenzilumab reduced neurotoxicity and cytokine release syndrome (CRS) related to CD19-targeted CAR T-cell therapy in a patient-derived xenograft model, said investigator Rosalie M. Sterner, an MD-PhD student in the department of immunology at Mayo Clinic, Rochester, Minn.
Other investigations showed that neutralizing or knocking out GM-CSF enhanced the antitumor functions of the CAR T cells, Ms. Sterner said in a podium presentation at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
“GM-CSF blockade does not impair CAR T-cell effector function, and in fact, enhances CAR T-cell effector functions in certain models, and actually can help to ameliorate CAR T-cell associated toxicities,” Ms. Sterner said.
Based on these early findings, the investigators have designed a phase 2 clinical trial to see if lenzilumab can prevent CAR T cell-related toxicities in patients with diffuse large B-cell lymphoma.
GM-CSF, a cytokine produced by T cells and myeloid cells, is the most statistically significantly elevated serum marker in patients with severe neurotoxicity related to CAR T-cell therapy, Ms. Sterner told attendees.
Investigations have shown that the combination of lenzilumab plus CD19-targeted T-cell therapy did not impair CAR T-cell function in vivo or in vitro, she said.
In other studies, they investigated the impact of GM-CSF neutralization in mice engrafted with primary acute lymphocytic leukemia (ALL) blasts and treated with high doses of CD19 CAR T-cells, lenzilumab, and a murine GM-CSF blocking antibody to neutralize the mouse GM-CSF. That strategy prevented weight loss, decreased myeloid cytokines, reduced cerebral edema, and enhanced disease control, Ms. Sterner said.
Investigators also reported on CD19 CAR T-cells with reduced GM-CSF secretion due to CRISPR/Cas9 gene editing of the GM-CSF gene during the CAR T-cell manufacturing process. Xenograft model results showed a slight enhancement of disease control for those GM-CSF knockout CAR T cells versus standard CAR T cells.
More details of the investigations were recently published in Blood (2019;133:697-709).
Taken together, the investigations highlight GM-CSF inhibition as a novel approach to reducing neurotoxicity and CRS that may also enhance CAR T-cell effector functions, Ms. Sterner said.
Ms. Sterner reported having no financial disclosures related to her presentation.
SOURCE: Sterner R et al. TCT 2019, Abstract 5.
HOUSTON – Neutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) may be an effective strategy not only to manage toxicities associated with chimeric antigen receptor (CAR) T-cell therapy, but also to enhance CAR-T cell function, an investigator reported at the Transplantation & Cellular Therapy Meetings.
The GM-CSF targeted monoclonal antibody lenzilumab reduced neurotoxicity and cytokine release syndrome (CRS) related to CD19-targeted CAR T-cell therapy in a patient-derived xenograft model, said investigator Rosalie M. Sterner, an MD-PhD student in the department of immunology at Mayo Clinic, Rochester, Minn.
Other investigations showed that neutralizing or knocking out GM-CSF enhanced the antitumor functions of the CAR T cells, Ms. Sterner said in a podium presentation at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
“GM-CSF blockade does not impair CAR T-cell effector function, and in fact, enhances CAR T-cell effector functions in certain models, and actually can help to ameliorate CAR T-cell associated toxicities,” Ms. Sterner said.
Based on these early findings, the investigators have designed a phase 2 clinical trial to see if lenzilumab can prevent CAR T cell-related toxicities in patients with diffuse large B-cell lymphoma.
GM-CSF, a cytokine produced by T cells and myeloid cells, is the most statistically significantly elevated serum marker in patients with severe neurotoxicity related to CAR T-cell therapy, Ms. Sterner told attendees.
Investigations have shown that the combination of lenzilumab plus CD19-targeted T-cell therapy did not impair CAR T-cell function in vivo or in vitro, she said.
In other studies, they investigated the impact of GM-CSF neutralization in mice engrafted with primary acute lymphocytic leukemia (ALL) blasts and treated with high doses of CD19 CAR T-cells, lenzilumab, and a murine GM-CSF blocking antibody to neutralize the mouse GM-CSF. That strategy prevented weight loss, decreased myeloid cytokines, reduced cerebral edema, and enhanced disease control, Ms. Sterner said.
Investigators also reported on CD19 CAR T-cells with reduced GM-CSF secretion due to CRISPR/Cas9 gene editing of the GM-CSF gene during the CAR T-cell manufacturing process. Xenograft model results showed a slight enhancement of disease control for those GM-CSF knockout CAR T cells versus standard CAR T cells.
More details of the investigations were recently published in Blood (2019;133:697-709).
Taken together, the investigations highlight GM-CSF inhibition as a novel approach to reducing neurotoxicity and CRS that may also enhance CAR T-cell effector functions, Ms. Sterner said.
Ms. Sterner reported having no financial disclosures related to her presentation.
SOURCE: Sterner R et al. TCT 2019, Abstract 5.
HOUSTON – Neutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) may be an effective strategy not only to manage toxicities associated with chimeric antigen receptor (CAR) T-cell therapy, but also to enhance CAR-T cell function, an investigator reported at the Transplantation & Cellular Therapy Meetings.
The GM-CSF targeted monoclonal antibody lenzilumab reduced neurotoxicity and cytokine release syndrome (CRS) related to CD19-targeted CAR T-cell therapy in a patient-derived xenograft model, said investigator Rosalie M. Sterner, an MD-PhD student in the department of immunology at Mayo Clinic, Rochester, Minn.
Other investigations showed that neutralizing or knocking out GM-CSF enhanced the antitumor functions of the CAR T cells, Ms. Sterner said in a podium presentation at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
“GM-CSF blockade does not impair CAR T-cell effector function, and in fact, enhances CAR T-cell effector functions in certain models, and actually can help to ameliorate CAR T-cell associated toxicities,” Ms. Sterner said.
Based on these early findings, the investigators have designed a phase 2 clinical trial to see if lenzilumab can prevent CAR T cell-related toxicities in patients with diffuse large B-cell lymphoma.
GM-CSF, a cytokine produced by T cells and myeloid cells, is the most statistically significantly elevated serum marker in patients with severe neurotoxicity related to CAR T-cell therapy, Ms. Sterner told attendees.
Investigations have shown that the combination of lenzilumab plus CD19-targeted T-cell therapy did not impair CAR T-cell function in vivo or in vitro, she said.
In other studies, they investigated the impact of GM-CSF neutralization in mice engrafted with primary acute lymphocytic leukemia (ALL) blasts and treated with high doses of CD19 CAR T-cells, lenzilumab, and a murine GM-CSF blocking antibody to neutralize the mouse GM-CSF. That strategy prevented weight loss, decreased myeloid cytokines, reduced cerebral edema, and enhanced disease control, Ms. Sterner said.
Investigators also reported on CD19 CAR T-cells with reduced GM-CSF secretion due to CRISPR/Cas9 gene editing of the GM-CSF gene during the CAR T-cell manufacturing process. Xenograft model results showed a slight enhancement of disease control for those GM-CSF knockout CAR T cells versus standard CAR T cells.
More details of the investigations were recently published in Blood (2019;133:697-709).
Taken together, the investigations highlight GM-CSF inhibition as a novel approach to reducing neurotoxicity and CRS that may also enhance CAR T-cell effector functions, Ms. Sterner said.
Ms. Sterner reported having no financial disclosures related to her presentation.
SOURCE: Sterner R et al. TCT 2019, Abstract 5.
REPORTING FROM TCT 2019