Background
Clinical trials using engineered CAR-T cells to treat solid tumor
Antigen | CAR design | Identifier | Disease condition | Phase | Status | Sponsor | Notes | Ref |
---|---|---|---|---|---|---|---|---|
FR-α | 1st (FcRγ) | NCT00019136 | Ovarian cancer | I | Completed | National Cancer Institute | [35] | |
4th | NCT03185468 | Bladder cancer, urothelial carcinoma bladder | I/II | Recruiting | Shenzhen Geno-immune Medical Institute | |||
CAIX | 1st | DDHK97-29/P00.0040C | Renal cell carcinoma | I/II | Completed | Erasmus University Medical Center | First clinical study of its nature in Europe | |
L1-CAM | 2nd and 3 | NCT02311621 | Neuroblastoma | I | Recruiting | Seattle Children’s Hospital | ||
1st | NCT00006480 | Neuroblastoma | I | Completed | Fred Hutchinson Cancer Center | [38] | ||
MSLN | NA | NCT01583686 | Cervical, pancreatic, ovarian, and lung cancer, mesothelioma | I/II | Recruiting | National Cancer Institute | [118] | |
2nd | NCT01355965 | Malignant pleural mesothelioma | I | Completed | University of Pennsylvania | Intravenous (IV) administration of RNA mesothelin redirected autologous T cell | ||
2nd | NCT02159716 | Pancreatic, ovarian cancer, malignant epithelial pleural mesothelioma | I | Completed | University of Pennsylvania | |||
2nd | NCT01897415 | Metastatic pancreatic ductal adenocarcinoma | I | Completed | University of Pennsylvania | Intravenous (IV) administration of RNA mesothelin redirected autologous T cell | [41] | |
2nd | NCT02465983 | Pancreatic cancer | I | Completed | University of Pennsylvania | |||
2nd | NCT02414269 | Mesothelioma, lung and breast cancer | I | Recruiting | MSKCC | iCasp9M28z T cell | ||
2nd | NCT02706782 | Pancreatic cancer | I | Recruiting | Shanghai GeneChem Co., Ltd. | Vascular intervention-mediated CAR-T infusion | ||
NA | NCT03030001 | Solid tumors | I/II | Recruiting | Ningbo Cancer Hospital | PD-1 antibody expressing mesothelin-specific CAR-T cells | ||
NA | NCT03182803 | Advanced solid tumors | I/II | Recruiting | Shanghai Cell Therapy Research Institute | CTLA-4/PD-1 antibodies expressing mesoCAR-T | ||
HER2 | NA | NCT00924287 | HER2-positive sarcoma | I/II | Terminated | National Cancer Institute | ||
2nd | NCT00902044 | HER2-positive sarcoma | I/II | Recruiting | Baylor College of Medicine | [28] | ||
NA | NCT01935843 | HER-2 positive solid tumors | I/II | Recruiting | Chinese PLA General Hospital | [42] | ||
2nd | NCT02547961 | Breast cancer | I/II | Completed | Fuda Cancer Hospital | |||
2nd | NCT02442297 | Glioblastoma | I | Recruiting | Baylor College of Medicine | |||
2nd | NCT01109095 | Glioblastoma multiforme | I | Ongoing | Baylor College of Medicine | Genetically modified HER.CAR CMV-specific CTLs | [43] | |
2nd | NCT00889954 | HER2 positive malignancies | I | Ongoing | Baylor College of Medicine | TGFbeta dominant-negative receptor (DNR) expressing EBV specific lymphocytes | ||
EGFR | 2nd | NCT01869166 | Advanced EGFR-positive solid tumors | I/II | Recruiting | Chinese PLA General Hospital | [44] | |
NA | NCT03182816 | Advanced solid tumor | I/II | Recruiting | Shanghai Cell Therapy Research Institute | Anti-CTLA-4/PD-1 expressing EGFR-CAR-T | ||
NA | NCT02873390 | Advanced solid tumor | Recruiting | Ningbo Cancer Hospital | PD-1 antibody expressing CAR-T cells | |||
NA | NCT02862028 | Advanced solid tumor | I/II | Recruiting | Shanghai International Medical Center | PD-1 antibody expressing CAR-T cells | ||
EGFRvIII | 3rd | NCT01454596 | Glioma, glioblastoma, brain cancer | I/II | Recruiting | National Cancer Institute | [120] | |
