CAR T-cell trials in hematologic malignancies
| Reference . | Vector . | scFv . | Hinge/transmembrane domain . | Signaling domain . | Other genes . | Culture . | Dose . | Lymphodepletion . | Cytokine support . | Number of patients . | Responses . | Persistence (peak and duration) . |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 81 | Electroporation | CD20 | IgG-CD4 | CD3ζ | SV40-neomycin | OKT3 + IL-2; 2-4 mo | 1 × 108/m2 to 3.3 × 109/m2 (3 infusions 2-5 d apart) | Cyclophosphamide or fludarabine | SC IL-2 in last 4 patients | 7 (indolent and MCL) | 2 maintained CR, 1 PR, 4 SD; all in NHL | 1-3 wk alone, 5-9 wk with IL-2; only detected by PCR |
| 20 | Electroporation | CD20 or CD19 | IgG-CD4 | CD3ζ | Neomycin (CD20) or hygromycin/HSV-tk (CD19) | OKT3 + IL-2 + irradiated LCL feeders; 3 mo | 108/m2 to 2 × 109/m2 (3 infusions) | Day 28 after ASCT for CD20, fludarabine for CD19 | IL-2 | 4 (2 FL, 2 DLBCL) | 2 maintained CR after ASCT | Detectable cells by PCR only at 1 wk after 3 of the 7 infusions |
| 21 | Gammaretrovirus | CD19 | IgG-CD28 | CD3ζ and CD28-CD3ζ | None | OKT3 + IL-2; 6-18 d | 2 × 107/m2 to 2 × 109/m2 | None | None | 6 (NHL) | 2 with SD; both NHL | CD28-CD3ζ persisted longer than 6 mo, only detectable by PCR (peak 1286 copies/μg at 2 wk in CD28-CD3ζ) |
| 30 | Gammaretrovirus | CD19 | CD28 | CD28 and CD3ζ | None | CD3/28 beads; 16 d | 0.4-3 × 107 CAR+ cells/kg (split over 2 d) | None or 1.5 g/m2 cyclophosphamide | None | 8 with CLL, 1 with ALL | 1 death, 1 reduction in LAD, 1 B-cell aplasia (ALL) | 2 CLL patients had detectable CAR at 1-3 wk, only 1 CLL and 1 ALL with persistence at 6-8 wk by IHC; 0.02-1 vector copies/100 cells by PCR of marrow at 2-3 wk |
| 33, 34 | Lentivirus | CD19 | CD8-CD8 | 4-1BB and CD3ζ | None | CD3/28 beads; 10 d | 1.46 × 105 to 1.6 × 107 CAR+ cells/kg | Bendamustine or pentostatin/ cyclophosphamide | None | 3 (CLL) | 2 CR, 1 PR; 3 B-cell aplasia | In vivo expansion of cells detectable by flow cytometry and PCR (peak >100 000 copies/μg of DNA in PBMCs at day 20, declined to 10-1000 copies/μg and persisted for 6 mo); >20% of the T cells CAR+ by flow |
| 27, 28 | Gammaretrovirus | CD19 | CD28 | CD28 and CD3ζ | none | OKT3 + IL-2; 24 d | 0.3-3 × 107 CAR+ cells/kg | 60 mg/kg cyclophosphamide ×2, fludarabine 25 mg/m2 × 5 | IV IL-2 every 8 h as tolerated | 8 (3 FL, 4 CLL, 1 MZL) | 6 objective remission (4 B cell aplasia) | Detectable by flow cytometry and PCR (peak at day 13, 19% CAR+ T cells, lasted 3-6 mo) |
| 19 | Electroporation | CD20 | IgG1-CD4 | CD28 and 4-1BB and CD3ζ | SV40-neomycinR | OKT3 + IL-2; > 69 d | 1 × 108 - 3.3 × 109/m2 (3 infusions) | 1 g/m2 cyclophosphamide at day −2 | SC IL-2 × 14 d | 4 enrolled, 3 treated (2 MCL, 1 FL) | No progression in 2 patients, 1 patient with delayed PR (no B-cell aplasia) | Peak at 1 −3% by PCR only, lasted 9-12 mo |
| 32 | Gammaretrovirus | CD19 | CD28 | CD28 and CD3ζ | none | CD3/28 beads; 14 d | 1.5-3 × 106 CAR+ cells/kg | 1.5-3 g/m2 cyclophosphamide at day −1 | None | 14 enrolled, 5 treated (ALL) | 5 converted to MRD−, including 2 with frank disease; 4 went to allo, 1 relapsed; transient B-cell aplasia | Detectable by flow cytometry (peak at 40% CAR+ T cells, lasted 3-8 wk) and PCR |
