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CHICAGO—Three of 6 pediatric patients with relapsed or refractory acute lymphoblastic leukemia (ALL) whose CD19 chimeric antigen receptor (CAR) T cells did not persist even after reinfusion demonstrated persistence when the PD-1 checkpoint inhibitor pembrolizumab was added to the regimen.
CAR T cells can persist for months or even years and have the potential to mediate long-term disease control.
But some patients recover their normal B cells, which is a marker of loss of functional CAR T cells. These patients are at a higher risk of disease relapse.
Investigators, therefore, undertook a pilot study to determine whether PD-1 checkpoint pathway inhibition can improve CAR T persistence in these patients.
Shannon L. Maude, MD, of the Children’s Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, shared some of the patient cases in this pilot study at the ASCO 2017 Annual Meeting (Abstract 103*).
The investigators hypothesized that possible anti-murine immunogenicity could be causing poor CAR T-cell persistence, since the first CAR T developed used scFv domains of murine origin.
If T-cell exhaustion caused poor CAR T-cell persistence, immune checkpoints might play a role. In this case, combination with PD-1 checkpoint blockade could improve persistence, they hypothesized.
The investigators proposed to administer a repeat CAR T-cell infusion for relapsed or refractory ALL patients with poor persistence and add pembrolizumab after retreatment if the patients still had poor persistence. Patients were offered the option of another reinfusion prior to treatment with pembrolizumab if their CAR T-cell persistence continued to be poor.
Investigators added pembrolizumab no earlier than 14 days after infusion and only after patients recovered from cytokine release syndrome (CRS).
The infusions in the pilot study were humanized CART19 (huCART19, CTL119), unless otherwise specified.
Patient 1 – Pembrolizumab for partial response
This patient had no response to the prior murine CD19 CAR infusion, but responded well to infusion with huCART19 with good CAR T-cell proliferation.
By day 28, the patient had achieved a complete response (CR) in bone marrow but had a minimal residual disease (MRD) level of 1.2%.
At 7 weeks, the patient had a CD19+ relapse with low levels of huCART19.
Investigators added pembrolizumb on day 52 after infusion, and the patient had a modest increase in huCART19.
The patient had a temporary clearance of peripheral blasts followed by disease progression.
Patient 2 – Pembrolizumab for no response
This patient had a CD19+ relapse at 12 months after prior murine CD19 CAR infusion.
The patient was treated with huCART19, had good proliferation, but a rapid drop of CART19, and no response of the disease with a CD19+ relapse.
The patient had a reinfusion of huCART19 at 6 weeks and investigators added pembrolizumab on day 14 after reinfusion.
The patient experienced good huCART19 proliferation and prolonged persistence, but by day 28 had persistent disease, this time with decreased expression of CD19+ cells.
Patient 3 – Pembrolizumab for poor persistence
This patient had a CR with a prior murine CD19 CAR, but had poor persistence and early B cell recovery at 2 months.
The patient had a CD19+ relapse, was treated with huCART19, and had good proliferation again.
The patient achieved an MRD-negative CR, but because of short persistence and early B-cell recovery at 2 months, relapsed at 15 months.
The patient was reinfused at 17 months and pembrolizumab was added on day 14. The patient entered CR with prolonged persistence, but ultimately B-cell recovery occurred.
The patient was reinfused a third time, and pembrolizumab was added to the regimen every 3 weeks. The patient is experiencing prolonged persistence and continued B-cell aplasia.
Patient 4 – Pembrolizumab for poor persistence
This patient had achieved a CR with murine CAR19, but had a CD19+ relapse at 9 months. The patient then received huCART19, had good proliferation and achieved a CR, but had short persistence and B-cell recovery at 2 months.
The patient relapsed at 12 months and was reinfused with huCART19 at 14 months.
Pembrolizumab was added on day 14 after reinfusion, but the patient had no huCART19 proliferation, no response, and CD19+ MRD.
Patient 5 – Pembrolizumab for poor persistence
The patient responded to a prior murine CART19, but had a CD19+ relapse at 12 months.
