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.
Materials and Methods: In two prospective phase 1 studies, adult patients with advanced GPC3+ HCC (Child-Pugh A) received autologous CAR-GPC3 T-cell therapy following cyclophosphamide- and fludarabine-induced lymphodepletion. The primary objective was to assess the treatment9s safety. Adverse events were graded using the Common Terminology Criteria for Adverse Events (version 4.03). Tumor responses were evaluated using the Response Evaluation Criteria in Solid Tumors (version 1.1). Results: A total of 13 patients received a median of 19.9 × 108 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 9 patients, respectively. CRS (grade 1/2) was reversible in 8 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.

/pdf/chimeric-antigen-receptor-glypican-3-t-cell-therapy-for-2qbrbo3fah.pdf

Chimeric Antigen Receptor-Glypican-3 T-Cell Therapy for Advanced Hepatocellular Carcinoma: Results of Phase I Trials

The past decade has witnessed significant advances in the systemic treatment of advanced hepatocellular carcinoma (HCC). Nevertheless, the newly developed treatment strategies have not achieved universal success and HCC patients frequently exhibit therapeutic resistance to these therapies. Precision treatment represents a paradigm shift in cancer treatment in recent years. This approach utilizes the unique molecular characteristics of individual patient to personalize treatment modalities, aiming to maximize therapeutic efficacy while minimizing side effects. Although precision treatment has shown significant success in multiple cancer types, its application in HCC remains in its infancy. In this review, we discuss key aspects of precision treatment in HCC, including therapeutic biomarkers, molecular classifications, and the heterogeneity of the tumor microenvironment. We also propose future directions, ranging from revolutionizing current treatment methodologies to personalizing therapy through functional assays, which will accelerate the next phase of advancements in this area. 

Precision treatment in advanced hepatocellular carcinoma.

Recent advances in systemic therapy for hepatocellular carcinoma (HCC) have led to debates about the feasibility of combination therapies, such as systemic therapy combined with surgery or transarterial chemoembolization, for patients with advanced HCC. However, a lack of consensus on the oncological resectability criteria has hindered discussions of “conversion therapy” and the optimal management in patients with HCC. To address this issue, the Japan Liver Cancer Association (JLCA) and the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS) established a working group and discussed the concept of borderline resectable HCC. Herein, we present a consensus statement from this expert panel on the resectability criteria for HCC from the oncological standpoint under the assumption of technically and liver-functionally resectable situations. The criteria for oncological resectability in HCC are classified into three grades: resectable, representing an oncological status for which surgery alone may be expected to offer clearly better survival outcomes as compared with other treatments; borderline resectable 1, representing an oncological status for which surgical intervention as a part of multidisciplinary treatment may be expected to offer survival benefit; and borderline resectable 2, representing an oncological status for which the efficacy of surgery is uncertain and the indication for surgery should be determined carefully under the standard multidisciplinary treatment. These criteria aim to provide a common language for discussing and analyzing the treatment strategies for advanced HCC. It is also expected that these criteria will be optimized, modified, and updated based on further advancements in systemic therapies and future validation studies.

Oncological Resectability Criteria for Hepatocellular Carcinoma in the Era of Novel Systemic Therapies: The Japan Liver Cancer Association and Japanese Society of Hepato-Biliary-Pancreatic Surgery Expert Consensus Statement 2023

Immunosuppression caused by incomplete radiofrequency ablation (iRFA) is a crucial factor affecting the effectiveness of RFA for solid tumors. However, little is known about the changes iRFA induces in the tumor immune microenvironment (TIME) of hepatocellular carcinoma (HCC), the primary application area for RFA. In this study, we found iRFA promotes a suppressive TIME in residual HCC tumors, characterized by M2 macrophage polarization, inhibited antigen presentation by dendritic cells (DCs), and reduced infiltration of cytotoxic T lymphocytes (CTLs). Interestingly, the STING agonist MSA-2 was able to reorganize M2-like tumor-promoting macrophages into M1-like anti-tumor states and enhance antigen presentation by DCs. To optimize the therapeutic effect of MSA-2, we used a calcium ion (Ca2+) responsive sodium alginate (ALG) as a carrier, forming an injectable hydrogel named ALG@MSA-2. This hydrogel can change from liquid to gel, maintaining continuous drug release in situ. Our results suggested that ALG@MSA-2 effectively activated anti-tumor immunity, as manifested by increased M1-like macrophage polarization, enhanced antigen presentation by DCs, increased CTL infiltration, and inhibited residual tumor growth. ALG@MSA-2 also resulted in a complete regression of contralateral tumors and widespread liver metastases in vivo. In addition, the excellent biosafety of ALG@MSA-2 was also proved by blood biochemical analysis and body weight changes in mice. In summary, this study demonstrated that the immune cascade of ALG@MSA-2 mediated the STING pathway activation and promoted a favorable TIME which might provide novel insights for the RFA treatment of HCC. 

