To evaluate the efficacy and safety of oral enterobacterial capsules in patients with intermediate and advanced HCC who have progressed after treating with immune checkpoint inhibitors in combination with anti-angiogenesis targeted agents.

This is a prospective, single-center, single-arm clinical study. For those who meet the enrollment conditions, the original regimen of immune checkpoint inhibitors combined with anti-angiogenic targeted drugs will remain unchanged after enrollment.On this basis, the study subjects started oral enterobacterial capsules to see whther enterobacterial capsules could improve the efficacy of patients receiving the above treatment regimens.

Oral administration of intestinal bacteria capsules 6 capsules/day, after observing no adverse reactions, oral administration for 10 consecutive days, 6 capsules/day from the second day to the tenth day, and then discontinued to the next course of treatment.

Total course of treatment: a total of 4 courses of oral intestinal bacteria capsules, each course of oral administration for 10 days, and a course of 21 days; A course of TKI combined with immune checkpoint inhibitors treatment is 21 days until the disease progresses or intolerable toxicity and side effects appear.

Observe the metrics: Primary Clinical Endpoint - Progression-Free Survival (PFS); Secondary Clinical Endpoints - Overall Growth Phase (OS), Objective Response Rate (ORR), Duration of Response (DOR), and Disease Control Rate (DCR). The new RECIST1.1 criteria were used for the efficacy evaluation system, the CTCAE5.0 grading system was used for the evaluation of common adverse reactions during treatment, and other indicators included imaging including conventional biochemical indexes such as CT and ultrasound, as well as quality of life scores.

Inclusion Criteria:

1. Age 18-75 years old, gender is not limited;
2. Confirmed imaging or histological diagnosis of unresectable HCC, BCLC stadium B or C;
3. Clinical diagnosis of HCC progression during TKIs combined with ICIs treatment;
4. Not suitable for local ablation or chemoembolization;
5. Child-Pugh Grade A;
6. ≥ 1 measurable lesion (RECIST v1.1)
7. ECOG PS 0-1

Exclusion Criteria:

1. Usage of antibiotics within 2 weeks prior enrollment;
2. Diagnosis of immunodeficiency (e.g. HIV, immunosuppressants)
3. Patients with known history of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation;
4. Female patients who are pregnant or breastfeeding;
5. Patients with untreated acute or chronic active hepatitis B or hepatitis C infection.
6. Patients are currently undergoing clinical trials of other drugs;
7. Patients are considered by the investigator to be unsuitable for inclusion.