NA | NCT02209376 | EGFRvIII positive glioma | I | Ongoing | University of Pennsylvania | |||
NCT03170141 | Glioblastoma multiforme | I/II | Recruiting | Shenzhen Geno-immune Medical Institute | 4SCAR-IgT cells producing PD1 and PD-L1 antibodies | |||
IL13Rα2 | 1st | NCT00730613 | Glioblastoma | I | Completed | City of Hope Medical Center | CAR expresses the Hy/TK selection/suicide fusion protein | [30] |
2nd | NCT02208362 | Glioblastoma | I | Recruiting | City of Hope Medical Center | Hinge-optimized | ||
1st | NCT01082926 | Glioblastoma | I | Completed | City of Hope Medical Center | T cells modified to express HyTK and to be resistant to glucocorticoids, in combination with interleukin-2 | ||
CEA | 2nd | NCT01373047 | Liver metastases | I | Completed | Roger Williams MC | ||
2nd | NCT02416466 | Liver metastases | I | Ongoing | Roger Williams MC | [122] | ||
2nd | NCT02349724 | Lung, colorectal, gastric, breast, and pancreatic cancer | I | Recruiting | Southwest Hospital | [123] | ||
2nd | NCT02862704 | Liver metastases | I/II | Recruiting | Xijing Hospital | MG7 specific CAR-T, which is a glycosylated protein of CEA | ||
NA | NCT02850536 | Liver metastases | I | Recruiting | Roger Williams MC | delivered via the hepatic artery using the Surefire Infusion System (SIS) | ||
NA | NCT00004178 | Solid tumor | I | Completed | Roger Williams MC | |||
1st | NCT01212887 | Adult solid tumor, | I | Terminated | Cancer Research UK | MFE23 scFv-expressing autologous anti-CEA MFEz T lymphocytes | ||
GD2 | 1st | NCT00085930 | Neuroblastoma | I | Ongoing | Baylor College of Medicine | 14g2a.zeta chimeric receptor-transduced autologous EBV specific cytotoxic T lymphocytes (EBV-CTL) w/o lymphodepletion | |
3rd | NCT01822652 | Neuroblastoma | I | Ongoing | Baylor College of Medicine | iC9-GD2-CD28-OX40 (iC9-GD2) T cells | [125] | |
3rd | NCT01953900 | Sarcomas | I | Ongoing | Baylor College of Medicine | [126] | ||
3rd | NCT02439788 | Neuroblastoma | I | Withdrawn | Baylor College of Medicine | 3rd generation GD2 specific CAR and inducible caspase 9 safety switch transduced autologous natural killer T cells | ||
NA | NCT01460901 | Neuroblastoma | I | Completed | Children’s Mercy Hospital, Kansas | [125] | ||
3rd | NCT02107963 | Osteosarcoma, neuroblastoma, Melanoma | I | Completed | National Cancer Institute | [127] | ||
4th | NCT02765243 | Neuroblastoma, effects of immunotherapy | II | Recruiting | Zhujiang Hospital | |||
4th | NCT02992210 | Solid tumor | I/II | Recruiting | Shenzhen Geno-immune Medical Institute | 4th generation CAR (4SCAR) fused with an inducible apoptotic caspase 9 domain | ||
MUC1 | NA | NCT02617134 | Glioma, colorectal and gastric carcinoma | I/II | Recruiting | PersonGen BioTherapeutics | ||
3rd | NCT02587689 | NSCLC, hepatocellular, pancreatic, and breast carcinoma | I/II | Recruiting | PersonGen BioTherapeutics | [29] | ||
NA | NCT03179007 | Advanced solid tumor | Recruiting | Ningbo Cancer Hospital | Anti-CTLA-4/PD-1 expressing MUC1-CAR-T | |||
PSMA | 2nd | NCT01140373 | Prostate cancer | I | Ongoing | MSKCC | ||
NA | NCT01929239 | Prostate cancer | I/II | Suspended (funding) | Roger Williams MC | [128] | ||
1st | BB-1ND12084 | Prostate cancer | I | Roger Williams MC | [48] | |||
4th | NCT03185468 | Bladder cancer, urothelial carcinoma bladder | I/II | Recruiting | Shenzhen Geno-immune Medical Institute | |||
PSCA | NA | NCT03198052 | Lung cancer | I | Recruiting | Guangzhou Medical University | ||
NA | NCT02744287 | Pancreatic cancer | I | Recruiting | Bellicum Pharmaceuticals | |||
FAP | 2nd | NCT01722149 | Malignant pleural mesothelioma | I | Recruiting | University of Zurich | [32] | |
