Table 1.
Summary of Reported Pharmacokinetic Data from Clinical Trials of CD19-Specific CAR-T Cells
| Reference | Trial | Indication (Number of Subjects) | Vector, Transgene, and Cells | Conditioning Regimen | Dose | Response | Cmax (Blood) | Time to Cmax | Persistence | t1/2 | AUC | Comment |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Lee et al., Lancet 201585 | NCT01593696, CD19 CAR T | B-ALL (20), DLBCL (1) | γ retrovirus (FMC63)-28z leukopheresis bulk T cells | Cytoxan + fludarabine | median: 1 × 106 CAR+/kg (mean, range: 1.3, 0.03–3.6) | 70% CR (ALL) | mean, ∼20 cells/μL (range, 0 to ∼45) by FCMa | 14 days | absent by D+68 (in evaluable non-HSCT subjects) | not reported | not reported | |
| Locke et al., 201763 | ZUMA-1, CD19 CAR T | DLBCL(7) | γ retrovirus (FMC63)-28z leukopheresis bulk T cells | Cytoxan + fludarabine | median: 2 × 106 CAR+/kg (mean, range: 1.7, 1.1–2) | 57% CR; 71% OR | not reported | 7–14 days | detectable at 12 months in 3, with ongoing response by qPCR | not reported | not reported | patient with lowest Cmax experienced CR, ongoing at 12 months |
| Ali et al., 201624 | NCT02215967, BCMA CAR T | MM (12) | γ retrovirus (11D-5-3)-28z leukopheresis bulk T cells | Cytoxan + fludarabine | median: 2 × 106 CAR+/kg (mean, range: 2.8, 0.3–9) | 8.3% CR; 25% PR | <10 cells/μL (dose 0.3 × 106 to 1 × 106 CAR+/kg); <10/μL to >250/μL (dose 3 × 106 to 9 × 106 CAR+/kg)a | not reported | CAR+ ≤0.1% of PBMCs by 3 months | not reported | not reported | patients with highest Cmax experienced best response |
| Wang et al., Blood 201686 | NCT01318317, CD19 CAR T day +2 post auto-HSCT | DLBCL (7), MCL (1) | lentivirus (FMC63)-z leukopheresis CD4-CD45RA-CD14-depleted, CD62L-enriched T cells | HSCT conditioning: bis-chloroethylnitrosourea; etoposide; Ara-C; melphalan | median: 50 × 106 total CAR+ (mean, range: 65.6, 25–100) | 63% CR, 25% PR | median, 280 (range, 0–925) CAR copies/mL (qPCR); mean, 1.6 CAR copies/μg gDNA | ∼2 weeks | mean persistence: 18.25 days (range 0–28) by qPCR | not reported | AUC25: mean 25.4 log10 CAR copies/μg gDNA | |
| Wang et al., Blood 201686 | NCT01815749, CD19 CAR T day +2 post auto-HSCT | DLBCL (4), MCL (4) | lentivirus (FMC63)-28z leukopheresis CD25-CD45RA-CD14-depleted, CD62L-enriched T cells | HSCT conditioning: bis-chloroethylnitrosourea; etoposide; Ara-C; melphalan | median: 200 × 106 total CAR+ (mean, range: 143.8, 50–200) | 100% CR | median, 692 (range, 267–27,790) CAR copies/mL (qPCR); mean, 2.79 CAR copies/μg gDNA | ∼2 weeks | mean persistence: 20.5 days (range 7–27) by qPCR | not reported | AUC25: mean 40.2 log10 CAR copies/μg DNA | |
| Gardner et al., 201725 | NCT02028455, CD19 CAR T | B-ALL, pediatric (43) | lentivirus (FMC63)-41BBz + EGFRt leukopheresis, CD4s and CD8s expanded separately, enriched for transgene, mixed 1:1 for infusion | Cytoxan (27); Cytoxan/etoposide (1); fludarabine (1); Cytoxan + fludarabine (13) | median: 1 × 106 CAR+/kg (mean, range: 2.55, 0.5–10) | 93% CR | mean 100–400 CAR+/μL (FCM)a | median 10 days (range, 7–18 days) | median 3 months (95% CI 2.07–6.44), by B cell aplasia | not reported | not reported | Cmax and AUC correlate with antigen burden but not with dose |
| Brentjens et al., 201159 | NCT00466531, NCT01044069, CD19 CAR T | CLL (8), B-ALL (1) | γ retrovirus (SJ25C1)-28z leukopheresis bulk T cells | no conditioning (3); Cytoxan (6) | median: 1.1 × 109 total CAR+ (mean, range: 1.24 × 109, 1.8 × 108 to 3.2 × 109) | reduction in lymphadenopathy (1 subject, CLL); persistent B cell aplasia (1 subject, ALL) | not reported | not reported | up to 8 weeks in 2 patients by IHC | not reported | not reported | presence of CAR+ cells determined by qPCR/flow cytometry after ex vivo restimulation |
| Mueller et al., 201720 | NCT01626495, NCT01029366, NCT01747486, CD19 CAR T | B-ALL, pediatric (55), adult (6), CLL (42) | lentivirus (FMC63)-41BBz leukopheresis bulk T cells | Cytoxan; Cytoxan/etoposide; clofarabine; fludarabine/Cytoxan; CVAD; bendamustine; no conditioning | range: 0.76 × 106 to 20.6 × 106 CAR+/kg, ALL; median: 1.6 × 108 total CAR+ (range: 0.14 × 108 to 11 × 108), CLL | ALL: 82%–93% CR; CLL: 35% CR, 18% PR | geometric mean (CV%), peds-ALL: 48,000 copies/μg gDNA (132) in CR/CRi patients, 17,200 copies/μg gDNA (779) in NR | CR: 11 days (range, 1–32); NR: 15 days (range, 1–32) | CR: median 192 days (range, 18–780 days); NR: median 28.5 (range, 1–32) by qPCR | CR: median 18.8 days (range, 0.7–400); NR 8.8 days (range, 1.2–11.8) | AUC0–28: CR- 328,212 copies/μg × days (CV% 208.5); NR: 8,688 copies/μg × days (CV% 1,910) | |
