Table 1.
CAR-T cell clinical trials for solid tumors with published results
| Cancer | Antigen | Identifier | Patients | Dosage–Route of administration | Persistence | Outcome | Adverse events | Notes | Reference |
|---|---|---|---|---|---|---|---|---|---|
| Pancreatic–biliary tract | EGFR | NCT01869166 | 16 | 3.48 × 106/kg (range 1.31 to 8.9 × 106/kg); Intravenous | Baseline levels within 1 month |
PR: 4 patients (2–4 months) SD: 8 patients (2–4 months) PD: 2 patients NE: 2 patients |
Grade ≥ 3 fever/fatigue, nausea/vomiting, mucosal/cutaneous toxicities, pleural effusion and pulmonary interstitial exudation (on-target/off-tumor toxicity); reversible | Positive correlation between CAR-T cell persistence and number of Tcm | Katz et al. 2020a) |
| MSLN | NCT02159716 |
15 (n = 5, PDAC) |
1–3 × 107 or 1–3 × 108/m2; Intravenous | 28 days |
SD: 11/15 patients (28 days); 3/8 patients (follow-up, 2–3 months) PFS: 2.1 months |
Low-grade fatigue, nausea, vomiting, confusion, diarrhea, fever; 1 patient with grade 4 sepsis | Antibodies against anti-MSLN CAR-T cells | Feng et al. 2017) | |
| MSLN | NCT01897415 | 6 | 3 times weekly for 3 weeks; Intravenous | Transient (mRNA CAR-T cells) |
SD: 2 patients (3.8 and 5.4 months respectively) |
Grade ≥ 3 back pain (1) and abdominal pain (1) | Construction utilizing mRNA electroporation | Pang et al. 2021) | |
| HER-2 | NCT01935843 | 11 | 2.1 × 106/kg (range 1.4–3.8 × 106/kg); Intravenous | Up to 80 days (9/11 patient’s serum CAR transgene copy numbers were > twofold of the baseline value at first evaluation timepoint) |
PR: 1 patient (4.5 months) SD: 5 patients (4.8 months) |
Mild-to-moderate nausea/vomiting, fatigue, myalgia/arthralgia, lymphopenia; Grade 3 acute fever/chill (1) and abnormal transaminase elevation (1) | Haas et al. 2019) | ||
| PSCA | NCT02744287 | 9 | 3 + 3 cell dose escalation, 1.25 × 106–2.5 × 106/kg; Intravenous | Up to > 3 weeks |
SD: 4 patients (≥ 8 weeks) 2 minor responses (not confirmed) PD: 2 patients |
Most common AEs were fatigue and nausea | Utilization of Rim-inducible costimulatory domain (molecular safety switch) | Beatty et al. 2018; Becerra et al. 2019a) | |
| CLDN18.2 | NCT03159819 | 12 (n = 5, PDAC) | 1–5 cycles, total of 0.5–55 X 108 cells; Intravenous | NA |
CR: 1 patient PR: 3 patients SD: 5 patients PD: 2 patients PFS: 130 days |
No grade 4 AEs except for lymphopenia, neutropenia; All CRS observed were grade 1 or 2 | Berdeja et al. 2021) | ||
| EGFR and CD133 | NCT01869166 NCT02541370 | 1 |
EGFR: 2.2 × 106/kg, 2.1 × 106/kg (first and second cycle, respectively) CD133: 1.22 × 106/kg |
EGFR: Baseline levels within 2 months CD133: Baseline levels within 4.5 months |
EGFR: PR (8.5 months) CD133: PR (4.5 months) |
EGFR: Mild chills, fever, fatigue, vomiting, muscle soreness, 9-day lasting lower fever and a grade 2 skin rash CD133: Fever, chills fatigue, intermittent upper abdominal dull pain,, sporadic pinpoint hemorrhages and Grade 3 congestive skin rash | Successive administration of two different CAR-T cell products | Liu et al. 2020) | |
| CEA | NCT02850536 | 1 |
4 infusions of 1 × 1010 cells; Hepatic artery infusions |