The patient was infused with huCART19 and had good proliferation but short persistence. The patient was reinfused at 6 months, but again had short persistence.
The patient was reinfused again at 8 months because of B-cell recovery, and pembrolizumab was added on day 14 and administered every 3 weeks thereafter.
The patient is experiencing prolonged persistence and continued B-cell aplasia.
Patient 6 – Pembrolizumab for lymphomatous disease
This patient, who had widespread lymphadenopathy and M3 bone marrow, had not received prior CAR T cells and was treated for the first time with a murine CART19 for r/r ALL.
The patient had good expansion of CART19, but by day 28, PET scan showed widespread lymph node disease despite CR in the bone marrow.
The patient was given pembrolizumab on day 32 after infusion and every 2-3 weeks thereafter. After the addition of pembrolizumab, the patient had increased CART19 cells in blood and a significant decrease in PET-avid disease.
Summary
Three of six patients achieved objective clinical responses with pembrolizumab: 2 had prolonged B-cell aplasia, and another had a decrease in PET-avid lymphomatous disease.
The addition of pembrolizumab was also well tolerated by the patients, with minimal side effects of fever in 2 patients, cytopenias in 2 patients, and no instances of severe CRS.
The investigators believe the addition of checkpoint pathway inhibitors has the potential to prolong CAR T-cell persistence and warrants further investigation. 
CHICAGO—Three of 6 pediatric patients with relapsed or refractory acute lymphoblastic leukemia (ALL) whose CD19 chimeric antigen receptor (CAR) T cells did not persist even after reinfusion demonstrated persistence when the PD-1 checkpoint inhibitor pembrolizumab was added to the regimen.
CAR T cells can persist for months or even years and have the potential to mediate long-term disease control.
But some patients recover their normal B cells, which is a marker of loss of functional CAR T cells. These patients are at a higher risk of disease relapse.
Investigators, therefore, undertook a pilot study to determine whether PD-1 checkpoint pathway inhibition can improve CAR T persistence in these patients.
Shannon L. Maude, MD, of the Children’s Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, shared some of the patient cases in this pilot study at the ASCO 2017 Annual Meeting (Abstract 103*).
The investigators hypothesized that possible anti-murine immunogenicity could be causing poor CAR T-cell persistence, since the first CAR T developed used scFv domains of murine origin.
If T-cell exhaustion caused poor CAR T-cell persistence, immune checkpoints might play a role. In this case, combination with PD-1 checkpoint blockade could improve persistence, they hypothesized.
The investigators proposed to administer a repeat CAR T-cell infusion for relapsed or refractory ALL patients with poor persistence and add pembrolizumab after retreatment if the patients still had poor persistence. Patients were offered the option of another reinfusion prior to treatment with pembrolizumab if their CAR T-cell persistence continued to be poor.
Investigators added pembrolizumab no earlier than 14 days after infusion and only after patients recovered from cytokine release syndrome (CRS).
The infusions in the pilot study were humanized CART19 (huCART19, CTL119), unless otherwise specified.
Patient 1 – Pembrolizumab for partial response
This patient had no response to the prior murine CD19 CAR infusion, but responded well to infusion with huCART19 with good CAR T-cell proliferation.
By day 28, the patient had achieved a complete response (CR) in bone marrow but had a minimal residual disease (MRD) level of 1.2%.
At 7 weeks, the patient had a CD19+ relapse with low levels of huCART19.
Investigators added pembrolizumb on day 52 after infusion, and the patient had a modest increase in huCART19.
The patient had a temporary clearance of peripheral blasts followed by disease progression.
Patient 2 – Pembrolizumab for no response
This patient had a CD19+ relapse at 12 months after prior murine CD19 CAR infusion.
The patient was treated with huCART19, had good proliferation, but a rapid drop of CART19, and no response of the disease with a CD19+ relapse.
The patient had a reinfusion of huCART19 at 6 weeks and investigators added pembrolizumab on day 14 after reinfusion.
The patient experienced good huCART19 proliferation and prolonged persistence, but by day 28 had persistent disease, this time with decreased expression of CD19+ cells.
