Purpose: Our preclinical studies demonstrated the potential of chimeric antigen receptor (CAR)-glypican-3 (GPC3) T-cell therapy for hepatocellular carcinoma (HCC). We report herein the first published results of CAR-GPC3 T-cell therapy for HCC. Patients and Methods: In two prospective phase I studies, adult patients with advanced GPC3 þ HCC (Child-Pugh A) received autologous CAR-GPC3 T-cell therapy following cyclophosphamide-and fludarabine-induced lymphodepletion. The primary objective was to assess the treatment's safety. Adverse events were graded using the Common Terminology Criteria for Adverse Events (version 4.03). Tumor responses were evaluated using the RECIST (version 1.1). Results: A total of 13 patients received a median of 19.9 Â 10 8 CAR-GPC3 T cells by a data cutoff date of July 24, 2019. We observed pyrexia, decreased lymphocyte count, and cytokine release syndrome (CRS) in 13, 12, and nine patients, respectively. CRS (grade 1/2) was reversible in eight patients. One patient experienced grade 5 CRS. No patients had grade 3/4 neurotoxicity. The overall survival rates at 3 years, 1 year, and 6 months were 10.5%, 42.0%, and 50.3%, respectively, according to the Kaplan-Meier method. We confirmed two partial responses. One patient with sustained stable disease was alive after 44.2 months. CAR T-cell expansion tended to be positively associated with tumor response. Conclusions: This report demonstrated the initial safety profile of CAR-GPC3 T-cell therapy. We observed early signs of antitumor activity of CAR-GPC3 T cells in patients with advanced HCC.

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3049 Background: HCC was commonly diagnosed and identified as leading causes of cancer death in China. Using a 10% cutoff score, GPC3 was detected in 63.6% of HCCs. Safety and preliminary efficacy of a GPC3 CAR-T was evaluated in 13 Chinese patients (pts) with r/r GPC3+ HCC in a Phase I trial. Methods: Pts between 18 and 70 yrs old with histopathological confirmed r/r GPC3+ HCC, Child-Pugh score≤B7, ECOG≤1, lymphocyte ≥ □0.7 x109, post-transduction positive T cells □ ≥30%, amplification by α CD3/CD28 ≥5 □, and without ascites and HIV infection were enrolled. Eligible pts undergo leukapheresis or whole blood colletion, which further developed into GPC3 CAR-T via lentiviral transduction. Standard release tests were conducted before administering GPC3 CAR-T in pts. Adverse events were graded per NCI CTCAE v.4.03. Efficacy was evaluated per modified RECIST (mRECIST). Results: All 13 pts, who received at least one infusion of GPC3 CAR-T, tolerated the treatment well. No dose-limiting toxicity (DLT) was identified, and only one SAE of grade 3 fever was reported. Preliminary analysis compared the clinical outcomes in pts who received GPC3 CAR-T without lymphodepleting conditioning (LDC) (Group A) vs. with LDC (Group B) at baseline. In Group A (N = 5), all pts developed progressive disease (PD) shortly after received a total infusion of GPC3 CAR-T ranging from 0.92x107 to 8.72 x107 cells/kg. In Group B (N = 8), following the LDC with fludarabine and cyclophosphamide, pts received a total infusion of GPC3 CAR-T ranging from 0.013x107 to 14.68 x107 cells/kg. Except two non-evaluable pts, the best response for the rest 6 pts are 1 PR, 3 SD, 2 PD. As of Feb 1, 2017, the PR pt remains alive for 385 days; 2 SD pts remain alive for 384 and 562 days, respectively; and one SD deceased at 108 days. Also worth to mention, one pt in Group A decided to remain on the study after PD, further received a total of 6.23 x107cells/kg infusions following a LDC given around Day 150, remains stable for 571 days as of Feb 1, 2017. Conclusions: Phase I trial shows GPC3 CAR-T is feasible and safe for Chinese pts with r/r GPC3+ HCC, and holds promising antitumor potential when LDC is applied along with GPC3 CAR-T. Clinical trial information: NCT02395250.

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