| 37 | Lentivirus | CD19 | CD8-CD8 | 4-1BB and CD3ζ | none | CD3/28 beads; 10 d | 1.4 × 106 and 1.2 × 107 CAR+ cells/kg | 1 with cyclophosphamide/etoposide; 1 with none | None | 2 (ALL; one post-allo and post-blinatumomab) | 2 CR; 1 durable > 18 mo, 1 with CD19-negative relapse; both with B-cell aplasia | In vivo expansion of cells detectable by flow cytometry (>70% CAR+ T cells) and PCR (peak >10 000 copies/ug of DNA in PBMCs at day ∼10) |
| 41 | Gammaretrovirus | Lewis-Y | CD8-CD28 | CD28 and CD3ζ | None | OKT3 + IL-2; 12 d | 1.4-9.2 × 106 CAR+ cells/kg | At bone marrow recovery from cyclophosphamide + fludarabine | None | 5 enrolled, 4 treated (AML) | 2 SD, 1 transient reduction in blasts, 1 transient cytogenetic remission | Up to 10 mo by qPCR, 1 patient with in vivo expansion (1100 copies/1000 cells at day 21) |
| 23 | Gammaretrovirus | CD19 | IgG-CD28 | CD28 and CD3ζ | None | Ad.pp65, EBV-LCLs, IL-2; 5-6 wk | 1.5 × 107 - 1.2 × 108 total T cells/m2 (allogeneic donor derived) | None | None | 8 patients post-allo | 4 of 8 patients with decreased B-cell counts; 2/6 with objective response; no GVHD | Detectable for median 8 wk in blood by PCR only (4.2-53 copies/μg DNA) |
| 29 | Gammaretrovirus | CD19 | CD28 | CD28 and CD3ζ | None | OKT3 + IL-2; 8 d | 0.4-7.8 × 106 CAR+ cells/kg (allogeneic donor derived) | None | None | 10 patients post-allo, post-DLI (4 CLL, 2 DLBCL, 4 MCL) | 2 PD, 6 SD, 1 PR, 1 CR; no GVHD; transient B-cell aplasia in 3 patients | Detectable by flow cytometry (2%-7% at day 12) and PCR (peak at 40 CAR+ cells/μL) for <1 mo |
| Reference . | Vector . | scFv . | Hinge/transmembrane domain . | Signaling domain . | Other genes . | Culture . | Dose . | Lymphodepletion . | Cytokine support . | Number of patients . | Responses . | Persistence (peak and duration) . |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 81 | Electroporation | CD20 | IgG-CD4 | CD3ζ | SV40-neomycin | OKT3 + IL-2; 2-4 mo | 1 × 108/m2 to 3.3 × 109/m2 (3 infusions 2-5 d apart) | Cyclophosphamide or fludarabine | SC IL-2 in last 4 patients | 7 (indolent and MCL) | 2 maintained CR, 1 PR, 4 SD; all in NHL | 1-3 wk alone, 5-9 wk with IL-2; only detected by PCR |
| 20 | Electroporation | CD20 or CD19 | IgG-CD4 | CD3ζ | Neomycin (CD20) or hygromycin/HSV-tk (CD19) | OKT3 + IL-2 + irradiated LCL feeders; 3 mo | 108/m2 to 2 × 109/m2 (3 infusions) | Day 28 after ASCT for CD20, fludarabine for CD19 | IL-2 | 4 (2 FL, 2 DLBCL) | 2 maintained CR after ASCT | Detectable cells by PCR only at 1 wk after 3 of the 7 infusions |
| 21 | Gammaretrovirus | CD19 | IgG-CD28 | CD3ζ and CD28-CD3ζ | None | OKT3 + IL-2; 6-18 d | 2 × 107/m2 to 2 × 109/m2 | None | None | 6 (NHL) | 2 with SD; both NHL | CD28-CD3ζ persisted longer than 6 mo, only detectable by PCR (peak 1286 copies/μg at 2 wk in CD28-CD3ζ) |
| 30 | Gammaretrovirus | CD19 | CD28 | CD28 and CD3ζ | None | CD3/28 beads; 16 d | 0.4-3 × 107 CAR+ cells/kg (split over 2 d) | None or 1.5 g/m2 cyclophosphamide | None | 8 with CLL, 1 with ALL | 1 death, 1 reduction in LAD, 1 B-cell aplasia (ALL) | 2 CLL patients had detectable CAR at 1-3 wk, only 1 CLL and 1 ALL with persistence at 6-8 wk by IHC; 0.02-1 vector copies/100 cells by PCR of marrow at 2-3 wk |
| 33, 34 | Lentivirus | CD19 | CD8-CD8 | 4-1BB and CD3ζ | None | CD3/28 beads; 10 d | 1.46 × 105 to 1.6 × 107 CAR+ cells/kg | Bendamustine or pentostatin/ cyclophosphamide | None | 3 (CLL) | 2 CR, 1 PR; 3 B-cell aplasia | In vivo expansion of cells detectable by flow cytometry and PCR (peak >100 000 copies/μg of DNA in PBMCs at day 20, declined to 10-1000 copies/μg and persisted for 6 mo); >20% of the T cells CAR+ by flow |
