Table 1.
Completed trials of anti-CD19 CAR immunotherapy in B-cell hematological malignancies
| Summary of trial | Cell number infused | Results | Toxicities | Ref. |
|---|---|---|---|---|
| Treatment of 2 patients with refractory FL | 108/m2 (dose #1) | 1 patient showed no response, the other was non-evaluable; limited CAR persistence was noted as a barrier to efficacy | Lymphopenia observed in both patients | [134] |
| Lymphodepletion: Flu after dose #1 | 109/m2 (#2, #3) | |||
| Exogenous cytokines: IL-2 | 2×109/m2 (#4, #5) | |||
| Treatment of 6 patients with relapsed or refractory NHL: 1 with SLL, 3 with DLBCL, and 2 with FL/DLBCL | Pt 1, 2: 2×107/m2 | CD28 costimulation greatly enhanced expansion and persistence of CAR T-cells; 2 patients experienced SD | Not reported | [48] |
| Lymphodepletion: None | Pt 3, 4: 1×108/m2 | |||
| Exogenous cytokines: None | Pt 4, 5: 2×108/m2 | |||
| Treatment of 3 patients with relapsed CLL | Pt 1: 1.6×107/kg | 2 patients obtained CRs, 1 obtained PR | Tumor lysis syndrome, lymphopenia, thrombocytopenia, and neutropenia were observed | [92,93] |
| Lymphodepletion: Pt 1: Benda; Pt 2: Benda/Ritux; Pt 3: Pento/Cy | Pt 2: 1.0×107/kg | |||
| Exogenous cytokines: None | Pt 3: 1.5×105/kg | |||
| Treatment of 8 patients with relapsed CLL and 2 patients with relapsed ALL | 1.8×108-3.2×109 | 3 of the 4 evaluable CLL patients who received Cy obtained obtained PRs or SD; the 3 CLL patients who did not receive Cy had no response | Most patients experienced fevers, B-cell aplasia observed in ALL patient | [89] |
| Lymphodepletion: Six of the patients received Cy | ||||
| Exogenous cytokines: None | ||||
| Treatment of 3 patients with relapsed FL, 1 patient with relapsed SMZL, and 4 patients with relapsed CLL | 0.3×107/kg-3.0×107/kg | 5 of the 7 evaluable patients obtained PRs, one obtained CR | Cytokine-associated toxicities including hypotension, fevers, fatigue, renal failure, and obtundation | [90,91] |
| Lymphodepletion: Flu/Cy | ||||
| Exogenous cytokines: IL-2 | ||||
| Treatment of 8 patients with relapsed ALL or CLL who had received prior HSCT | 1.9×107-1.1×108 | 3 patients obtained CRs, 1 obtained PR, 1 experienced SD | No infusion-related toxicities | [135] |
| Lymphodepletion: None | ||||
| Exogenous cytokines: None | ||||
| Treatment of 10 patients with relapsed CLL, DLBCL, and MCL who had received prior HSCT and DLI | 0.4×106/kg-7.8×106/kg | 1 patient obtained CR, 1 obtained PR, 6 experienced SD | Toxicities included transient hypotension and fever | [136] |
| Lymphodepletion: None | ||||
| Exogenous cytokines: None | ||||
| Treatment of 2 children with relapsed and refractory ALL | Pt 1: 1.4×106/kg | Both patients obtained CRs | Cytokine release syndrome and B-cell aplasia were observed in both patients | [95] |
| Lymphodepletion: Pt 1: None; Pt 2: Cy/VP16 | Pt 2: 1.2×107/kg | |||
| Exogenous cytokines: None | ||||
| Treatment of 16 patients with relapsed of refractory ALL | 3.0×106/kg | 88% of patients obtained CRs | 7 patients experienced severe cytokine release syndrome, some patients experienced neurologic toxic effects | [54] |
| Lymphodepletion: Cy | ||||
| Exogenous cytokines: None | ||||
| Treatment of 30 patients with relapsed or refractory ALL | 0.8×106/kg-1.7×107/kg | 90% of patients obtained CRs | 8 patients experienced sever cytokine release syndrome, some patients experienced neurologic toxic effects | [53] |
| Lymphodepletion: 15 patients received Flu/Cy, 12 received a different lymphodepletion regimen | ||||
| Exogenous cytokines: None | ||||
| Treatment of 14 patients with relapsed or refractory B-cell malignancies | Not reported | Cells cultured with IL-7 and IL-15 prior to infusion showed greater persistence and efficacy in vivo than those cultured in IL-2 | None reported | [137] |
| Lymphodepletion: None | ||||
| Exogenous cytokines: None | ||||
| Treatment of 21 patients with relapsed of refractory ALL or NHL | Most patients received 1×106/kg (maximum tolerated dose), four received a second dose at 3×106/kg | 67% of patients obtained CRs | 3 patients experienced sever cytokine release syndrome | [138] |
| Lymphodepletion: Flu/Cy | ||||
| Exogenous cytokines: None | ||||
| Treatment of 15 patients with relapsed of refractory B-cell malignancies: 9 with DLBCL, 2 with indolent lymphomas, and 4 with CLL | 1×106/kg-5×106/kg | 8 of the 13 evaluable patients obtained CRs, 4 obtained PRs, 1 experienced SD | Toxicities in some patients including fever, hypotension, delirium, and other neurologic toxicities; 1 patient died suddenly due to an unknown cause 16 days after cell infusion | [94] |
| Lymphodepletion: Flu/Cy | ||||
| Exogenous cytokines: None | ||||
| Treatment of a patient with refractory multiple myeloma as an addition to high-dose melphalan and HSCT | 5×107 | Durable CR was obtained; enhanced response attributed to anti-CD19 CAR T-cell activity | Hypogammaglobulinemia was observed | [139] |
| Lymphodepletion: Cy | ||||
| Exogenous cytokines: None | ||||
| Treatment of 29 patients with relapsed or refractory NHL: 19 with DLBCL, 8 with FL, and 2 with MCL | 5×108 | Of the 18 evaluable patients, overall response rate was 50% for DLBLC patients and 100% for FL patients | 15 patients experienced cytokine release syndrome, 3 patients experienced neurologic toxic effects | [140] |
| Lymphodepletion: Cy, Benda, EPOCH, radiation/Cy, or Flu/Cy | ||||
| Exogenous cytokines: None | ||||
| Treatment of 7 patients with relapsed or refractory NHL after HDT-ASCT | 7 patients received 5×106/kg, 1 received 1×107/kg | 5 patients obtained CRs | One patient experienced prolonged cytopenias and died of mucormycosis pneumonia 38 days after HDT-ASCT; 4 patients experienced cytokine release syndrome | [141] |
| Lymphodepletion: BEAM | ||||
| Exogenous cytokines: None |
ALL: acute lymphocytic leukemia; ASCT: autologous hematopoietic stem cell transplantation; BEAM: carmustine, etoposide, cytarabine, and melphalan; Benda: bendamustine; Ritux: rituximab; CLL: chronic lymphocytic leukemia; CR: complete response; Cy: Cyclophosphamide; DLBC: diffuse large B-cell lymphoma; DLI: donor lymphocyte infusion; EPOCH: etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin; FL: follicular lymphoma; Flu: fludarabine; HDT: high-dose therapy; MCL: mantle cell lymphoma; NHL: non-Hodgkin’s lymphoma; Pento: pentostatin; PR: partial response; SD: stable disease; SLL: small lymphocytic lymphoma; SMZL, splenic marginal zone lymphoma; VP-16: etoposide.