CHIMERIC ANTIGEN RECEPTOR (CAR)-MODIFIED T CELLS TARGETING CD19 INDUCE SUSTAINED REMISSIONS IN CHILDREN AND YOUNG ADULTS WITH RELAPSED/REFRACTORY ALL
(Abstract release date: 05/21/15)
EHA Library. Maude S. 06/12/15; 103074; S111
Disclosure(s): The Children's Hospital of Philadelphia
Dr. Shannon Maude
Contributions
Contributions
Abstract
Abstract: S111
Type: Oral Presentation
Presentation during EHA20: From 12.06.2015 11:30 to 12.06.2015 11:45
Location: Room C1
Background
Relapsed/refractory pediatric acute lymphoblastic leukemia (ALL) poses a substantial therapeutic challenge. Targeted immunotherapy using chimeric antigen receptor (CAR)-modified T cells combines the specificity of an antibody’s single chain variable fragment (scFv) with intracellular T cell signaling domains, delivering T cells with potent cytotoxicity to antigen-expressing tumor cells. We previously reported complete remissions and prolonged persistence in children and adults with ALL treated with CD19-specific CART cells (CTL019). We now report on outcomes and longer follow-up of the first 40 patients with relapsed/refractory ALL treated on the pediatric trial of CTL019 in the largest cell therapy experience reported to date.
Aims
Establish the safety and efficacy of CTL019 for patients with relapsed/refractory CD19+ ALL.
Methods
After informed consent, T cells collected from the patient were transduced with a lentiviral vector encoding a CAR composed of anti-CD19 scFv, CD3z, and 4-1BB domains, activated/expanded ex vivo with anti-CD3/anti-CD28 beads, cryopreserved, and then infused. 35/40 patients received lymphodepleting chemotherapy the week prior to cell infusion.
Results
Of 40 patients aged 5-22y (median 11y) with CD19+ ALL, 33 had detectable disease prior to CTL019 cell infusion, while 7 were negative for minimal residual disease (MRD). 28 had relapsed after prior stem cell transplantation (SCT). A median of 3.6x106 CTL019 cells/kg (0.98-17x106/kg) were infused in 1-3 fractions. At assessment 1 month after infusion, 37/40 (93%) were in a complete remission (CR). MRD <0.01% by flow cytometry was achieved in 34 patients. A CR rate of 86% was achieved in 22 patients with an M3 marrow (>25% marrow lymphoblasts) at infusion. With median follow-up 7 mo (1-31 mo) as of January 1, 2015, 26 patients had ongoing CR, with only 5 receiving subsequent therapy (1 donor lymphocyte infusion [DLI], 4 SCT), 6-month EFS was 72% (95% CI, 59-89%), and OS was 77% (95% CI, 64-92%). CTL019 cells were detected in the CSF and 4 patients with CNS2a disease at infusion have experienced ongoing CRs in CSF. Ten patients subsequently relapsed, 5 with CD19(-) disease. CTL019 persistence was accompanied by B cell aplasia, which continued up to 30 months in patients with ongoing CR. Cytokine release syndrome (CRS) was seen in almost all (37) patients. Dramatic elevations in ferritin were observed, suggesting an association of macrophage activation syndrome with CRS. Severe CRS requiring hemodynamic or respiratory support occurred in 33% of patients, was associated with high pre-treatment disease burden and with elevations in CRP and IL6 after infusion. Severe CRS was rapidly reversed in each case with the anti-IL6R agent tocilizumab, demonstrating the importance of IL6 in driving CRS.
Summary
Single-agent CTL019 immunotherapy can induce potent and durable responses in patients with relapsed/refractory ALL. CRS was effectively controlled with IL6 blockade. Long-term disease control is possible without subsequent stem cell transplantation.
Keyword(s): Acute lymphoblastic leukemia, CD19, Immunotherapy, Targeted therapy
Session topic: ALL clinical trials
Type: Oral Presentation
Presentation during EHA20: From 12.06.2015 11:30 to 12.06.2015 11:45
Location: Room C1
Background
Relapsed/refractory pediatric acute lymphoblastic leukemia (ALL) poses a substantial therapeutic challenge. Targeted immunotherapy using chimeric antigen receptor (CAR)-modified T cells combines the specificity of an antibody’s single chain variable fragment (scFv) with intracellular T cell signaling domains, delivering T cells with potent cytotoxicity to antigen-expressing tumor cells. We previously reported complete remissions and prolonged persistence in children and adults with ALL treated with CD19-specific CART cells (CTL019). We now report on outcomes and longer follow-up of the first 40 patients with relapsed/refractory ALL treated on the pediatric trial of CTL019 in the largest cell therapy experience reported to date.