STING agonist-based hydrogel enhances immune activation in synergy with radiofrequency ablation for hepatocellular carcinoma treatment.

Objective. To investigate the clinical effect of iodine-125 seed implantation combined with chemotherapy in patients with primary liver cancer and the effect on peripheral blood Th1/Th2 cells. Methods. A total of 136 patients with primary liver cancer from April 2017 to June 2018 were selected as subjects and randomly divided into the control group and observation group with 68 cases in each group. The control group was treated with chemotherapy, and the observation group was treated with iodine-125 seed implantation on the basis of the control group. After 3 months of treatment, the curative effect was investigated. Serum tumor markers, peripheral blood Th1/Th2 cells, and side effects and recurrence rate were compared between the two groups. Results. The levels of serum tumor markers in both groups at 3 months after treatment were lower than before treatment ( ). Three months after treatment, the levels of tumor markers AFP, AFP-L3, and GP73 in the observation group were 14.61 ± 3.49 μg/L, 3.29 ± 0.41 ng/mL, and 51.24 ± 4.51 μg/L, respectively, which were lower than those in the control group, 32.53 ± 4.59 μg/L, 5.63 ± 0.63 ng/mL, and 71.52 ± 6.05 μg/L ( ). At 3 months after treatment, the level of including interleukin-2 (IL-2) and tumor necrosis factor-α (TNF-α) in Th1 cells of the observation group was higher than that of the control group ( ), whereas the levels of IL-4, IL-6, and IL-10 in Th2 cells were lower than those in the control group ( ). There was no statistical significance in the incidence of leukopenia, thrombocytopenia, and gastrointestinal reactions between the two groups ( ). The recurrence rate of the observation group at 12, 24, and 36 months after treatment was lower than that of the control group ( ). Conclusion. Iodine-125 seed implantation combined with chemotherapy in patients with primary liver cancer can reduce the level of serum tumor markers, improve the level of peripheral blood Th1/Th2 cells, and reduce the recurrence rate of patients without increasing the incidence of side effects, which is worthy of promoting the application of iodine-125 seed implantation.

/pdf/clinical-effect-of-iodine-125-seed-implantation-in-patients-2wuv0p3wxp.pdf

Clinical Effect of Iodine-125 Seed Implantation in Patients with Primary Liver Cancer and Its Effect on Th1/Th2 Cells in Peripheral Blood.

Background: Primary liver cancer, around 75%–85% are hepatocellular carcinoma in China, is the fourth most common malignancy and the second leading cause of tumor-related death, thereby posing a significant threat to the life and health of the Chinese people. 

Summary: Since the publication of Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China in June 2017, which were updated by the National Health Commission in December 2019, additional high-quality evidence has emerged from researchers worldwide regarding the diagnosis, staging, and treatment of liver cancer, that requires the guidelines to be updated again. The new edition (2022 Edition) was written by more than 100 experts in the field of liver cancer in China, which not only reflects the real-world situation in China, but also may re-shape the nationwide diagnosis and treatment of liver cancer. 

Key Messages: The new guideline aims to encourage the implementation of evidence-based practice, and improve the national average five-year survival rate for patients with liver cancer, as proposed in the "Health China 2030 Blueprint."


/pdf/guidelines-for-the-diagnosis-and-treatment-of-primary-liver-2y5hxs3l.pdf

Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2022 Edition)


 This study aimed to make a comprehensive, nationwide survey of supportive care for cancer patients in China. Two sets of questionnaires, one for medical professionals and one for patients, were distributed. Responses were received from 12,686 medical care personnel and 11,172 patients or their family representatives from 34 provinces. It was found that only about one-fourth of caregivers felt they had much knowledge about oncology supportive care, and nearly 10% admitted to having little or no knowledge. Multidisciplinary teams for supportive care were more often available in tertiary hospitals (19.9%) than in non-tertiary hospitals (15.4%) (p < 0.05). Pain was the most common patient concern; however, pain treatment was only the fifth most common therapy administered by health care providers. Patient concerns were more often subjective (pain, economic burden, appearance, and sexual dysfunction), whereas caregiver treatments were more often directed at objective concerns (nutrition and adverse reactions to treatment regimens). Patients reported that they received no guidance or guidance only when they proposed it for psychological (25%), physical exercise (15%), nutrition (40%), or spiritual (40%-65%) needs. We conclude that the concept of supportive care is widely accepted and implemented throughout China. However, gaps exist in caregiver knowledge about supportive oncology care, the use of multidisciplinary teams, especially in non-tertiary hospitals, and the interventions between what caregivers give and what patients subjectively need. Improvements in caregiver education in supportive oncology care and the delivery of care are needed.

Where are we and where to go for supportive cancer care in China? A national survey of patients and healthcare providers

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Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2022 Edition)

Where are we and where to go for supportive cancer care in China? A national survey of patients and healthcare providers