Comparison of blinatumomab vs CD19 CAR T cells
| . | Bispecific antibody constructs . | CAR T cells . |
|---|---|---|
| FDA approval | Blinatumomab: pediatric and adult patients with r/r ALL, MRD+ (0.1%) ALL (first or second remission) | Axi-cel: adult with r/r (>2 prior Tx lines) DLBCL, PMBCL |
| Tisa-cel: r/r ALL <26 y of age, adults with r/r (>2 prior Tx lines) DLBCL | ||
| EMA approval | Blinatumomab: pediatric (>1 y of age) r/r ALL and adults with r/r Ph− ALL, adults with MRD+ (0.1%) Ph− ALL (first or second remission) | Axi-cel: adults with r/r (>2 prior Tx lines) DLBCL, PMBCL |
| Tisa-cel: r/r ALL <26 y of age; adults with r/r (>2 prior Tx lines) DLBCL | ||
| Design | Recombinant soluble protein | Retro- or lentiviral-transduced CAR T cells |
| Availability | Off the shelf | 17-54 d from patient presentation to CAR T transfusion (national vs international patient recruitment, different trial design)6,8 |
| Manufacturing failures | Not applicable | ≤10%38 |
| Manufacturing and dosing variability | Not applicable | CAR T-cell product variability due to differences in T-cell subset composition, CAR transduction efficacy, number of viable CAR T cells; number of transfused CAR T cells differs from 0.2 × 106 to 6 × 108,26 |
| Effector cell | Endogenous CD4 and CD8 T cells | Engineered, commonly using autologous CD4 and CD8 T cells |
| Effector cell function | Relies on endogenous T-cell composition and function at time of infusion | Relies on T-cell composition and function at time of leukapheresis; further modulation of CAR T function after transfusion through patient- and disease-related parameters (eg TME)26 |
| Lymphodepletion prior to start of therapy | No lymphodepletion required | Lymphodepletion with cyclophosphamide and fludarabine prior to CAR T-cell transfusion mandatory (tisa-cel: exceptions in case of WBCs <1×109/L within 1 wk prior to transfusion)39 |
| Safety: AE ≥III | CRS:4.9%, ICANS: 9%, hematotoxicity: neutropenia: 28%; lymphopenia: 1.5%; decrease in white-cell count: 5.2%; decrease in platelet count: 6.4% (lower rate of infections compared with SOC; short half-life (<2 h), interruption possible4 | CRS: 46%; ICANS: 12%-32%; hematotoxicity: ≤23%-45%; JULIET trial: cytopenia not resolved by day 28: 32%, CAR T cells persist for months/years6,7 |
| Neoplasia through genetic interference, genotoxic side effects | Not applicable | Rare40 |
| B-cell aplasia | Recovery after completion of infusion: 6-18 mo41 | Months to years depending on persistence of functional CAR T cells; hypogammaglobulinemia for months to years15 |
| ORR | 44% in r/r ALL, 78% in MRD+ ALL4,5 | 81% in r/r ALL, 54%-82% in r/r DLBCL6-8 |
| Financial toxicity | Product: US$72 000; average no. of cycles: 1-2; in-hospital days: r/r setting: 9 d within the first cycle (MRD setting: 3 d), 2 d second cycle; additional costs: pump equipment, possible IgG-replacement therapy for 6-12 mo | Products: > US$350 000; no. of treatment applications: 1; additional costs: logistics, leukapheresis, lymphodepleting chemotherapy, average 10-d in-hospital stay (outpatient to long-term stay, including ICU), possible IgG-replacement therapy for months to years37 |
| Target antigen | CD19 target antigen loss: 3%-21%42 | CD19 target antigen loss: 7%-35%23,26 |
| Multiple target antigens | High flexibility to combine different BiTE constructs given in parallel or sequentially, dual-specific BiTE constructs in clinical trials, individualized combinatorial approach of targeting BiTE construct and immunomodulatory construct feasible | Various dual-targeting CAR T-cell constructs in clinical trials; possibility to apply simultaneously vs sequentially |
| PD-L1 upregulation in target cells | PD-L1 upregulation commonly observed43 | PD-L1 upregulation commonly observed26 |
| T-cell exhaustion | Potentially, reversal through treatment-free intervals (induction: 4 wk on, 2 wk off; maintenance: 4 wk on, 8 wk off) | Preclinical work: drug-induced cessation of CAR receptor signaling to prevent or reverse exhaustion; genetically engineered CAR T cells to counteract exhaustion35,44 |
| . | Bispecific antibody constructs . | CAR T cells . |
|---|---|---|
