Cancer Newsletter: Breakthrough! The Renji Hospital team used CAR-T cells to achieve clinical cure for two patients with advanced liver cancer

Liver cancer is a heavy burden for Chinese people.

Data released by the International Agency for Research on Cancer (IARC) last year showed that in China, there are over 410,000 new cases of liver cancer and over 390,000 deaths due to liver cancer each year, accounting for 45.3% and 47.1% of the global total, respectively. What’s even more alarming is that the 5-year survival rate for liver cancer patients in China is only 12.1%.

For patients with liver cancer combined with inferior vena cava tumor thrombus (IVCTT), not only do they lack effective treatment options, but their prognosis is extremely poor. Research has shown that the median overall survival after surgery for such patients is only 17.76 months, while for those receiving other local or systemic treatments, the median overall survival is only 5.88 to 15.36 months. Therefore, new treatment strategies are urgently needed to improve the prognosis of these patients.

Recently, a research team led by Zhai Bo from Renji Hospital, affiliated with Shanghai Jiao Tong University School of Medicine, published a groundbreaking research paper as the cover article in the prestigious journal “Cancer Communications”.

Two patients with recurrent advanced liver cancer, after receiving local treatments (microwave ablation and gamma knife) to control intrahepatic tumors, inferior vena cava tumor thrombus, and metastases, received targeted GPC3 CAR-T cell (CAR-GPC3 T cell) therapy. Both patients ultimately achieved a disease-free survival of over 5 years and an overall survival of over 8 years, achieving clinical cure.

GPC3 (Glypican-3) is highly expressed on the surface of liver cancer cells, and the higher the level of GPC3 expression, the poorer the prognosis for liver cancer patients.

Research has also found that the expression levels of GPC3 are relatively low in other tissues or organs. Therefore, GPC3 has been identified as a potential target for the prognosis and treatment of liver cancer.

As early as 2015, the Interventional Oncology Department of Renji Hospital began exploring the use of targeted CAR-GPC3 T cell therapy for liver cancer and initiated the world’s first clinical trial. These two patients were enrolled at that time, and we will now look at the treatment history of these two patients one by one.

The first patient is a 50-year-old male with hepatitis B-related cirrhosis, diagnosed with stage Ib hepatocellular carcinoma in December 2014. After two transarterial chemoembolization (TACE) treatments, the patient’s condition achieved partial relief, and he underwent microwave ablation (MWA) in March 2015.

Unfortunately, the patient’s condition progressed rapidly, and he developed inferior vena cava tumor thrombus within 6 weeks after undergoing microwave ablation. Due to economic reasons, the patient gave up systemic treatment and voluntarily joined the clinical trial initiated by Zhai Bo’s team (NCT02395250).

After enrollment, the doctors used microwave ablation to treat the liver lesions and gamma knife to treat the inferior vena cava tumor thrombus. Subsequently, the patient received autologous CAR-GPC3 T cell therapy.

It is gratifying that the alpha-fetoprotein (AFP) levels of this patient rapidly decreased from 1210 ng/mL on the 14th day to 121 ng/mL and gradually returned to normal range within the following two months. After using CAR-GPC3 T cells, the patient did not receive any other treatment. Nevertheless, this patient has been free of cancer signs for over 5 years and has a total survival time of over 8 years. It is worth mentioning that no treatment-related toxic reactions were observed in the major organs of this patient related to CAR-GPC3 T cell therapy.

The second patient is a 54-year-old male with hepatitis B-related cirrhosis, diagnosed with stage Ib liver cancer, and underwent surgical resection treatment in December 2014.

After 6 weeks of surgery, the tumor relapsed. From February to June 2015, the patient underwent one hepatic artery chemotherapy embolization and two microwave ablation treatments. Unfortunately, these treatments did not control the tumor, and by July 2015, magnetic resonance imaging (MRI) showed rapid progression of the disease, with liver recurrence, inferior vena cava cancer thrombus, and retroperitoneal lymph node metastasis.

In August 2015, the patient received gamma knife treatment for inferior vena cava cancer thrombus; in October of the same year, he underwent two microwave ablations to treat recurrent liver tumors. Eventually, the patient also voluntarily joined a clinical trial and received autologous CAR-GPC3 T cell therapy.

Like the first patient, this patient also remained disease-free for more than 5 years and had a total survival time of more than 8 years without receiving any further anti-cancer treatment. As for the adverse reactions of CAR-GPC3 T cell therapy, only fever, fatigue, transient leukopenia, thrombocytopenia, and grade 1 cytokine release syndrome occurred during infusion. In the last telephone follow-up in March 2023, this patient’s physical condition was still good.

Treatment of the second patient:

The treatment outcomes of the two patients mentioned above are encouraging.

It is well known that although CAR-T cells have rewritten the treatment paradigm for hematological malignancies, there are few successful cases of CAR-T cell therapy for solid tumors. There are many reasons that limit the efficacy of CAR-T cell therapy for solid tumors, among which the most critical are the immunosuppressive microenvironment of tumors and the difficulty of T cells infiltrating tumors.

In this study, the team led by Dr. Zhai first used a local treatment plan to clear the radiologically visible tumor lesions, and then applied CAR-T cells, effectively solving the adverse effects of the tumor microenvironment on CAR-T cells. More importantly, these two successful cases also verified a hypothesis – CAR-T cells can clear radiologically invisible lesions and circulating tumor cells, thereby achieving the goal of inhibiting tumor recurrence.

If the above hypothesis can be confirmed in larger-scale clinical trials, it will have a significant impact on the treatment of solid tumors.

Reference:

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[2].Zeng H, Chen W, Zheng R, et al. Changing cancer survival in China during 2003-15: a pooled analysis of 17 population-based cancer registries. Lancet Glob Health. 2018;6(5):e555-e567. doi:10.1016/S2214-109X(18)30127-X

[3].Kokudo T, Hasegawa K, Matsuyama Y, et al. Liver resection for hepatocellular carcinoma associated with hepatic vein invasion: A Japanese nationwide survey. Hepatology. 2017;66(2):510-517. doi:10.1002/hep.29225

[4].Lou J, Li Y, Liang K, et al. Hypofractionated radiotherapy as a salvage treatment for recurrent hepatocellular carcinoma with inferior vena cava/right atrium tumor thrombus: a multi-center analysis. BMC Cancer. 2019;19(1):668. Published 2019 Jul 5. doi:10.1186/s12885-019-5870-3

[5].Rim CH, Jeong BK, Kim TH, et al. Effectiveness and feasibility of external beam radiotherapy for hepatocellular carcinoma with inferior vena cava and/or right atrium involvement: a multicenter trial in Korea (KROG 17-10). Int J Radiat Biol. 2020;96(6):759-766. doi:10.1080/09553002.2020.1721607

[6].Shi Y, Shi D, Chi J, et al. Combined local therapy and CAR-GPC3 T-cell therapy in advanced hepatocellular carcinoma: a proof-of-concept treatment strategy. Cancer Commun (Lond). 2023;43(9):1064-1068. doi:10.1002/cac2.12472

[7].Shi D, Shi Y, Kaseb AO, et al. Chimeric Antigen Receptor-Glypican-3 T-Cell Therapy for Advanced Hepatocellular Carcinoma: Results of Phase I Trials. Clin Cancer Res. 2020;26(15):3979-3989. doi:10.1158/1078-0432.CCR-19-3259