| 27, 28 | Gammaretrovirus | CD19 | CD28 | CD28 and CD3ζ | none | OKT3 + IL-2; 24 d | 0.3-3 × 107 CAR+ cells/kg | 60 mg/kg cyclophosphamide ×2, fludarabine 25 mg/m2 × 5 | IV IL-2 every 8 h as tolerated | 8 (3 FL, 4 CLL, 1 MZL) | 6 objective remission (4 B cell aplasia) | Detectable by flow cytometry and PCR (peak at day 13, 19% CAR+ T cells, lasted 3-6 mo) |
| 19 | Electroporation | CD20 | IgG1-CD4 | CD28 and 4-1BB and CD3ζ | SV40-neomycinR | OKT3 + IL-2; > 69 d | 1 × 108 - 3.3 × 109/m2 (3 infusions) | 1 g/m2 cyclophosphamide at day −2 | SC IL-2 × 14 d | 4 enrolled, 3 treated (2 MCL, 1 FL) | No progression in 2 patients, 1 patient with delayed PR (no B-cell aplasia) | Peak at 1 −3% by PCR only, lasted 9-12 mo |
| 32 | Gammaretrovirus | CD19 | CD28 | CD28 and CD3ζ | none | CD3/28 beads; 14 d | 1.5-3 × 106 CAR+ cells/kg | 1.5-3 g/m2 cyclophosphamide at day −1 | None | 14 enrolled, 5 treated (ALL) | 5 converted to MRD−, including 2 with frank disease; 4 went to allo, 1 relapsed; transient B-cell aplasia | Detectable by flow cytometry (peak at 40% CAR+ T cells, lasted 3-8 wk) and PCR |
| 37 | Lentivirus | CD19 | CD8-CD8 | 4-1BB and CD3ζ | none | CD3/28 beads; 10 d | 1.4 × 106 and 1.2 × 107 CAR+ cells/kg | 1 with cyclophosphamide/etoposide; 1 with none | None | 2 (ALL; one post-allo and post-blinatumomab) | 2 CR; 1 durable > 18 mo, 1 with CD19-negative relapse; both with B-cell aplasia | In vivo expansion of cells detectable by flow cytometry (>70% CAR+ T cells) and PCR (peak >10 000 copies/ug of DNA in PBMCs at day ∼10) |
| 41 | Gammaretrovirus | Lewis-Y | CD8-CD28 | CD28 and CD3ζ | None | OKT3 + IL-2; 12 d | 1.4-9.2 × 106 CAR+ cells/kg | At bone marrow recovery from cyclophosphamide + fludarabine | None | 5 enrolled, 4 treated (AML) | 2 SD, 1 transient reduction in blasts, 1 transient cytogenetic remission | Up to 10 mo by qPCR, 1 patient with in vivo expansion (1100 copies/1000 cells at day 21) |
| 23 | Gammaretrovirus | CD19 | IgG-CD28 | CD28 and CD3ζ | None | Ad.pp65, EBV-LCLs, IL-2; 5-6 wk | 1.5 × 107 - 1.2 × 108 total T cells/m2 (allogeneic donor derived) | None | None | 8 patients post-allo | 4 of 8 patients with decreased B-cell counts; 2/6 with objective response; no GVHD | Detectable for median 8 wk in blood by PCR only (4.2-53 copies/μg DNA) |
| 29 | Gammaretrovirus | CD19 | CD28 | CD28 and CD3ζ | None | OKT3 + IL-2; 8 d | 0.4-7.8 × 106 CAR+ cells/kg (allogeneic donor derived) | None | None | 10 patients post-allo, post-DLI (4 CLL, 2 DLBCL, 4 MCL) | 2 PD, 6 SD, 1 PR, 1 CR; no GVHD; transient B-cell aplasia in 3 patients | Detectable by flow cytometry (2%-7% at day 12) and PCR (peak at 40 CAR+ cells/μL) for <1 mo |
allo, allogeneic hematopoietic stem cell transplantation; ASCT, autologous stem cell transplantation; CR, complete response; DLBCL, diffuse large B-cell lymphoma; DLI, donor lymphocyte infusion; FL, follicular lymphoma; GVHD, graft-versus-host disease; HSV-tk, herpes simplex virus thymidine kinase; IHC, immunohistochemistry; IV, intravenous; MCL, mantle cell lymphoma; LAD, lymphadenopathy; LCL, lymphoblastoid cell line; MRD, minimal residual disease; PBMC, peripheral blood mononuclear cell; PCR, polymerase chain reaction; PD, progressive disease; PR, partial response; qPCR, quantitative polymerase chain reaction; SC, subcutaneous; SD, stable disease.