Patient 3 – Pembrolizumab for poor persistence
This patient had a CR with a prior murine CD19 CAR, but had poor persistence and early B cell recovery at 2 months.
The patient had a CD19+ relapse, was treated with huCART19, and had good proliferation again.
The patient achieved an MRD-negative CR, but because of short persistence and early B-cell recovery at 2 months, relapsed at 15 months.
The patient was reinfused at 17 months and pembrolizumab was added on day 14. The patient entered CR with prolonged persistence, but ultimately B-cell recovery occurred.
The patient was reinfused a third time, and pembrolizumab was added to the regimen every 3 weeks. The patient is experiencing prolonged persistence and continued B-cell aplasia.
Patient 4 – Pembrolizumab for poor persistence
This patient had achieved a CR with murine CAR19, but had a CD19+ relapse at 9 months. The patient then received huCART19, had good proliferation and achieved a CR, but had short persistence and B-cell recovery at 2 months.
The patient relapsed at 12 months and was reinfused with huCART19 at 14 months.
Pembrolizumab was added on day 14 after reinfusion, but the patient had no huCART19 proliferation, no response, and CD19+ MRD.
Patient 5 – Pembrolizumab for poor persistence
The patient responded to a prior murine CART19, but had a CD19+ relapse at 12 months.
The patient was infused with huCART19 and had good proliferation but short persistence. The patient was reinfused at 6 months, but again had short persistence.
The patient was reinfused again at 8 months because of B-cell recovery, and pembrolizumab was added on day 14 and administered every 3 weeks thereafter.
The patient is experiencing prolonged persistence and continued B-cell aplasia.
Patient 6 – Pembrolizumab for lymphomatous disease
This patient, who had widespread lymphadenopathy and M3 bone marrow, had not received prior CAR T cells and was treated for the first time with a murine CART19 for r/r ALL.
The patient had good expansion of CART19, but by day 28, PET scan showed widespread lymph node disease despite CR in the bone marrow.
The patient was given pembrolizumab on day 32 after infusion and every 2-3 weeks thereafter. After the addition of pembrolizumab, the patient had increased CART19 cells in blood and a significant decrease in PET-avid disease.
Summary
Three of six patients achieved objective clinical responses with pembrolizumab: 2 had prolonged B-cell aplasia, and another had a decrease in PET-avid lymphomatous disease.
The addition of pembrolizumab was also well tolerated by the patients, with minimal side effects of fever in 2 patients, cytopenias in 2 patients, and no instances of severe CRS.
The investigators believe the addition of checkpoint pathway inhibitors has the potential to prolong CAR T-cell persistence and warrants further investigation.
CHICAGO—Three of 6 pediatric patients with relapsed or refractory acute lymphoblastic leukemia (ALL) whose CD19 chimeric antigen receptor (CAR) T cells did not persist even after reinfusion demonstrated persistence when the PD-1 checkpoint inhibitor pembrolizumab was added to the regimen.
CAR T cells can persist for months or even years and have the potential to mediate long-term disease control.
But some patients recover their normal B cells, which is a marker of loss of functional CAR T cells. These patients are at a higher risk of disease relapse.
Investigators, therefore, undertook a pilot study to determine whether PD-1 checkpoint pathway inhibition can improve CAR T persistence in these patients.
Shannon L. Maude, MD, of the Children’s Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, shared some of the patient cases in this pilot study at the ASCO 2017 Annual Meeting (Abstract 103*).
The investigators hypothesized that possible anti-murine immunogenicity could be causing poor CAR T-cell persistence, since the first CAR T developed used scFv domains of murine origin.
If T-cell exhaustion caused poor CAR T-cell persistence, immune checkpoints might play a role. In this case, combination with PD-1 checkpoint blockade could improve persistence, they hypothesized.
The investigators proposed to administer a repeat CAR T-cell infusion for relapsed or refractory ALL patients with poor persistence and add pembrolizumab after retreatment if the patients still had poor persistence. Patients were offered the option of another reinfusion prior to treatment with pembrolizumab if their CAR T-cell persistence continued to be poor.
