Table 1.
Neurotoxicity in CD19-directed chimeric antigen receptor (CAR) T cell clinical trials
| References (first author. year) | NCT | N | Age range (Years) | CAR construct | Lympho-depletion (N) | CRR (%) | ORR (%) | NT (%) | sNT (%) | CRSa (%) | saga (%) | Loci (%) | steroids (%) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ALL | |||||||||||||
| Lee. 2015 [5] | NCT01593696 | 20 | 5–27 | 28z | Flu/Cy | 70g 60h |
n/a | 30 | 5 | 75c* | 30 | 27 | 13 |
| Gardner. 2017 [4] | NCT02028455 | 43 | 1–25 | 4–1BB | Cy (27) or Flu/Cy (14) | 93h 93h |
n/a | 44 | 21b | 93c* | 23 | 42 | 25 |
| Maude. 2018 [6] | NCT02435849 | 75 | 3–23 | 4–1BB(tisagenle-ckucel) | Flu/Cy (71) orCy/Etop (1) | 81g 81h |
n/a | 40 | 13 | 77p | 46 | 48 | 0 |
| Maude. 2014[7] |
NCT01626495 NCT01029366 |
30 | 5–60 | 4-IBB(CT1.019, tisafpnlecleucel) | Cy/VP (5). Ara-CJEtop (I). Flu/Cy (15). Cy (3). Clo (1). CVAD-A (1).orCVAD-B (1) |
90g 79h |
n/a | 43 | NR | 88* | 27 | 30 | 20 |
| Turtle. 2016 [3]c | NCT01865617 | 30 | 20–73 | 4–1BB | Cy/Etop (2). Cy (I I), or Flu/Cy (17) | 100g 93h |
n/a | 50 | 50 | 83c | 23 | 27 | 37 |
| Park. 2018 [2] | NCT01044069 | 53 | 23–74 | 28z (19–28z) | Cy (43) or Flu/cy (10) | 83g 67h |
n/a | 44 | 42 | 85M | 26 | 42 | 38 |
| NHL | |||||||||||||
| Kochenderfer. 2015 [10] | NCT00924326 | 11 | 30–68 | 28z | Flu/Cy (15) | 36 | 80 | NR | 45 | NRc | 36 | 25 | 0 |
| Turtle. 2016 [9] | NCT01865617 | 32 | 36–70 | 4-IBB | Cy or Cy/Etop (12) or Flu/Cy (20) | 33 | 63 | 28 | 28d | 63c* | 13 | 9 | 13 |
| Schuster. 2017 [11] | NCT02030834 | 28 | 25–77 | 4-IBB (CTL019) | Cy (11), modEPOCH (3). bend (8). Cy/T81 (4). Cy/Etop (I). Flu/Cy (1). Carbo/Gem (10) |
57 | 64 | 39 | 11 | 57p | 18 | 20 | 6 |
| Neelapu, 2017 [12] | NCT07248216 | 101 | 23–76 | 28z (axicabtagene cibaleucel) | Flu/Cy (101) | 54 | 82 | 64 | 28 | 93L | 13 | 43 | 27 |
| CLL | |||||||||||||
| Turtle. 2017 [14]c | NCT01865617 | 24 | 40–73 | 4–188 | Cy (1). Flu (2) Flu/Cy (21) | 29 | 71 | 33 | 25d | 83L | 8 | 25 | 25 |
| Fraietta. 2018 [16] |
NCT01029366 NCT01747486 NCT02640209 |
41 | 61–66e | 4–188 | n/a | 20 | 39 | 6f | 0f | 69f | 38f | NR | NR |
4–1BB 4–1BB costimulatory domain, 28z CD28-CD3zeta costimulatory domain, ALL acute lymphoblastic leukemia, Ara-C cytarabine, Bend bendamustine, Carbo carboplatin, CHOP Children’s Hospital of Philadelphia, CLL chronic lymphocytic leukemia, clo clofarabine, CRR complete remission rate, CRS cytokine release syndrome, CTCAE Common Terminology Criteria for Adverse Events, CVAD-A cyclophosphamide + vincristine + adriamycin, CVAD-B methotrexate + cytarabine, Cy cyclophosphamide, Etop etoposide, Flu fludarabine, Gem gemcitabine, mod-EPOCH modified EPOCH (doxorubicin, etoposide, cyclophosphamide), MSKCC Memorial Sloan Kettering Cancer Center, n/a not available, NCT national clinical trial, NHL non-Hodgkin’s lymphoma, NR reported, NT neurotoxicity, ORR overall response rate, sCRS severe CRS (CTCAE grade 3 or greater, or as defined in the publication), sNT severe neurotoxicity (CTCAE grade 3 or greater), steroids corticosteroids, TBI total body irradiation, toci tocilizumab, VP etoposide
The CRS grading system is indicated by the following superscripts: C = CTCAE criteria; L = Lee criteria [22]; P = Penn/CHOP criteria [26]; M = MSKCC criteria [2];
indicates modified crite-ria, please refer to the individual publication for details
CTCAE grade 3 or greater, and/or any seizures
Data on expanded cohort available in [23]
CTCAE grade 3 or greater, and/or any seizures, and/or grade 2 delirium
Only median age reported
Toxicities only reported for the 16 patients who responded to CAR T cells
Morphologic remission
Minimal residual disease-negative remission