Overcoming Immunotherapy Resistance in Hepatocellular Carcinoma

Each year, approximately 1,000 patients in the Netherlands are diagnosed with liver cancer. When liver cancer can no longer be treated with surgery or thermal ablation, cure is no longer possible. In recent years, immunotherapy has become increasingly important in the treatment of liver cancer. Unfortunately, the combination of immunotherapy (atezolizumab) and an anti-angiogenic agent (bevacizumab) results in a durable response in only 15-20% of patients. The aim of this study is to identify a strategy to enhance the effectiveness of immunotherapy, enabling the patient's immune system to better recognize and attack the cancer. Two recent clinical observations suggested that the immune system may be activated by external radiotherapy or radioembolization. Following these treatments, both patients unexpectedly showed regression of multiple non-irradiated liver metastases. One of these patients had initially experienced disease progression during immunotherapy, but after radiotherapy subsequently demonstrated regression of all metastatic lesions. In this clinical study (16 patients in total), we will investigate whether the immune system can be reactivated after failure of immunotherapy. Patients will be eligible for participation after disease progression during immunotherapy for liver cancer. In Group A, eight patients will receive three fractions of external radiotherapy directed at the most dominant liver lesion or an extrahepatic metastasis. In Group B, eight patients will receive radioembolization of the most dominant liver lesion. There will be no randomization. Group A will be enrolled first, and Group B will open only after completion of enrollment in Group A. The primary outcome measure is the number of patients in each group who achieve disease control at 6 months, defined as stable disease or tumor regression lasting for at least 6 months. During the study, participating patients will undergo extensive blood analyses, tumor biopsies of both treated and untreated lesions, and multiple CT scans. Through these investigations, we aim to characterize the tumor microenvironment in detail, evaluate the role of different immune cell populations, and gain a better understanding of why these treatments administered after immunotherapy failure may still be capable of reactivating the immune system.

Inclusion Criteria: * Adult individuals at least 18 years old * Unresectable multifocal or metastatic HCC, as determined by the multidisciplinary tumor board; * Subject has histologically or cytologically confirmed unresectable multifocal or metastatic HCC (all other histological types are excluded); * Child-Pugh (CP) class A (well-compensated disease) or B ≤ 7 (acceptable functional compromise); * Progressive HCC after failure of first-line atezolizumab-based systemic therapy; * Life expectancy ≥12 weeks per investigator assessment; * At least one non-targeted measurable lesion per RECIST version 1.1 (the irradiated/targeted lesion in both cohorts will not be considered as measurable); * Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1; * Agree to undergo multiple tumor biopsies, CT imaging, and blood withdrawals; * Adequate baseline laboratory results (defined as a hemoglobin ≥5.0 mmol/l, an absolute neutrophil count ≥1.5 x 109/l, platelet count ≥75 x 109/l, creatinine clearance ≥30 ml/min, bil-irubin \ 90%); * Evidence of bleeding diathesis or clinically significant coagulopathy; * Requirement for immunosuppressive doses of systemic corticosteroids (\>10 mg/day prednisone equivalents) or other systemic immunosuppressive medication.