| FDA approval | Blinatumomab: pediatric and adult patients with r/r ALL, MRD+ (0.1%) ALL (first or second remission) | Axi-cel: adult with r/r (>2 prior Tx lines) DLBCL, PMBCL |
| Tisa-cel: r/r ALL <26 y of age, adults with r/r (>2 prior Tx lines) DLBCL | ||
| EMA approval | Blinatumomab: pediatric (>1 y of age) r/r ALL and adults with r/r Ph− ALL, adults with MRD+ (0.1%) Ph− ALL (first or second remission) | Axi-cel: adults with r/r (>2 prior Tx lines) DLBCL, PMBCL |
| Tisa-cel: r/r ALL <26 y of age; adults with r/r (>2 prior Tx lines) DLBCL | ||
| Design | Recombinant soluble protein | Retro- or lentiviral-transduced CAR T cells |
| Availability | Off the shelf | 17-54 d from patient presentation to CAR T transfusion (national vs international patient recruitment, different trial design)6,8 |
| Manufacturing failures | Not applicable | ≤10%38 |
| Manufacturing and dosing variability | Not applicable | CAR T-cell product variability due to differences in T-cell subset composition, CAR transduction efficacy, number of viable CAR T cells; number of transfused CAR T cells differs from 0.2 × 106 to 6 × 108,26 |
| Effector cell | Endogenous CD4 and CD8 T cells | Engineered, commonly using autologous CD4 and CD8 T cells |
| Effector cell function | Relies on endogenous T-cell composition and function at time of infusion | Relies on T-cell composition and function at time of leukapheresis; further modulation of CAR T function after transfusion through patient- and disease-related parameters (eg TME)26 |
| Lymphodepletion prior to start of therapy | No lymphodepletion required | Lymphodepletion with cyclophosphamide and fludarabine prior to CAR T-cell transfusion mandatory (tisa-cel: exceptions in case of WBCs <1×109/L within 1 wk prior to transfusion)39 |
| Safety: AE ≥III | CRS:4.9%, ICANS: 9%, hematotoxicity: neutropenia: 28%; lymphopenia: 1.5%; decrease in white-cell count: 5.2%; decrease in platelet count: 6.4% (lower rate of infections compared with SOC; short half-life (<2 h), interruption possible4 | CRS: 46%; ICANS: 12%-32%; hematotoxicity: ≤23%-45%; JULIET trial: cytopenia not resolved by day 28: 32%, CAR T cells persist for months/years6,7 |
| Neoplasia through genetic interference, genotoxic side effects | Not applicable | Rare40 |
| B-cell aplasia | Recovery after completion of infusion: 6-18 mo41 | Months to years depending on persistence of functional CAR T cells; hypogammaglobulinemia for months to years15 |
| ORR | 44% in r/r ALL, 78% in MRD+ ALL4,5 | 81% in r/r ALL, 54%-82% in r/r DLBCL6-8 |
| Financial toxicity | Product: US$72 000; average no. of cycles: 1-2; in-hospital days: r/r setting: 9 d within the first cycle (MRD setting: 3 d), 2 d second cycle; additional costs: pump equipment, possible IgG-replacement therapy for 6-12 mo | Products: > US$350 000; no. of treatment applications: 1; additional costs: logistics, leukapheresis, lymphodepleting chemotherapy, average 10-d in-hospital stay (outpatient to long-term stay, including ICU), possible IgG-replacement therapy for months to years37 |
| Target antigen | CD19 target antigen loss: 3%-21%42 | CD19 target antigen loss: 7%-35%23,26 |
| Multiple target antigens | High flexibility to combine different BiTE constructs given in parallel or sequentially, dual-specific BiTE constructs in clinical trials, individualized combinatorial approach of targeting BiTE construct and immunomodulatory construct feasible | Various dual-targeting CAR T-cell constructs in clinical trials; possibility to apply simultaneously vs sequentially |
| PD-L1 upregulation in target cells | PD-L1 upregulation commonly observed43 | PD-L1 upregulation commonly observed26 |
| T-cell exhaustion | Potentially, reversal through treatment-free intervals (induction: 4 wk on, 2 wk off; maintenance: 4 wk on, 8 wk off) | Preclinical work: drug-induced cessation of CAR receptor signaling to prevent or reverse exhaustion; genetically engineered CAR T cells to counteract exhaustion35,44 |
AE, adverse event; ICU, intensive care unit; IgG, immunoglobulin G; Ph, Philadelphia chromosome; PMBCL, primary mediastinal B-cell lymphoma; SOC, standard of care; Tx, treatment; WBCs, white blood cells.