Aims
Establish the safety and efficacy of CTL019 for patients with relapsed/refractory CD19+ ALL.
Methods
After informed consent, T cells collected from the patient were transduced with a lentiviral vector encoding a CAR composed of anti-CD19 scFv, CD3z, and 4-1BB domains, activated/expanded ex vivo with anti-CD3/anti-CD28 beads, cryopreserved, and then infused. 35/40 patients received lymphodepleting chemotherapy the week prior to cell infusion.
Results
Of 40 patients aged 5-22y (median 11y) with CD19+ ALL, 33 had detectable disease prior to CTL019 cell infusion, while 7 were negative for minimal residual disease (MRD). 28 had relapsed after prior stem cell transplantation (SCT). A median of 3.6x106 CTL019 cells/kg (0.98-17x106/kg) were infused in 1-3 fractions. At assessment 1 month after infusion, 37/40 (93%) were in a complete remission (CR). MRD <0.01% by flow cytometry was achieved in 34 patients. A CR rate of 86% was achieved in 22 patients with an M3 marrow (>25% marrow lymphoblasts) at infusion. With median follow-up 7 mo (1-31 mo) as of January 1, 2015, 26 patients had ongoing CR, with only 5 receiving subsequent therapy (1 donor lymphocyte infusion [DLI], 4 SCT), 6-month EFS was 72% (95% CI, 59-89%), and OS was 77% (95% CI, 64-92%). CTL019 cells were detected in the CSF and 4 patients with CNS2a disease at infusion have experienced ongoing CRs in CSF. Ten patients subsequently relapsed, 5 with CD19(-) disease. CTL019 persistence was accompanied by B cell aplasia, which continued up to 30 months in patients with ongoing CR. Cytokine release syndrome (CRS) was seen in almost all (37) patients. Dramatic elevations in ferritin were observed, suggesting an association of macrophage activation syndrome with CRS. Severe CRS requiring hemodynamic or respiratory support occurred in 33% of patients, was associated with high pre-treatment disease burden and with elevations in CRP and IL6 after infusion. Severe CRS was rapidly reversed in each case with the anti-IL6R agent tocilizumab, demonstrating the importance of IL6 in driving CRS.
Summary
Single-agent CTL019 immunotherapy can induce potent and durable responses in patients with relapsed/refractory ALL. CRS was effectively controlled with IL6 blockade. Long-term disease control is possible without subsequent stem cell transplantation.
Keyword(s): Acute lymphoblastic leukemia, CD19, Immunotherapy, Targeted therapy
Session topic: ALL clinical trials
Abstract: S111
Type: Oral Presentation
Presentation during EHA20: From 12.06.2015 11:30 to 12.06.2015 11:45
Location: Room C1
Background
Relapsed/refractory pediatric acute lymphoblastic leukemia (ALL) poses a substantial therapeutic challenge. Targeted immunotherapy using chimeric antigen receptor (CAR)-modified T cells combines the specificity of an antibody’s single chain variable fragment (scFv) with intracellular T cell signaling domains, delivering T cells with potent cytotoxicity to antigen-expressing tumor cells. We previously reported complete remissions and prolonged persistence in children and adults with ALL treated with CD19-specific CART cells (CTL019). We now report on outcomes and longer follow-up of the first 40 patients with relapsed/refractory ALL treated on the pediatric trial of CTL019 in the largest cell therapy experience reported to date.
Aims
Establish the safety and efficacy of CTL019 for patients with relapsed/refractory CD19+ ALL.
Methods
After informed consent, T cells collected from the patient were transduced with a lentiviral vector encoding a CAR composed of anti-CD19 scFv, CD3z, and 4-1BB domains, activated/expanded ex vivo with anti-CD3/anti-CD28 beads, cryopreserved, and then infused. 35/40 patients received lymphodepleting chemotherapy the week prior to cell infusion.
