CARsgen Therapeutics Holdings Limited (Stock Code: 2171.HK), a company focused on innovative CAR T-cell therapies for the treatment of hematologic malignancies and solid tumors, announced the publication of two cases of long-term disease-free survival in the treatment of advanced hepatocellular carcinoma (HCC) with CARsgen’s innovative CAR-GPC3 T-cell therapy. These results were recently published in Cancer Communications as the cover story, titled “Combined local therapy and CAR-GPC3 T-cell therapy in advanced hepatocellular carcinoma: a proof-of-concept treatment strategy” https://onlinelibrary.wiley.com/doi/10.1002/cac2.12472）[1].
Hepatocellular carcinoma is one of the most common malignant tumors, with approximately 780,000 annual incidence cases globally. There is an urgent need for new therapeutic techniques and strategies to improve the prognosis of these patients. Recurrence and metastasis are the primary factors impacting HCC patients’ lives. For HCC patients with concurrent inferior vena cava tumor thrombus, treatment options are limited, and overall prognosis is poor. Even with surgical resection, the median overall survival is only 17.8 months postoperatively [2]. For those undergoing other local or systemic treatments, the median overall survival ranges from 5.9 to 15.4 months [2-4].
In May 2015, the Department of Interventional Oncology of Renji Hospital in Shanghai collaborated with CARsgen Therapeutics to initiate the first clinical study with CAR T-cell therapy targeting the GPC3 (Glypican-3) protein in advanced hepatocellular carcinoma. (Partial data from this study was published in Clin Cancer Res. 2020[5]). At the time of enrollment, two patients already presented inferior vena cava tumor thrombus, and one of them also had retroperitoneal lymph node metastasis, a particularly poor prognosis factor for the outcome. However, both patients maintained a tumor-free status during long-term follow-up after receiving a combination of local and CAR T-cell therapies. Recently, the two patients returned to Renji Hospital for a follow-up examination, which confirmed the absence of tumor recurrence. Researchers at Renji Hospital held a brief celebration event together with these two patients.
Patient 1, upon confirmed diagnosis of liver cancer, underwent two rounds of interventional therapy and one session of microwave ablation. However, his disease rapidly progressed and he developed an inferior vena cava tumor thrombus. Following localized treatments (microwave ablation and gamma knife) targeting intrahepatic recurrent tumors and the inferior vena cava tumor thrombus, the patient was enrolled in the CAR-GPC3 T-cell clinical trial. Six months later, tumor biomarkers AFP returned to normal, and imaging showed no evident active tumors. To date, the patient has remained tumor-free for over 8 years (July 2015 to August 2023). Patient 2, following liver cancer resection, experienced intrahepatic tumor recurrence. Despite multiple intensive sessions of TACE and microwave ablation, the tumor could not be effectively controlled. Multiple recurrences (greater than 6 lesions) appeared within the liver, and the patient developed retroperitoneal lymph node metastasis and inferior vena cava tumor thrombus. Through localized treatments (microwave ablation and gamma knife) addressing intrahepatic tumors, the inferior vena cava tumor thrombus, and peritoneal lymph node metastases, combined with CAR T-cell therapy, the patient has currently achieved over 7 years of tumor-free survival (July 2016 to August 2023). Meanwhile, pyrexia, fatigue, transient leukopenia, thrombocytopenia, and grade 1 cytokine release syndrome were reported during CAR-GPC3 T-cell infusions in this patient.
Throughout the follow-up period, both patients only received oral anti-hepatitis B virus medication, with no other cancer treatments administered.
Professor Bo Zhai, the principal investigator of this study and the Director of the Department of Interventional Oncology of Renji Hospital, Shanghai Jiao Tong University School of Medicine, said, “The treatment of advanced hepatocellular carcinoma has always been a great challenge, particularly for patients with inferior vena cava tumor thrombus, a poor prognosis factor. In this case report, two patients achieved long-term tumor-free survival through a combination of localized treatment and CAR T-cell therapy targeting GPC3, offering new hope for advanced hepatocellular carcinoma patients. Despite the tremendous efforts of scientists, the development of CAR T-cell therapy for solid tumors still encounter various challenges, such as the inherent physical and immune barriers of solid tumors, tumor cell heterogeneity, antigen specificity, and the potential risks associated with CAR T-cell therapy.”
Dr. Zonghai Li, Founder, Chairman of the Board, Chief Executive Officer, and Chief Scientific Officer of CARsgen, added, “With the mission of making cancer curable, CARsgen has been developing various innovative strategies for the treatment of solid tumors using CAR-T cells. For example, we firstly reported the combination of small-molecule drugs with CAR-GPC3 T-cell therapy to achieve sustained complete response in a subject with advanced hepatocellular carcinoma [6]. This time, after receiving local therapy and targeted CAR-GPC3 T-cell infusion, two patients with advanced hepatocellular carcinoma reported in the study have achieved disease-free survival for more than seven years, demonstrating that CAR T-cell therapies have the potential to cure solid tumors through innovative treatment strategies.”
References
- Shi Y, et. al. Cancer Commun (Lond). 2023 Jul 21.
- Kokudo T, et. al. Hepatology. 2017 Aug; 66(2):510-517.
- Lou J, et. al. BMC Cancer. 2019 Jul 5;19(1):668.
- Rim CH, et. al. Int J Radiat Biol. 2020 Jun; 96(6):759-766.
- Shi DH, et al. Clin Cancer Res. 2020; 26(15):3979-3989.
- Sun H, et. al. Front Immunol. 2022 Aug 17;13:963031