NA | Complete metabolic response of metastatic disease (13 months) | Grade 1–3 fever, chills/rigors, tachycardia, hypotension, diarrhea, fatigue, mild abdominal distension, myalgias,,thrombocytopenia, electrolyte dysfunction and transient elevations in liver function tests | Becerra et al. 2019b) | ||
| Metastatic colorectal | TAG-72 |
C-9701 C-9702 |
10 (C-9701) 6 (C-9702) |
1 × 108 – 1 × 1010 cells; C-9701: Intravenous C-9702: Hepatic artery infusions |
C-9701: Up to 14 weeks C-9702: Up to 48 weeks |
Best response was PD |
C-9701: Chills, fever, dizziness, paresthesia, headache, tachycardia, myalgia, hypoxia, grade-3 chills (1), retinal artery occlusion (1) C-9702: Fever, abdominal pain, increased bilirubin, headache, nausea, vomiting, anemia, transient; Hypotension and mild congestive heart failure (1) |
First human clinical trials of CAR-T cells for solid tumors; IFN-α co-administration; Antibodies against TAG-72 binding domain |
Zhang et al. 2017) |
| CEA | NCT01373047 | 6 |
1 × 108 –1 × 1010 cells; Hepatic artery infusions |
NA |
SD: 1 patient (23 months) PD: 4 patients NE: 1 patient |
All patients experienced transient grade 1–2 liver enzyme elevations; Grade 3 fever and tachycardia (1), attributed to IL-2 co-administration; Grade 3 liver enzyme elevations (1) | Thistlethwaite et al. 2017) | ||
| CEA | NCT02416466 | 6 |
3 infusions of 1 × 1010 cells; Hepatic artery infusions |
NA |
SD: 3 patients mOS: 6.9 months (range 3.8–10.8 months) |
Grade 1–2 liver function test elevations, fever, hypereosinophilia, and edema; Grade 3 colitis (2), fever (2), and edema (2); Hypertensive crisis (1) | Tumoricidal synergism of SIR -Sphere brachytherapy and anti-CEA CAR-T cells | Hege et al. 2017) | |
| CEA | NCT01212887 | 14 | 1 × 109–5 × 1010 cells; Intravenous | Up to 2 weeks |
SD: 7 patients (3,7 months; range 2,7–5,1 months) PD: 7 patients |
Acute respiratory toxicity (pulmonary infiltrates, respiratory distress) in Cohort 4 patients (4). (premature termination of the trial) | On-target/off-tumor toxicity | Katz et al. 2020b) | |
| CEA | NCT02349724 | 10 | 1 × 105–1 × 108/kg; Intravenous | Up to 4–6 weeks |
SD: 7 patients PD: 2 patients NE: 1 patient |
Only grade 2 fever (2) was related to CAR-T cell therapy; 1 instance of duodenal perforation was attributed to dyspepsia | 3rd generation CAR-T cells | Sureban et al. 2019) | |
| Hepatocellular carcinoma | CD133 | NCT02541370 | 21 | 0.5 × 106—2 × 106/kg; Intravenous | Up to 12 months |
PR: 1 patient SD: 14 patients PD: 6 patients PFS: 6.8 months (range 4.3–8.4 months) mOS: 12 months (range 9.3–15.3 months) |
Nausea, anemia, thrombocytopenia, constipation, hypotension, bilirubinemia; Grade 3 anemia (2), hyperbilirubinemia (4) |
Phase II trial; Association between plasma biomarkers and outcome (PFS, OS) |
Carl et a. 2018) |
| GPC3, MSLN | NCT03198546 | 6 (n = 4, HCC) | 0.25 × 106–8.7 × 106/kg; Intravenous, Intratumor, hepatic artery infusions, intraperitoneal | NA |
CR: 1 patient (9 months) PR: 1 patient SD: 2 patients (6 months; range 3–9 months) PD: 2 patients |
Fever, fatigue | Car-T cells engineered to secrete IL-17 and CCL19 | Zhan et al. 2019) | |
| Lung (malignant pleural mesothelioma) | MSLN | NCT01355965 | 2 (MPM, PDAC) | 2 × 108 – 1 × 109 cells; Intravenous, intratumor, intraperitoneal | Transient (mRNA CAR-T cells) |
PR: 1 patient (6 month) SD: 1 patient |
