CD19-targeted CAR T-cell therapy

In pilot clinical trials conducted at the Children’s Hospital of Philadelphia (CHOP) and the Hospital of the University of Pennsylvania, 30 children and adults (25 of whom were aged 22 years or younger) with multiply relapsed or refractory CD19-positive ALL were given T cells transduced with CD19-directed 4-1BB CAR lentiviral vector.[171][Level of evidence C2]

In pilot clinical trials conducted at the Children’s Hospital of Philadelphia (CHOP) and the Hospital of the University of Pennsylvania, 30 children and adults (25 of whom were aged 22 years or younger) with multiply relapsed or refractory CD19-positive ALL were given T cells transduced with CD19-directed 4-1BB CAR lentiviral vector.[171][Level of evidence C2]

CR was obtained in 90% of patients, including 15 of 18 patients (83%) who had previously received allogeneic HSCT.

In pilot clinical trials conducted at the Children’s Hospital of Philadelphia (CHOP) and the Hospital of the University of Pennsylvania, 30 children and adults (25 of whom were aged 22 years or younger) with multiply relapsed or refractory CD19-positive ALL were given T cells transduced with CD19-directed 4-1BB CAR lentiviral vector.[171][Level of evidence C2]

The 6-month EFS rate was 67%, with most patients showing persistence of the CAR T cells and B-cell aplasia through 6 months.

In pilot clinical trials conducted at the Children’s Hospital of Philadelphia (CHOP) and the Hospital of the University of Pennsylvania, 30 children and adults (25 of whom were aged 22 years or younger) with multiply relapsed or refractory CD19-positive ALL were given T cells transduced with CD19-directed 4-1BB CAR lentiviral vector.[171][Level of evidence C2]

All 30 patients experienced some degree of cytokine release syndrome. Eight patients (27%) had severe symptoms requiring vasopressors and/or respiratory support. Cytokine release syndrome was effectively treated with tocilizumab.

A report of a phase I trial of 45 children and young adults with relapsed/refractory CD19-positive B-ALL who received 4-1BB–based lentiviral vector expanded CAR T cells showed the following:[175]

A report of a phase I trial of 45 children and young adults with relapsed/refractory CD19-positive B-ALL who received 4-1BB–based lentiviral vector expanded CAR T cells showed the following:[175]

An overall remission rate of 89% for all patients enrolled using an intent-to-treat analysis.

A report of a phase I trial of 45 children and young adults with relapsed/refractory CD19-positive B-ALL who received 4-1BB–based lentiviral vector expanded CAR T cells showed the following:[175]

Improved long-term persistence of CAR T cells and B-cell aplasia in patients who: (1) received lymphodepleting strategies that contain fludarabine and cyclophosphamide, and (2) started the treatment with a higher percentage of cells expressing CD19, either on blasts or normal B cells.

A global phase II trial of the anti-CD19 4-1BB vector developed at the CHOP and the University of Pennsylvania led to U.S. Food and Drug Administration approval of tisagenlecleucel for children with multiply relapsed or refractory B-ALL.[148]

A global phase II trial of the anti-CD19 4-1BB vector developed at the CHOP and the University of Pennsylvania led to U.S. Food and Drug Administration approval of tisagenlecleucel for children with multiply relapsed or refractory B-ALL.[148]

Of 92 patients enrolled, 75 were infused with successfully manufactured CAR T cells. Eighty-one percent of infused patients had two measures noting CR within the first 3 months of infusion, and 100% of the remissions were MRD negative.

A global phase II trial of the anti-CD19 4-1BB vector developed at the CHOP and the University of Pennsylvania led to U.S. Food and Drug Administration approval of tisagenlecleucel for children with multiply relapsed or refractory B-ALL.[148]

The EFS rate of infused patients was 73% at 6 months and 50% at 12 months. The OS rate of infused patients was 90% at 6 months and 70% at 12 months.

