ALLOGENIC ADOPTIVE IMMUNOTHERAPY OF ACUTE MYELOID LEUKEMIA (AML) BY TARGETING CD123 WITH CAR T-CELLS
(Abstract release date: 05/21/15)
EHA Library. Galetto R. 06/13/15; 103221; S469
Disclosure(s): Cellectis
Dr. Roman Galetto
Contributions
Contributions
Abstract
Abstract: S469
Type: Oral Presentation
Presentation during EHA20: From 13.06.2015 12:15 to 13.06.2015 12:30
Location: Room Stolz 2
Background
Adoptive immunotherapy using autologous T-cells endowed with chimeric antigen receptors (CARs) has given rise to long-term durable remissions and remarkable objective response rates in patients with refractory leukemia, raising hopes that a wider application of CAR technology may lead to a new paradigm in cancer treatment. However, a limitation of the current autologous approach is that CAR T-cells must be manufactured on a 'per patient basis'.
Aims
To overcome this limitation we have developed a standardized platform for manufacturing T-cells from third-party healthy donors to generate allogeneic 'off-the-shelf' engineered CAR+ T-cell–based frozen products.
Methods
This allogenic platform utilizes Transcription Activator-Like Effector Nuclease (TALEN) gene editing technology to inactivate the TCRa constant (TRAC) gene, eliminating the potential for T-cells bearing alloreactive TCR’s to mediate Graft versus Host Disease (GvHD). We have previously demonstrated that editing of the TRAC gene can be achieved at high frequencies, yielding up to 80% of TCRab negative cells and allowing efficient production and purification of TCR-deficient T-cells that no longer mediate alloreactivity in a xeno-GvHD mouse model. As a safety feature, T-cells are engineered to co-express the RQR8 gene, with the aim of rendering them sensitive to the monoclonal antibody rituximab.
Results
Here, we have adapted this allogeneic platform to the production of T cells targeting CD123, the transmembrane alpha chain of the interleukin-3 receptor, which is expressed on tumor cells from the majority of patients with Acute Myeloid Leukemia (AML). In a first step, we have screened multiple antigen recognition domains in the context of different CAR architectures to identify effective CAR candidates displaying activity against cells expressing variable levels of the CD123 antigen. In addition, experiments in an orthotopic AML mouse model using UCART123 cells demonstrate important anti-tumor activity in vivo.
Summary
The ability to carry out large scale manufacturing of allogeneic, non alloreactive CD123 specific T-cells from a single healthy donor can offer the possibility of an off-the-shelf treatment that would be immediately available for administration to a large number of AML patients.
Keyword(s): Allogeneic, AML, Immunotherapy
Session topic: Gene therapy, cellular immunotherapy and vaccination
Type: Oral Presentation
Presentation during EHA20: From 13.06.2015 12:15 to 13.06.2015 12:30
Location: Room Stolz 2
Background
Adoptive immunotherapy using autologous T-cells endowed with chimeric antigen receptors (CARs) has given rise to long-term durable remissions and remarkable objective response rates in patients with refractory leukemia, raising hopes that a wider application of CAR technology may lead to a new paradigm in cancer treatment. However, a limitation of the current autologous approach is that CAR T-cells must be manufactured on a 'per patient basis'.
Aims
To overcome this limitation we have developed a standardized platform for manufacturing T-cells from third-party healthy donors to generate allogeneic 'off-the-shelf' engineered CAR+ T-cell–based frozen products.
Methods
This allogenic platform utilizes Transcription Activator-Like Effector Nuclease (TALEN) gene editing technology to inactivate the TCRa constant (TRAC) gene, eliminating the potential for T-cells bearing alloreactive TCR’s to mediate Graft versus Host Disease (GvHD). We have previously demonstrated that editing of the TRAC gene can be achieved at high frequencies, yielding up to 80% of TCRab negative cells and allowing efficient production and purification of TCR-deficient T-cells that no longer mediate alloreactivity in a xeno-GvHD mouse model. As a safety feature, T-cells are engineered to co-express the RQR8 gene, with the aim of rendering them sensitive to the monoclonal antibody rituximab.
Results
Here, we have adapted this allogeneic platform to the production of T cells targeting CD123, the transmembrane alpha chain of the interleukin-3 receptor, which is expressed on tumor cells from the majority of patients with Acute Myeloid Leukemia (AML). In a first step, we have screened multiple antigen recognition domains in the context of different CAR architectures to identify effective CAR candidates displaying activity against cells expressing variable levels of the CD123 antigen. In addition, experiments in an orthotopic AML mouse model using UCART123 cells demonstrate important anti-tumor activity in vivo.
Summary
The ability to carry out large scale manufacturing of allogeneic, non alloreactive CD123 specific T-cells from a single healthy donor can offer the possibility of an off-the-shelf treatment that would be immediately available for administration to a large number of AML patients.