CD133 | 1st, 2nd | NCT02541370 | CD133-positive malignancies | I | Recruiting | Chinese PLA General Hospital | [45] | |
cMet | NA | NCT01837602 | Breast | I | Ongoing | University of Pennsylvania | cMet RNA CAR-T cells | [47] |
2nd | NCT03060356 | Malignant melanoma, breast cancer | I | Recruiting | University of Pennsylvania | cMet RNA CAR-T cells | ||
EphA2 | NA | NCT02575261 | Glioma | I/II | Completed | Fuda Cancer Hospital | ||
GPC3 | 2nd | NCT02715362 | Hepatic carcinoma | I/II | Recruiting | Shanghai GeneChem Co., Ltd. | Administration by transcatheter arterial infusion (TAI) method | |
NCT02723942 | Hepatocellular carcinoma | I/II | Completed | Fuda Cancer Hospital, Guangzhou | ||||
NCT02876978 | Lung squamous cell carcinoma | I | Recruiting | Carsgen Therapeutics, Ltd. | ||||
NCT03130712 | Hepatocellular carcinoma | I/II | Recruiting | Shanghai GeneChem Co., Ltd. | ||||
3rd | NCT03198546 | Hepatocellular carcinoma | I | Recruiting | Guangzhou Medical University | |||
VEGFR-II | NA | NCT01218867 | Melanoma, renal cancer | I/II | Completed | National Cancer Institute | ||
ROR1 | NA | NCT02706392 | Breast, lung carcinoma | I | Recruiting | Fred Hutchinson Cancer Center | [129] | |
EpCAM | NA | NCT02729493 | Liver neoplasms | Recruiting | Sinobioway Cell Therapy Co., Ltd. | |||
NA | NCT02725125 | Stomach neoplasms | Recruiting | Sinobioway Cell Therapy Co., Ltd. | ||||
2nd | NCT02915445 | Malignant neoplasm of nasopharynx, breast Cancer | I | Recruiting | Sichuan University | |||
2nd | NCT03013712 | Solid tumors | I/II | Recruiting | First Affiliated Hospital of Chengdu Medical College | |||
MUC16ecto | 2nd | NCT02498912 | Solid tumors | I | Recruiting | MSKCC | T cells genetically engineered to secrete IL-12 | [130] |
Tumor-associated antigens and CAR design
T cell dosage, administration, and persistence
Clinical outcomes and toxicities
Antigen | Identifier | Patients n Age (median; range) | Dosage | Persistence | Outcome n (median; range) in month | Adverse events | Ref |
---|---|---|---|---|---|---|---|
FR-a | NCT00019136 | 14 (33–60) | 0.3–5 × 1010 T cells | Up to > 1 year | NE: 14 | Grade 3/4 toxicities including hypotension and dyspnea as well as less frequently fatigue, leukopenia, rigors, sinus tachycardia, and diarrhea, in some patients receiving IL-2 | [35] |
CAIX | DDHK9729/P00.0040C | 12 62,5 (46–74) | 0.2–2.1 × 109 (split dose over 2 × 5 days) | Up to 4 weeks | NE: 12 | Transient liver enzyme disturbances (grade 3/4) observed in 4 patients, caused by attack of CAR-T cells to CAIX-expressing bile duct epithelial cells | |
L1-CAM | NCT00006480 | 6 9,5 (7–16) | 1 × 108–1.1 × 109/m2 (split dose; 2–3 times of infusions 14 days apart) | Up to 42 days | CR: 1 (1,5) SD: 1 (1) PD: 4 | Grade 3 lymphopenia, neutropenia, low hemoglobin and bacteremia caused by 108/m2 CAR-T cells infusion grade 3 pneumonitis for one patient, which was associated with 109/m2 CAR-T cells infusion | [38] |
MSLN | NCT01355965 | 2 78 (75–81) | 3 infusions with 0.1–1 × 109 cells or 8 infusions with 3 × 108 cells and 2 infusions with 2 × 108 cells | Transient (mRNA CAR) | PR: 1 (6) SD: 1 | Anaphylactic reaction in one patient, leading to grade 4 cardiac arrest, respiratory failure, disseminated intravenous coagulation, and CRS grade 4 jejunal obstruction, grade 3 abdominal pain, and grade 2 lymphcytosis for another patient | |
NCT01897415 | NA | 3 times per week for 3 weeks | Transient (mRNA CAR) | SD: 2 | Grade > 3 toxicities included abdominal pain (1) and back pain (1) | [41] | |