Anaphylactic reaction with subsequent grade 4 cardiac arrest, respiratory failure, DIC and CRS (1); Grade 4 jejunal obstruction, grade 3 abdominal pain, and grade 2 lymphcytosis (1) | Severe anaphylactic reaction due to formation of IgE antibodies against the murine- based SS1 scFv CAR portion | Schuberth et al. 2013; Petrausch et al. 2012) |
| MSLN | NCT02414269 | 31 | 1 × 105–6 × 107/kg; Intrapleural (intracavitary and intratumoral) | NA |
Complete metabolic response: 2 patients PR: 5 patients SD: 4 patients |
Grade 1–2 toxicities; Grade 3 CRS (1) and dyspnea (1) | Infusions under image guidance by computed tomography or ultrasound | Carpenito et al. 2009; Zhang et al. 2021) | |
| EGFR | NCT03182816 | 9 | 1 × 106–3 × 106/kg; Intravenous | Up to 28 days |
PR: 1 patient (> 13 months) SD: 6 patients PD: 2 patients PFS: 7.13 months (range 2.71–17.10 months) mOS: 15.63 months (8.82–22.03 months) |
Grade 1–2 fever, chills, muscle weakness, nausea/vomiting, skin rash; Grade 3 fever (1) | piggyBac transposon system | Zhao et al. 2010) | |
| FAP | NCT01722149 | 4 | 1 × 106/kg Intrapleural | CAR-T cells detected in the blood of 1 patient | NE | Grade 2 upper respiratory infection; Grade 3 lymphopenia (1), thromboembolic event (2) (not related to CAR-T cell therapy) | Ghosn et al. 2022; Adusumilli et al. 2019) | ||
| Renal cell carcinoma | CAIX | DDHK9729/P00.0040C | 12 | 2 × 107–2 × 109 cells; Intravenous | Up to 4 weeks | NE | Grade 3–4 liver enzyme disturbances | CAIX expression on bile duct epithelium (on-target/off-tumor toxicity) | Beatty et al. 2014) |
| Breast | c-MET | NCT01837602 | 6 | 3 × 107–3 × 108 cells; Intratumor | Transient (mRNA CAR-T cells) |
SD: 1 patient PD: 2 patients Death: 3 patients |
Grade I erythema occurred at the intratumoral injection sites, myalgia/arthralgia | Teachey et al. 2016) | |
| c-MET | NCT03060356 | 7 (n = 4, BC) | 1 × 108; Intravenous | Transient (mRNA CAR-T cells) |
SD:4 patients PD:3 patients |
Grade 1–2 anemia, fatigue, malaise | Khoury et al. 2001) | ||
| Ovarian | FR-a | NCT00019136 | 14 | 3 × 109–5 × 1010 cells; Intravenous |
Up to 12 months (1); most up to 3 weeks |
PD: 14 patients | Grade 1–2 fatigue, nausea, vomiting, edema, diarrhea, bilirubinemia, leukopenia, thrombocytopenia; Grade 3–4 hypotension, dyspnea, leukopenia, rigors, sinus tachycardia, diarrhea (attributed to IL-2 administration) | Development of an inhibitory factor against CAR-T cells | Tchou et al. 2017) |
| Prostate | PSMA | BB-1ND12084 | 5 | 1 × 109–1 × 1010 cells; Intravenous | Up to 4 weeks |
PR: 3 patients NE: 2 patients |
Grade 1–2 fatigue, intermittent low-grade fevers, myalgias (due to IL-2 administration) Grade 3–4 neutropenia (5), neutropenic fever (5), thrombocytopenia (3), anemia (1), hypocalcemia (1), hypophosphatemia (1), appendicitis (1) | Inverse correlation between IL-2 levels and CAR-T cell engrafment | Slovin et al. 2022) |
| PSMA | NCT01140373 | 7 | 1 × 107 to 3 × 107/kg; Intravenous | Up to 2 weeks |
SD: 2 patients (6–16 months) PD: 2 patients NE: 3 patients |
All patients had intermittent fever spikes (up to 39 °C) | Arcangeli et al. 2020) | ||
| PSMA | NCT03089203 | 13 | 1 × 107–3 × 108/kg; Intravenous | NA |
3 patients with PSA reduction of ≥ 30%; 1 patient with PSA reduction of ≥ 98%; |