A global phase II trial of the anti-CD19 4-1BB vector developed at the CHOP and the University of Pennsylvania led to U.S. Food and Drug Administration approval of tisagenlecleucel for children with multiply relapsed or refractory B-ALL.[148]

The CIBMTR performed a real-world analysis of 255 patients with ALL that largely duplicated the outcomes shown in the pivotal trials, with an initial CR rate of 85.5%. The 12-month duration of response rate was 69.9%, the EFS rate was 52.4%, and the OS rate was 77.2%.[180]

Children younger than 3 years were not included in the approval trial for tisagenlecleucel. A subgroup of patients, infants diagnosed at younger than 1 year with KMT2A-rearranged leukemia, often have disease that is highly refractory to intensive chemotherapy approaches. A multicenter retrospective study reported the outcomes of children younger than 3 years (originally diagnosed as high-risk infant ALL) with relapsed or refractory B-ALL who received commercial tisagenlecleucel.[181]

Children younger than 3 years were not included in the approval trial for tisagenlecleucel. A subgroup of patients, infants diagnosed at younger than 1 year with KMT2A-rearranged leukemia, often have disease that is highly refractory to intensive chemotherapy approaches. A multicenter retrospective study reported the outcomes of children younger than 3 years (originally diagnosed as high-risk infant ALL) with relapsed or refractory B-ALL who received commercial tisagenlecleucel.[181]

Thirty-eight eligible patients were screened, 35 of whom (92%) were infused with tisagenlecleucel (2 patients did not receive an infusion because CAR T-cell manufacturing failed and 1 patient had disease progression).

Children younger than 3 years were not included in the approval trial for tisagenlecleucel. A subgroup of patients, infants diagnosed at younger than 1 year with KMT2A-rearranged leukemia, often have disease that is highly refractory to intensive chemotherapy approaches. A multicenter retrospective study reported the outcomes of children younger than 3 years (originally diagnosed as high-risk infant ALL) with relapsed or refractory B-ALL who received commercial tisagenlecleucel.[181]

Twenty-nine of 38 patients (76%) had KMT2A rearrangements, and 25 (66%) experienced relapse after previous HSCTs.

Children younger than 3 years were not included in the approval trial for tisagenlecleucel. A subgroup of patients, infants diagnosed at younger than 1 year with KMT2A-rearranged leukemia, often have disease that is highly refractory to intensive chemotherapy approaches. A multicenter retrospective study reported the outcomes of children younger than 3 years (originally diagnosed as high-risk infant ALL) with relapsed or refractory B-ALL who received commercial tisagenlecleucel.[181]

With a median follow-up of 14 months, the 12-month OS rate was 84%, the EFS rate was 69%, and the stringent EFS rate was 41%.

Children younger than 3 years were not included in the approval trial for tisagenlecleucel. A subgroup of patients, infants diagnosed at younger than 1 year with KMT2A-rearranged leukemia, often have disease that is highly refractory to intensive chemotherapy approaches. A multicenter retrospective study reported the outcomes of children younger than 3 years (originally diagnosed as high-risk infant ALL) with relapsed or refractory B-ALL who received commercial tisagenlecleucel.[181]

Feasibility, outcomes, and toxicity were comparable with those of older children.

A subsequent study from the University of Pennsylvania reported the 3-year updated results of the global phase II ELIANA (NCT02435849) trial that included 79 patients who were treated with tisagenlecleucel.[182][Level of evidence C2]

A subsequent study from the University of Pennsylvania reported the 3-year updated results of the global phase II ELIANA (NCT02435849) trial that included 79 patients who were treated with tisagenlecleucel.[182][Level of evidence C2]

The overall remission rate was 82% at 3 months.

