GPC3 CAR-T Leads to Long Term Complete Response in Hepatocellular Carcinoma

A patient with hepatocellular carcinoma (HCC) who received CARsgen Therapeutics’ CT011, an autologous chimeric antigen receptor T-cell (CAR-T) therapy that targets tumor-associated antigen Glypican-3 (GPC3), in combination with tyrosine-kinase inhibitor sorafenib, achieved a complete response (CR) in 12 months with no progression for more than 36 months, according to a case report published in Frontiers in Immunology.^1,2

After the first cycle of CT011 was administered, the patient achieved partial responses within 3 months, and after the CR was reached, it persisted for approximately 12 months. The tumor did not have progression as of the December 7, 2021, data cutoff. The combination therapy was well-tolerated, with all grade 3 and higher adverse events being hematological toxicities, including decreased white blood cell count, lymphocytopenia, thrombocytopenia, and neutropenia, which were considered expected outcomes of the conditioning regimen and were recovered from within 2 weeks of therapy.

"There is great expectation for CAR-T cells to provide curative potential in treating solid tumors,” Zonghai Li, chairman of the board, chief executive officer, and chief scientific officer, CARsgen Therapeutics, said in a statement regarding the case report’s publication.¹ “When enrolled into the clinical trial, the patient in this reported case had undergone local therapies such as TACE and interventional ablation but had not received systemic therapies such as anti-angiogenesis inhibitors. Based on the finding of our earlier preclinical research, we adopted the combination therapy of sorafenib and CT011 as treatment regimens. It was very encouraging to see that the patient achieved a complete response and a long survival period without recurrence for more than 2 years. While directly indicating that GPC3 CAR-T may be used for early-line treatment of HCC, this case report also provides new evidence supporting the adoption of CAR T-cells in the early-line treatment of other solid tumors."

The patient was a 60-year-old Asian male with hepatitis B virus (HBV)-related HCC.² He had previously undergone liver tumor resection, trans-arterial chemoembolization therapy for liver tumor, and microwave ablation therapy for lung metastasis. He was enrolled in a clinical trial for CT011 in patients with malignant tumors (NCT03302403) and underwent leukapheresis, and after 7 days began a twice-daily dosing regimen of 400 mg of sorafenib. Four cycles of CT011 were administered, with 2 infusions per cycle. Lymphodepletion was carried out with cyclophosphamide and fludarabine before each cycle. The total amount of CT011 cells infused across the 4 cycles was 4×10⁹.

The patient did not experience any treatment-related adverse events that were deemed serious, nor did he experience neurotoxicity or infusion reactions. Grade 1 and 2 treatment-related adverse events included cytokine release syndrome, anemia, chills, hypotension, pyrexia, hypoalbuminemia, hypokalemia, and prolonged activated partial thromboplastin time.

“To the best of our knowledge, this is the first reported case with a CR after the combination therapy of CAR-T cells with tyrosine kinase inhibitors,” first author Hongwei Sun and colleagues wrote.² “The clinical outcome demonstrated that the combination therapy of CAR-GPC3 T-cell and sorafenib may be a new promising approach for GPC3+ aHCC patients.”

The investigators concluded that an additional study will be necessary to further confirm the safety and efficacy of CT011 and sorafenib combination therapy.

REFERENCES

1. Case report of long term complete response in hepatocellular carcinoma to CARsgen's GPC3 CAR T cells (CT011) published in Frontiers in Immunology. News release. CARsgen Therapeutics Holdings Limited. August 18, 2022. https://www.carsgen.com/en/media/news/case-report-of-long-term-complete-response-in-hepatocellular-carcinoma-to-carsgen-s-gpc3-car-t-cells-ct011-published-in-frontiers-in-immunology/ 

2. Sun H, Xing C, Jiang S, et al. Long term complete response of advanced hepatocellular carcinoma to glypican-3 specific chimeric antigen receptor T-Cells plus sorafenib, a case report. Front Immunol. Published online August 17, 2022. doi:10.3389/fimmu.2022.963031