Keyword(s): Allogeneic, AML, Immunotherapy
Session topic: Gene therapy, cellular immunotherapy and vaccination
Abstract: S469
Type: Oral Presentation
Presentation during EHA20: From 13.06.2015 12:15 to 13.06.2015 12:30
Location: Room Stolz 2
Background
Adoptive immunotherapy using autologous T-cells endowed with chimeric antigen receptors (CARs) has given rise to long-term durable remissions and remarkable objective response rates in patients with refractory leukemia, raising hopes that a wider application of CAR technology may lead to a new paradigm in cancer treatment. However, a limitation of the current autologous approach is that CAR T-cells must be manufactured on a 'per patient basis'.
Aims
To overcome this limitation we have developed a standardized platform for manufacturing T-cells from third-party healthy donors to generate allogeneic 'off-the-shelf' engineered CAR+ T-cell–based frozen products.
Methods
This allogenic platform utilizes Transcription Activator-Like Effector Nuclease (TALEN) gene editing technology to inactivate the TCRa constant (TRAC) gene, eliminating the potential for T-cells bearing alloreactive TCR’s to mediate Graft versus Host Disease (GvHD). We have previously demonstrated that editing of the TRAC gene can be achieved at high frequencies, yielding up to 80% of TCRab negative cells and allowing efficient production and purification of TCR-deficient T-cells that no longer mediate alloreactivity in a xeno-GvHD mouse model. As a safety feature, T-cells are engineered to co-express the RQR8 gene, with the aim of rendering them sensitive to the monoclonal antibody rituximab.
Results
Here, we have adapted this allogeneic platform to the production of T cells targeting CD123, the transmembrane alpha chain of the interleukin-3 receptor, which is expressed on tumor cells from the majority of patients with Acute Myeloid Leukemia (AML). In a first step, we have screened multiple antigen recognition domains in the context of different CAR architectures to identify effective CAR candidates displaying activity against cells expressing variable levels of the CD123 antigen. In addition, experiments in an orthotopic AML mouse model using UCART123 cells demonstrate important anti-tumor activity in vivo.
Summary
The ability to carry out large scale manufacturing of allogeneic, non alloreactive CD123 specific T-cells from a single healthy donor can offer the possibility of an off-the-shelf treatment that would be immediately available for administration to a large number of AML patients.
Keyword(s): Allogeneic, AML, Immunotherapy
Session topic: Gene therapy, cellular immunotherapy and vaccination
Type: Oral Presentation
Presentation during EHA20: From 13.06.2015 12:15 to 13.06.2015 12:30
Location: Room Stolz 2
Background
Adoptive immunotherapy using autologous T-cells endowed with chimeric antigen receptors (CARs) has given rise to long-term durable remissions and remarkable objective response rates in patients with refractory leukemia, raising hopes that a wider application of CAR technology may lead to a new paradigm in cancer treatment. However, a limitation of the current autologous approach is that CAR T-cells must be manufactured on a 'per patient basis'.
Aims
To overcome this limitation we have developed a standardized platform for manufacturing T-cells from third-party healthy donors to generate allogeneic 'off-the-shelf' engineered CAR+ T-cell–based frozen products.
Methods
This allogenic platform utilizes Transcription Activator-Like Effector Nuclease (TALEN) gene editing technology to inactivate the TCRa constant (TRAC) gene, eliminating the potential for T-cells bearing alloreactive TCR’s to mediate Graft versus Host Disease (GvHD). We have previously demonstrated that editing of the TRAC gene can be achieved at high frequencies, yielding up to 80% of TCRab negative cells and allowing efficient production and purification of TCR-deficient T-cells that no longer mediate alloreactivity in a xeno-GvHD mouse model. As a safety feature, T-cells are engineered to co-express the RQR8 gene, with the aim of rendering them sensitive to the monoclonal antibody rituximab.
Results
Here, we have adapted this allogeneic platform to the production of T cells targeting CD123, the transmembrane alpha chain of the interleukin-3 receptor, which is expressed on tumor cells from the majority of patients with Acute Myeloid Leukemia (AML). In a first step, we have screened multiple antigen recognition domains in the context of different CAR architectures to identify effective CAR candidates displaying activity against cells expressing variable levels of the CD123 antigen. In addition, experiments in an orthotopic AML mouse model using UCART123 cells demonstrate important anti-tumor activity in vivo.
Summary
The ability to carry out large scale manufacturing of allogeneic, non alloreactive CD123 specific T-cells from a single healthy donor can offer the possibility of an off-the-shelf treatment that would be immediately available for administration to a large number of AML patients.
Keyword(s): Allogeneic, AML, Immunotherapy
Session topic: Gene therapy, cellular immunotherapy and vaccination
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