Results
Of 40 patients aged 5-22y (median 11y) with CD19+ ALL, 33 had detectable disease prior to CTL019 cell infusion, while 7 were negative for minimal residual disease (MRD). 28 had relapsed after prior stem cell transplantation (SCT). A median of 3.6x106 CTL019 cells/kg (0.98-17x106/kg) were infused in 1-3 fractions. At assessment 1 month after infusion, 37/40 (93%) were in a complete remission (CR). MRD <0.01% by flow cytometry was achieved in 34 patients. A CR rate of 86% was achieved in 22 patients with an M3 marrow (>25% marrow lymphoblasts) at infusion. With median follow-up 7 mo (1-31 mo) as of January 1, 2015, 26 patients had ongoing CR, with only 5 receiving subsequent therapy (1 donor lymphocyte infusion [DLI], 4 SCT), 6-month EFS was 72% (95% CI, 59-89%), and OS was 77% (95% CI, 64-92%). CTL019 cells were detected in the CSF and 4 patients with CNS2a disease at infusion have experienced ongoing CRs in CSF. Ten patients subsequently relapsed, 5 with CD19(-) disease. CTL019 persistence was accompanied by B cell aplasia, which continued up to 30 months in patients with ongoing CR. Cytokine release syndrome (CRS) was seen in almost all (37) patients. Dramatic elevations in ferritin were observed, suggesting an association of macrophage activation syndrome with CRS. Severe CRS requiring hemodynamic or respiratory support occurred in 33% of patients, was associated with high pre-treatment disease burden and with elevations in CRP and IL6 after infusion. Severe CRS was rapidly reversed in each case with the anti-IL6R agent tocilizumab, demonstrating the importance of IL6 in driving CRS.
Summary
Single-agent CTL019 immunotherapy can induce potent and durable responses in patients with relapsed/refractory ALL. CRS was effectively controlled with IL6 blockade. Long-term disease control is possible without subsequent stem cell transplantation.
Keyword(s): Acute lymphoblastic leukemia, CD19, Immunotherapy, Targeted therapy
Session topic: ALL clinical trials
Type: Oral Presentation
Presentation during EHA20: From 12.06.2015 11:30 to 12.06.2015 11:45
Location: Room C1
Background
Relapsed/refractory pediatric acute lymphoblastic leukemia (ALL) poses a substantial therapeutic challenge. Targeted immunotherapy using chimeric antigen receptor (CAR)-modified T cells combines the specificity of an antibody’s single chain variable fragment (scFv) with intracellular T cell signaling domains, delivering T cells with potent cytotoxicity to antigen-expressing tumor cells. We previously reported complete remissions and prolonged persistence in children and adults with ALL treated with CD19-specific CART cells (CTL019). We now report on outcomes and longer follow-up of the first 40 patients with relapsed/refractory ALL treated on the pediatric trial of CTL019 in the largest cell therapy experience reported to date.
Aims
Establish the safety and efficacy of CTL019 for patients with relapsed/refractory CD19+ ALL.
Methods
After informed consent, T cells collected from the patient were transduced with a lentiviral vector encoding a CAR composed of anti-CD19 scFv, CD3z, and 4-1BB domains, activated/expanded ex vivo with anti-CD3/anti-CD28 beads, cryopreserved, and then infused. 35/40 patients received lymphodepleting chemotherapy the week prior to cell infusion.
Results
Of 40 patients aged 5-22y (median 11y) with CD19+ ALL, 33 had detectable disease prior to CTL019 cell infusion, while 7 were negative for minimal residual disease (MRD). 28 had relapsed after prior stem cell transplantation (SCT). A median of 3.6x106 CTL019 cells/kg (0.98-17x106/kg) were infused in 1-3 fractions. At assessment 1 month after infusion, 37/40 (93%) were in a complete remission (CR). MRD <0.01% by flow cytometry was achieved in 34 patients. A CR rate of 86% was achieved in 22 patients with an M3 marrow (>25% marrow lymphoblasts) at infusion. With median follow-up 7 mo (1-31 mo) as of January 1, 2015, 26 patients had ongoing CR, with only 5 receiving subsequent therapy (1 donor lymphocyte infusion [DLI], 4 SCT), 6-month EFS was 72% (95% CI, 59-89%), and OS was 77% (95% CI, 64-92%). CTL019 cells were detected in the CSF and 4 patients with CNS2a disease at infusion have experienced ongoing CRs in CSF. Ten patients subsequently relapsed, 5 with CD19(-) disease. CTL019 persistence was accompanied by B cell aplasia, which continued up to 30 months in patients with ongoing CR. Cytokine release syndrome (CRS) was seen in almost all (37) patients. Dramatic elevations in ferritin were observed, suggesting an association of macrophage activation syndrome with CRS. Severe CRS requiring hemodynamic or respiratory support occurred in 33% of patients, was associated with high pre-treatment disease burden and with elevations in CRP and IL6 after infusion. Severe CRS was rapidly reversed in each case with the anti-IL6R agent tocilizumab, demonstrating the importance of IL6 in driving CRS.
Summary
Single-agent CTL019 immunotherapy can induce potent and durable responses in patients with relapsed/refractory ALL. CRS was effectively controlled with IL6 blockade. Long-term disease control is possible without subsequent stem cell transplantation.
Keyword(s): Acute lymphoblastic leukemia, CD19, Immunotherapy, Targeted therapy
Session topic: ALL clinical trials
{{ help_message }}
{{filter}}