A subsequent study from the University of Pennsylvania reported the 3-year updated results of the global phase II ELIANA (NCT02435849) trial that included 79 patients who were treated with tisagenlecleucel.[182][Level of evidence C2]

With a median follow-up of 38.8 months, the median duration of remission of the 66 patients with a complete response has not been reached. The estimated relapse-free survival (RFS) rate was 58% at 24 months and 52% at 36 months.

A subsequent study from the University of Pennsylvania reported the 3-year updated results of the global phase II ELIANA (NCT02435849) trial that included 79 patients who were treated with tisagenlecleucel.[182][Level of evidence C2]

Of the 32 patients in CR who received no additional therapy, the estimated RFS rate was 81% at 24 months and 76% at 36 months.

A report from the Pediatric Oncology Branch at the NCI described the use of a different CD19-targeted CAR T-cell product with a CD28 costimulatory domain that used a retroviral vector for gene transduction.[178]

A report from the Pediatric Oncology Branch at the NCI described the use of a different CD19-targeted CAR T-cell product with a CD28 costimulatory domain that used a retroviral vector for gene transduction.[178]

This CD19-CAR T-cell product induced complete responses in 70% of patients (14 of 20) (aged 1–30 years) with relapsed/refractory B-ALL.

A report from the Pediatric Oncology Branch at the NCI described the use of a different CD19-targeted CAR T-cell product with a CD28 costimulatory domain that used a retroviral vector for gene transduction.[178]

Persistence of CAR T cells in this study was 1 to 2 months, with recovery of normal B-cell lymphopoiesis in patients who achieved CR.

A report from the Pediatric Oncology Branch at the NCI described the use of a different CD19-targeted CAR T-cell product with a CD28 costimulatory domain that used a retroviral vector for gene transduction.[178]

In a subsequent follow-up study of 50 children and young adults who were treated with CD19-CAR T cells, 21 patients achieved an MRD-negative CR and received an allogeneic HSCT. In these 21 patients, the median OS was 70.2 months, and the 5-year EFS rate was 61.9%.[183][Level of evidence C2]

Another report described a multicenter trial of 25 children and young adults who were treated with anti-CD19, anti-CD28z CAR T cells. Investigators increased the dose of lymphodepleting cyclophosphamide during the trial and analyzed outcomes on the basis of low-dose and high-dose preconditioning, as well as the presence of MRD versus morphological evidence of disease before treatment.[184][Level of evidence A1]

Another report described a multicenter trial of 25 children and young adults who were treated with anti-CD19, anti-CD28z CAR T cells. Investigators increased the dose of lymphodepleting cyclophosphamide during the trial and analyzed outcomes on the basis of low-dose and high-dose preconditioning, as well as the presence of MRD versus morphological evidence of disease before treatment.[184][Level of evidence A1]

All toxicities were reversible, including 16% of patients with severe cytokine release syndrome and 28% of patients with severe neurotoxicity.

Another report described a multicenter trial of 25 children and young adults who were treated with anti-CD19, anti-CD28z CAR T cells. Investigators increased the dose of lymphodepleting cyclophosphamide during the trial and analyzed outcomes on the basis of low-dose and high-dose preconditioning, as well as the presence of MRD versus morphological evidence of disease before treatment.[184][Level of evidence A1]

The overall complete response rate was 75%, and 89% of patients in CR were MRD negative.

Another report described a multicenter trial of 25 children and young adults who were treated with anti-CD19, anti-CD28z CAR T cells. Investigators increased the dose of lymphodepleting cyclophosphamide during the trial and analyzed outcomes on the basis of low-dose and high-dose preconditioning, as well as the presence of MRD versus morphological evidence of disease before treatment.[184][Level of evidence A1]

The response rate was superior in the high-dose cyclophosphamide cohort than in the low-dose cohort (94% vs. 38%); the response rate was higher in the MRD cohort than in the morphological disease cohort (93% vs. 50%).