Investigators added pembrolizumab no earlier than 14 days after infusion and only after patients recovered from cytokine release syndrome (CRS).
The infusions in the pilot study were humanized CART19 (huCART19, CTL119), unless otherwise specified.
Patient 1 – Pembrolizumab for partial response
This patient had no response to the prior murine CD19 CAR infusion, but responded well to infusion with huCART19 with good CAR T-cell proliferation.
By day 28, the patient had achieved a complete response (CR) in bone marrow but had a minimal residual disease (MRD) level of 1.2%.
At 7 weeks, the patient had a CD19+ relapse with low levels of huCART19.
Investigators added pembrolizumb on day 52 after infusion, and the patient had a modest increase in huCART19.
The patient had a temporary clearance of peripheral blasts followed by disease progression.
Patient 2 – Pembrolizumab for no response
This patient had a CD19+ relapse at 12 months after prior murine CD19 CAR infusion.
The patient was treated with huCART19, had good proliferation, but a rapid drop of CART19, and no response of the disease with a CD19+ relapse.
The patient had a reinfusion of huCART19 at 6 weeks and investigators added pembrolizumab on day 14 after reinfusion.
The patient experienced good huCART19 proliferation and prolonged persistence, but by day 28 had persistent disease, this time with decreased expression of CD19+ cells.
Patient 3 – Pembrolizumab for poor persistence
This patient had a CR with a prior murine CD19 CAR, but had poor persistence and early B cell recovery at 2 months.
The patient had a CD19+ relapse, was treated with huCART19, and had good proliferation again.
The patient achieved an MRD-negative CR, but because of short persistence and early B-cell recovery at 2 months, relapsed at 15 months.
The patient was reinfused at 17 months and pembrolizumab was added on day 14. The patient entered CR with prolonged persistence, but ultimately B-cell recovery occurred.
The patient was reinfused a third time, and pembrolizumab was added to the regimen every 3 weeks. The patient is experiencing prolonged persistence and continued B-cell aplasia.
Patient 4 – Pembrolizumab for poor persistence
This patient had achieved a CR with murine CAR19, but had a CD19+ relapse at 9 months. The patient then received huCART19, had good proliferation and achieved a CR, but had short persistence and B-cell recovery at 2 months.
The patient relapsed at 12 months and was reinfused with huCART19 at 14 months.
Pembrolizumab was added on day 14 after reinfusion, but the patient had no huCART19 proliferation, no response, and CD19+ MRD.
Patient 5 – Pembrolizumab for poor persistence
The patient responded to a prior murine CART19, but had a CD19+ relapse at 12 months.
The patient was infused with huCART19 and had good proliferation but short persistence. The patient was reinfused at 6 months, but again had short persistence.
The patient was reinfused again at 8 months because of B-cell recovery, and pembrolizumab was added on day 14 and administered every 3 weeks thereafter.
The patient is experiencing prolonged persistence and continued B-cell aplasia.
Patient 6 – Pembrolizumab for lymphomatous disease
This patient, who had widespread lymphadenopathy and M3 bone marrow, had not received prior CAR T cells and was treated for the first time with a murine CART19 for r/r ALL.
The patient had good expansion of CART19, but by day 28, PET scan showed widespread lymph node disease despite CR in the bone marrow.
The patient was given pembrolizumab on day 32 after infusion and every 2-3 weeks thereafter. After the addition of pembrolizumab, the patient had increased CART19 cells in blood and a significant decrease in PET-avid disease.
Summary
Three of six patients achieved objective clinical responses with pembrolizumab: 2 had prolonged B-cell aplasia, and another had a decrease in PET-avid lymphomatous disease.
The addition of pembrolizumab was also well tolerated by the patients, with minimal side effects of fever in 2 patients, cytopenias in 2 patients, and no instances of severe CRS.
The investigators believe the addition of checkpoint pathway inhibitors has the potential to prolong CAR T-cell persistence and warrants further investigation.