Table 2.
CAR T cell design and production and clinical aspects of largest clinical trials to date investigating CD19-targeted CAR T cells in the treatment of CLL and B-NHL.
| Institution/ Reference |
Population/ # Reported |
Gene Transfer Method |
scFv | Co- Stimulatory Domain |
Lymphodepleting Chemotherapy (LDC) |
CAR T cell Doses | Disease-Related Outcomes |
|---|---|---|---|---|---|---|---|
| Memorial Sloan Kettering Cancer Center26 | Adult CLL (n=8) | Gamma-retrovirus | SJ25C1 | CD28 | None or Cy 1.5–3 g/m2 | Cohort receiving no LDC: 1.2–3.0×107 CAR+ T cells/kg Cy cohort: 0.4–1.0×107 CAR+ T cells/kg |
ORR: 1/8 (PR); two others with ≥2 months of SD, all in Cy cohort |
| Memorial Sloan Kettering Cancer Center27 | Adult CLL (n=8) | Gamma-retrovirus | SJ25C1 | CD28 | Cy 600 mg/m2 | 3×106, 1×107, or 3×107 CAR+ T cells/kg |
ORR: 4/8 (CCR, n=2; PR, n=2) |
| National Cancer Institute34 | Adult CLL and B-NHL (n=8) | Gamma-retrovirus | FMC63 | CD28 | Cy 60 mg/kg × 2d + Flu 25 mg/m2 × 5d | 0.3–3.0×107 CAR+ T cells/kg | ORR: 6/8 (CLL, ¾; FL, 2/3); CR, n=1 (CLL) and PR, n=5 |
| National Cancer Institute35 | Adult B-NHL (n=15) | Gamma-retrovirus | FMC63 | CD28 | Cy 60 mg/kg × 1–2d + Flu 25 mg/m2 × 5d | 1 – 5×106 CAR+ T cells/kg | CR: 4/7 (refractory DLBCL), 4/6 (indolent B-NHL) |
| National Cancer Institute52 | Adult CLL and B-NHL (n=15) | Gamma-retrovirus | FMC63 | CD28 | None (administered following AlloHSCT) | 0.4–8.2×106 CAR+ T cells/kg | For pts with CLL, ORR: 2/5 (CR, n=1; PR, n=1; SD, n=1) For pts with other B-NHL, ORR: 2/10 (CR, n=1; PR, n=1; SD, n=7) |
| Fred Hutchinson Cancer Research Center37 | Adult CLL and B-NHL (n=28) | Lentivirus | FMC63 | 4-1BB | Cy 60 mg/kg ×1 ± etoposide or Cy 60 mg/kg ×1 + Flu 25 mg/m2 × 3d | 2×105, 2×106, and 2×107 CAR+ T cells/kg;1:1 CD4+:CD8+ |
ORR: 6/12 (CR, n=1, PR, n=5 in Cy cohort) and 8/12 (CR, n=5, PR, n=3 in Cy + Flu cohort) |
| University of Pennsylvania30 | Adult CLL (n=14) | Lentivirus | FMC63 | 4-1BB | Investigator’s choice | 0.14–11×108 CAR+ T cells | ORR: 8/14 (MRD negative CR, n=4; PR, n=4) Median PFS: 7 months Median OS: 29 months |
| University of Pennsylvania31 | Adult CLL (n=35 total; n=21 at stage 2 dose) | Lentivirus | FMC63 | 4-1BB | Investigator’s choice | Stage 1: 5×107 vs. 5×108 CAR+ T cells Stage 2: 5×108 CAR+ T cells |
ORR in stage 1: 10/23 (CR, n=5; PR, n=5) ORR in pts treated with stage 2 CAR T cell dose: 9/17 (CR, n=6; PR, n=3) |
| University of Pennsylvania36 | Adult B-NHL (n=24)† | Lentivirus | FMC63 | 4-1BB | Investigator’s choice | 3.08–8.87 ×106 CAR+ T cells/kg | ORR: 15/22 (DLBCL, 7/13; FL, 7/7, MCL, 1/2) PFS: 62% at 11.7 months |
scFv=Single chain fragment variable fragment, Cy=cyclophosphamide, Flu=fludarabine, VP=etoposide, OS=overall survival, EFS=event free survival, MRD=minimal residual disease, CR=complete response, CCR=clinical complete response, PR=partial response, pts=patients, DLBCL=diffuse large B cell lymphoma, FL=follicular lymphoma, MCL=mantle cell lymphoma, AlloHSCT=allogeneic hematopoietic stem cell transplantation.
†
38 enrolled, 24 received the protocol-specified dose and were included in the analysis