Adoptive Immunotherapy for Hematological Malignancies Using T Cells Gene-Modified to Express Tumor Antigen-Specific Receptors
Abstract
:1. Introduction
2. Gene-Modified T Cells Redirected Towards Therapeutic Targets
Taregt Ag. of TCR | Cell Dose (× 109) | Target Disease Pt.No. (n) | Preconditioning | AEs (Grade) | Clinical Responses | Ref. |
---|---|---|---|---|---|---|
MART-1 | 1.0–86 | melanoma | Cy + Flud | No | PR 2/17 | [37] |
(n = 17) | ||||||
MART-1* | 1.5–107 | melanoma (20) | Cy + Flud | skin, eye (G2) | PR 6/20 | [27] |
gp100** | 1.8–110 | melanoma (16) | ear (G3) | CR 1/16,PR 2/16 | ||
(n = 36) | ||||||
p53**/gp100** | 0.5–27.7 | breast ca. (4) | Cy + Flud | N/A | PR 1/9 | [38] |
melanoma (2) | ||||||
esoph.ca. (1) | ||||||
others (2) | ||||||
CEA* | 0.2–0.4 | colorectal ca. | Cy + Flud | colitis (G3) | PR 1/3 | [28] |
(n = 3) | CEA decreased 3/3 | |||||
NY-ESO-1* | 1.6–130 | melanoma (11) | Cy + Flud | No | CR 2/11, PR 3/11 | [29] |
synovial cell ca.(6) | PR 4/6 | |||||
(n = 17) | ||||||
MAGE-A3* | 29–79 | melanoma (7) | Cy + Flud | mental disturbance (G4) | Tumor regression | [25] |
synovial cell ca.(1) | 2/3 died of necrotizing | 5/9 | ||||
esoph.ca. (1) | leukoencephalopathy | |||||
(n = 9) | (on-target AE) | |||||
MAGE-A3* | 5.3 & 2.4 | melonoma (1) | Cy | 2/2 died of cardiogenic | NE | [26] |
myeloma (1) | melphalan + autoSCT | shock | ||||
(n = 2) | (off-target AE) |
3. Lessons from Clinical Trials Using T Cells Gene-Modified by Tumor Antigen-Specific Receptor Gene Transfer
Target Ag. of CAR | Cell Dose | Target disease Pt.No. (n) | Preconditioning | AEs (Grade) | Clinical Responses | Ref. |
---|---|---|---|---|---|---|
L1-cell adhesion | 1 × 108 | neuroblastoma (6) | none | pancytopenia (G3) | PR 1/6 | [64] |
molecule/CAR* | Or 109/m2 | bacteremia, pneumonitis | ||||
HER2/CAR** | 1 × 101° | colon cancer with | Cy + Flud | died of acute pulmonary | N/E | [65] |
lung/liver meta. (1) | failure | |||||
GD2/CAR* | 0.2–0.5–1 | neuroblastoma (19) | none | no | CR 3/19, PR 1/19 | [66] |
EBV-CTL | × 108 | |||||
CD19/CAR*** | 1.1 × 109 | CLL (3) | CTx for CLL | lymphopenia (G3) | CR | [51] |
5.8 × 108 | B cell aplasia | PR | ||||
1.4 × 107 | CR | |||||
CD19/CAR# | 1.0–11.1 | CLL (8) | none for 3 | hypotension (G3) | PR 1/8 in CLL | [53] |
× 109 | ALL (2) | Cy (1500 mg or 3000 mg) | 1 died of shock, renal failure | B cell aplasia | ||
for others | B cell aplasia | |||||
CD19/CAR# | 0.5–5.5 | CLL (4) | Cy + Flud | hypotension (G3/4) | CR 1/4, PR 2/4 in CLL | [52] |
× 107 /Kg | FL (4) | renal failure, infection | PR 3/4 in FL | |||
B cell aplasia | B cell aplasia | |||||
CD20/CAR** | 4.4 × 109 /m2 | MCL (2) | Cy (1000 mg/m2 ) | hypoxia (G3), fever (G2) | PR in FL | [67] |
FL (1) | ||||||
CD19/CAR# | 1.0–11.1 | B-ALL (5) | Cy (1500 mg or 3000 mg) | fever (G2) | CR 2/6 (no MRD) | [54] |
× 106 /Kg | ||||||
CD19/CAR*** | 1.4–12 | ALL (2) | CTx for ALL | CRS (G3-4) | CR 2/2 | [55] |
× 106 /Kg | B cell aplasia | |||||
CD19/CAR # | 3 × 106 /kg | refractory B-ALL (16) | Cy (1500 mg or 3000 mg) | CRS (G3-4) (7/16) | CR 14/16 | [56] |
ph+ (4/16) | neurologic complication (3/7) | molecular CR 10/14 | ||||
respiratory ventilation (3/3) | transit to allo-HSCT | |||||
(7/14) |
4. Adverse Effects of Gene-Modified T Cells
5. Attempts to Address Challenging Issues
6. Conlusions
Conflict of Interest
References
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Fujiwara, H. Adoptive Immunotherapy for Hematological Malignancies Using T Cells Gene-Modified to Express Tumor Antigen-Specific Receptors. Pharmaceuticals 2014, 7, 1049-1068. https://doi.org/10.3390/ph7121049
Fujiwara H. Adoptive Immunotherapy for Hematological Malignancies Using T Cells Gene-Modified to Express Tumor Antigen-Specific Receptors. Pharmaceuticals. 2014; 7(12):1049-1068. https://doi.org/10.3390/ph7121049
Chicago/Turabian StyleFujiwara, Hiroshi. 2014. "Adoptive Immunotherapy for Hematological Malignancies Using T Cells Gene-Modified to Express Tumor Antigen-Specific Receptors" Pharmaceuticals 7, no. 12: 1049-1068. https://doi.org/10.3390/ph7121049