Grade ≥ 2 CRS (5), including one patients (≥ 98 PSA reduction) with grade 4 CRS, concurrent sepsis and death | Dominant-negative TFG-β receptor CAR-T cells | Chekmasova et al. 2010) | |
| PSMA | NCT04249947 | 10 | 0.25 × 106–15 × 106/kg; Intravenous | NA |
3 patients with PSA reduction of ≥ 50%; 1 patient with PSA reduction of ≥ 99%; |
Grade 3 cytopenia (6), infection (1); Grade 1–2 CRS (5); Grade ≥ 3 CRS with macrophage activation syndrome/uveitis (1) |
iCasp9-based safety switch | Owens et al. 2018) | |
| Glioblastoma | IL13Ra2 | NCT00730613 | 3 | 1 × 107–1 × 108/kg (3 infusions of 1 × 107, 5 × 107, 1 × 108/kg followed by 9 doses of 1 × 108/kg; Intracavitary via a catheter/reservoir system; Intratumor | Up to 14 weeks |
PR: 2 patients (12 months; 10–14 months) PD: 1 patient |
Grade 3 headache (2), grade 3 neurologic event (shuffling gait and tongue deviation) (1) | Morgan et al. 2012) | |
| IL13Ra2 | NCT02208362 | 1 | 2 × 106–10 × 1010; Intracavitary (6 infusions) Intraventricular (10 infusions) | Levels detectable up to 149 days | CR: 7.5 months | Grade 1–2 headaches, generalized fatigue, myalgia, olfactory auras | Vitanza et al. 2021) | ||
| HER-2 | NCT03500991 | Estimated enrollment 45 patients (early interim analysis of 3 patients) | 1 × 107 –10 × 107; (weekly infusions for 3 weeks followed by a week off) Intracavitary, intraventricular | NA | Evidence of local CNS immune activation in all patients (CXCL10 and CCL2 increase in CSF) | Mild grade 1–2 toxicities; Grade 3 headache (2), grade 3 back pain (1) | Humphrey et al. 1990) | ||
| HER-2 | NCT01109095 | 17 | 1 × 107–1 × 108/m2; Intravenous | Up to 12 weeks |
PR:1 patient (8 months) SD: 7 patients (> 6 weeks) PD: 8 patients |
NA | Brown et al. 2016) | ||
| EGFRvIII | NCT02209376 | 10 | 1.75 × 108–5 × 108 cells; Intravenous | Up to 1 month |
SD: 1 patient (> 18 months) PD: 2 patients NE: 7 patients |
Mainly grade 1–2 nervous system toxicities; Grade 3 left ventricular systolic dysfunction (1), muscle weakness (1), facial muscle weakness (1), headache (1), intracranial hemorrhage (1), seizure (2); Grade 4 cerebral edema (2) |
Brown et al. 2015) |
CR complete response, PR partial response, SD stable disease, PD progressive disease, NE not evaluable, NA not available, PFS progress free survival, mOS median overall survival, AEs adverse events, CRS cytokine release syndrome, Tcm central memory T- cells, Rim rimiducid, IFN-α interferon-alpha, IL-2 interleukin-2, IL-17 interleukin-17, TGF-β transforming growth factor beta, SIR selective internal radiation, CCL2 chemokine ligand 2, CCL19 chemokine ligand 19, CXCL10 CXC motif chemokine ligand 10, iCasp9 inducible caspase 9, CAR chimeric antigen receptor, CEA carcinoembryonic antigen, MSLN mesothelin, EGFR epidermal growth factor receptor, EGFRvIII epidermal growth factor receptor variant III, HER-2 human epidermal growth factor receptor-2, GPC3 glypican-3, PSMA prostate-specific membrane antigen, CLDN18.2 claudin, IL13RA2 interleukin 13 receptor alpha 2, PSCA prostate stem cell antigen, TAG-72 tumor-associated glycoprotein-72, FAP fibroblast activating protein, CAIX carbonic anhydrase IX, c-MET c-mesenchymal- epithelial transition factor, FR-α folate receptor alpha