| Hu et al., 201787 | ChiCTR-OCC-15007008, CD19 CAR T | B-ALL (15) | lentivirus (FMC63)-41BBz leukopheresis bulk T cells | Cytoxan + fludarabine | median: 3.7 × 106 CAR+/kg (mean, range: 4.4, 1.1–9.8) | 40% CR | median, 342 CAR+ cells/mL (95% CI, 140–532) in grade 3 CRS group; median, 96 CAR+ cells/mL (95% CI, 61.5–132.8) in grade 1 to 2 CRS/non-CRS group | not reported | up to 7 months in one patient | not reported | not reported | |
| Turtle et al., 201631 | NCT01865617, CD19 CAR T | B-ALL (30) | lentivirus (FMC63)-41BBz + EGFRt leukopheresis, CD4+ and CD8+/CD8+Tcm-enriched expanded separately, enriched for transgene, mixed 1:1 for infusion | Cytoxan (11); Cytoxan + etoposide (2); Cytoxan + fludarabine (17) | median: 2 × 106 CAR+/kg (mean, range: 2.42, 0.2–20) | 93% remission by flow cytometry, 86% MRD-negative CR | not reported | 7–14 daysa | not reported | not reported | not reported | |
| Turtle et al., 201788 | NCT01865617, CD19 CAR T | CLL (24) | lentivirus (FMC63)-41BBz + EGFRt leukopheresis, CD4+ and CD8+/CD8+Tcm-enriched expanded separately, enriched for transgene, mixed 1:1 for infusion | Cytoxan (1); fludarabine (2); Cytoxan + fludarabine (21) | median: 2 × 106 CAR+/kg (mean, range: 2.42, 0.2– 20) | 21% CR, 53% PR by IWCLL criteria | not reported | not reported | not reported | not reported | not reported | |
| Pan et al., 201789 | ChiCTR-IIh-16008711, CD19 CAR T | B-ALL (51) | lentivirus (FMC63)-41BBz leukopheresis bulk T cells | Cytoxan + fludarabine; no conditioning (1) | mean, range: 1 × 105 CAR+/kg, 0.05–14 | 90% CR | not reported | 8–11 days | undetectable in blood on day +30 (42 subjects), present at day 40, 45, and 60 (3 subjects) by FCM | not reported | not reported | |
| Davila et al., 201458 | NCT01044069, CD19 CAR T | B-ALL (16) | γ retrovirus (SJ25C1)-28z leukopheresis bulk T cells | Cytoxan | 3 × 106 CAR T cells/kg (15 subjects); 4.8 × 105 CAR+ cells/kg (1 subject) | 88% overall CR | not reported | 7–14 days | low undetectable by 2 to 3 months, complicated by progression to allo-HSCT in 7 subjects | not reported | not reported | |
| Rossig et al., 201790 | CD19TPALL, CD19 CAR T, in vivo vaccination to boost CAR T cells in cohort 2 | B-ALL, pediatric (11) | γ retrovirus (FMC63)-28z EBV-specific CTL | fludarabine; fludarabine + vincristine + dexamethasone | median: 4.55 × 107 CAR+/m2 (mean, range: 4.62, 1.08– 7.2) | 36.4% continued, 9.1% CR, 9.1% PR | not reported | not reported | cohort 1 (no vaccination): median, 0 days (range 0–28); cohort 2 (vaccination): median, 56 days (range, 0–221) | not reported | not reported | |
| Kochenderfer et al., 201748b | NCT00924326, CD19 CAR T | DLBCL (19), FL (2), MCL (1) | γ retrovirus (FMC63)-28z leukopheresis bulk T cells | Cytoxan + fludarabine | median: 2 × 106 CAR+/kg (mean, range: 1.86, 1–6) | 55% CR, 18% PR | median, 98 CAR+/μL in subjects with remission; median, 15 CAR+/μL in subjects without remission | median, 8.5 days (range, 6–35 days) | 0 to 1 CAR+/μL by 3 months | not reported | not reported | |
| Kochenderfer et al., 201591b | NCT00924326, CD19 CAR T | DLBCL (9), CLL (4), other indolent lymphoma (2) | γ retrovirus (FMC63)-28z leukopheresis bulk T cells | Cytoxan + fludarabine | median: 2.5 × 106 CAR+/kg (mean, range: 2.3, 1–5) | 53% CR, 26.7% PR | range, 9–777 CAR+ cells/μL | 7–17 days | not reported | not reported | not reported |
B-ALL, B cell acute lymphoblastic leukemia; FCM, flow cytometry; HSCT, hematopoietic stem cell transplant; OR, overall response; MM, multiple myeloma; MCL, mantle cell lymphoma; PBMC, peripheral blood mononuclear cell; gDNA, genomic DNA; CI, confidence interval; NR, non-responder; MRD, minimal residue disease; IWCLL, international workshop on chronic lymphocytic leukemia; FL, follicular lymphoma.
a
Estimate from graphical data presented in report, without numerical values explicitly reported.
b
There is likely some patient overlap between these last two reports by Kochenderfer et al. (neither is a complete subset of the other).