Another report described a multicenter trial of 25 children and young adults who were treated with anti-CD19, anti-CD28z CAR T cells. Investigators increased the dose of lymphodepleting cyclophosphamide during the trial and analyzed outcomes on the basis of low-dose and high-dose preconditioning, as well as the presence of MRD versus morphological evidence of disease before treatment.[184][Level of evidence A1]

Of 18 responding patients, 15 underwent consolidative HSCT.

Another report described a multicenter trial of 25 children and young adults who were treated with anti-CD19, anti-CD28z CAR T cells. Investigators increased the dose of lymphodepleting cyclophosphamide during the trial and analyzed outcomes on the basis of low-dose and high-dose preconditioning, as well as the presence of MRD versus morphological evidence of disease before treatment.[184][Level of evidence A1]

Improvement in OS only occurred in patients who received the higher dose of cyclophosphamide conditioning.

In an effort to overcome early loss of functional CD19-targeted CAR T cells, a humanized 4-1BB approach was tested in children and young adults with relapsed or refractory B-ALL or B-lymphoblastic lymphoma. Patients were treated in two cohorts: (1) patients without previous CAR T-cell exposure (CAR-naïve group) and (2) patients with previous CAR exposure who did not respond to more standard CARs, based on mouse-derived antibodies (re-treated group).[185]

In an effort to overcome early loss of functional CD19-targeted CAR T cells, a humanized 4-1BB approach was tested in children and young adults with relapsed or refractory B-ALL or B-lymphoblastic lymphoma. Patients were treated in two cohorts: (1) patients without previous CAR T-cell exposure (CAR-naïve group) and (2) patients with previous CAR exposure who did not respond to more standard CARs, based on mouse-derived antibodies (re-treated group).[185]

CR was achieved in 98% of CAR-naïve patients and 64% of re-treated patients.

In an effort to overcome early loss of functional CD19-targeted CAR T cells, a humanized 4-1BB approach was tested in children and young adults with relapsed or refractory B-ALL or B-lymphoblastic lymphoma. Patients were treated in two cohorts: (1) patients without previous CAR T-cell exposure (CAR-naïve group) and (2) patients with previous CAR exposure who did not respond to more standard CARs, based on mouse-derived antibodies (re-treated group).[185]

At 6 months, of those who responded, 27% of CAR-naïve patients and 48% of re-treated patients lost CAR persistence.

In an effort to overcome early loss of functional CD19-targeted CAR T cells, a humanized 4-1BB approach was tested in children and young adults with relapsed or refractory B-ALL or B-lymphoblastic lymphoma. Patients were treated in two cohorts: (1) patients without previous CAR T-cell exposure (CAR-naïve group) and (2) patients with previous CAR exposure who did not respond to more standard CARs, based on mouse-derived antibodies (re-treated group).[185]

For CAR-naive patients, the RFS rate was 84% (95% CI, 72%–97%) at 12 months and 74% (95% CI, 60%–90%) at 24 months.

In an effort to overcome early loss of functional CD19-targeted CAR T cells, a humanized 4-1BB approach was tested in children and young adults with relapsed or refractory B-ALL or B-lymphoblastic lymphoma. Patients were treated in two cohorts: (1) patients without previous CAR T-cell exposure (CAR-naïve group) and (2) patients with previous CAR exposure who did not respond to more standard CARs, based on mouse-derived antibodies (re-treated group).[185]

For the re-treatment cohort, the RFS rate was 74% (95% CI, 56%–97%) at 12 months and 58% (95% CI, 37%–90%) at 24 months.

In an effort to overcome early loss of functional CD19-targeted CAR T cells, a humanized 4-1BB approach was tested in children and young adults with relapsed or refractory B-ALL or B-lymphoblastic lymphoma. Patients were treated in two cohorts: (1) patients without previous CAR T-cell exposure (CAR-naïve group) and (2) patients with previous CAR exposure who did not respond to more standard CARs, based on mouse-derived antibodies (re-treated group).[185]

While these results appear favorable, they were not directly compared to currently approved CAR T cells.