HER2 | NCT00924287 | 1 39 | 1 × 1010 total | NA | Death: 1 | Respiratory distress and dramatic pulmonary infiltrate on chest X-ray were observed soon after CAR-T cell administration. Severe hypotension, bradycardia, gastrointestinal bleeding, resulting in a cardiac arrest. The patient died 5 days after the CAR-T infusion. | [119] |
NCT01109095 | 17 49 (11–79) | 1 × 106-1 × 108/m2 | Up to 12 weeks | SD: 7 PD: 8 PR: 1 | NA | [43] | |
NCT00902044 | 19 16 (7–29) | 1 × 104-1 × 108/m2 (up to 9 infusions) | Up to 18 month | SD: 4 (0,5; 0,5–14) PD: 13 NE: 2 | Fever observed in 1 patient | [28] | |
NCT01935843 | 11 61 (50–75) | 2.1 × 106/kg (range 1.4–3.8 × 106/kg), 1 to 2 cycles | Up to 80 days | PR: 1 (4.5) SD: 5 (4.8; 1.5–8.3) | Mild-to-moderate fatigue, nausea, vomiting, myalgia, arthralgia, and lymphopenia, Except one grade 3 acute febrile syndrome and one abnormal elevation of transaminase | [42] | |
EGFR | NCT01869166 | 11 58 (40–66) | 4 × 105–2.54 × 107/kg | Up to 37 weeks | PR: 2 (3; 2–3,5) SD: 5 (5,5; 2–8+) PD: 4 | Mild skin toxicity, nausea, vomiting, dyspnea, and hypotension; one patient suffered from a transient grade 3/4 increase in serum lipase | [44] |
EGFR and CD133 | NCT01869166 NCT02541370 | 1 52 | EGFR: 2.2 × 106/kg first cycle, 2.1 × 106/kg second cycle, CD133: 1.22 × 106/kg | NA | EGDR: PR (8.5) CD133: PR (2.5) | EGFR: mild chills, fever, fatigue, vomiting and muscle soreness, and a 9-day duration of delayed lower fever CD133: an intermittent upper abdominal dull pain, chills, fever, and rapidly deteriorative grade 3 systemic subcutaneous hemorrhages and congestive rashes together with serum cytokine release | [45] |
IL-13Ra2 | NCT00730613 | 3 57 (36–57) | 1.6 × 108 for first cycle + 3 × 108 for second to fourth cycle (split dose in each cycle; 3 infusions 2 days apart) | Up to 14 weeks | PR: 2 (12; 10–14) PD: 1 | Grade 3 headache in two patients receiving 108 CAR-T cells infusion grade 3 neurologic adverse events observed in 1 patient | [30] |
NCT02208362 | 1 50 | Intracavitary infusions (cycles 1 through 6) and intraventricular infusions (cycles 7 through 16), maximum dose: 10 × 106 cells | Detectable at 149 days after enrollment | CR:7.5 | No CAR-T cell infusion related toxic effects of grade 3 or higher were observed | [33] | |
CEA | NCT01373047 | 7 53,5 (51–66) | 1 × 108–1 × 1010 cells (single hepatic artery infusion) | NA | SD: 1 (23) PD: 5 NE: 1 | Grade 3 fever and tachycardia (1 patient), associated to high-dose IL-2 administration. grade 1/2 transient elevations of alkaline phosphatase, total bilirubin and aspartate aminotransferase levels observed in all patients | [31] |
GD2 | NCT00085930 | 19 7 (3–29) | 1.2 × 107-1 × 108/m2 (single infusion) | Up to 192 weeks for ATC and 96 weeks for CTLs | CR: 11 PR: 1 SD: 1 PD: 6 | Mild to moderate local pain at the site of tumor necrosis in two patients | |
MUC1 | NCT02587689 | 1 | 5 × 105 cells per lesion | NA | PR: 1 | Mild headache, muscle pain, nasal congestion, and abdominal bloating discomfort, and a transient CRS was experienced | [29] |
PSMA | BB-IND 12084 | 5 61 (51–75) | 1 × 109–1 × 1010 cells | Up to 4 week | PR: 3 NE: 2 | Grade 3/4 hematologic toxicities including neutropenia, neutropenic fever, and thrombocytopenia in all the patients; anemia, hypocalcemia, hypophosphatemia, and appendicitis in one patient. Grade 1/2 skin rash, fatigue, intermittent low-grade fevers, and muscle pain in some patients | [48] |
VEGFR-II | NCT01218867 | 23 | 1 × 106–3 × 1010 cells | NA | PR: 1 SD: 1 PD: 21 | Grade 3/4 toxicity include nausea, vomiting, hypoxia, and elevated levels of aspartate transaminase, alanine transaminase, and bilirubin | Results available at www.ClinicalTrials.gov |