Interventional Oncology Meets Immuno-oncology: Combination Therapies for Hepatocellular Carcinoma

Abstract

The management of hepatocellular carcinoma (HCC) is undergoing transformational changes due to the emergence of various novel immunotherapies and their combination with image-guided locoregional therapies. In this setting, immunotherapy is expected to become one of the standards of care in both neoadjuvant and adjuvant settings across all disease stages of HCC. Currently, more than 50 ongoing prospective clinical trials are investigating various end points for the combination of immunotherapy with both percutaneous and catheter-directed therapies. This review will outline essential tumor microenvironment mechanisms responsible for disease evolution and therapy resistance, discuss the rationale for combining locoregional therapy with immunotherapy, summarize ongoing clinical trials, and report on developing imaging end points and novel biomarkers that are relevant to both diagnostic and interventional radiologists participating in the management of HCC.

Graphical abstract

Figure 1:

Chart shows the spectrum of the immune status of the hepatocellular carcinoma (HCC) tumor microenvironment, which can be described as expressing a “hot” or “cold” phenotype. Immuno-evasive tumors are characterized by the presence of immunosuppressive cell populations and genotypic pathways that prevent the infiltration of cytotoxic T cells. While some HCCs indeed demonstrate the presence of cytotoxic T cells, immune-exhausted tumors exhibit molecular drivers such as transforming growth factor beta (TGF-β) and immunosuppressive cell populations, rendering these T cells inactive. The immuno-permissive class, characterized by the presence of activated immune cells and inflammatory cytokines, is often encountered in responders to immunotherapy. IFN-γ = interferon gamma, MDSCs = myelodysplastic stem cells, PD-1 = programmed cell death protein 1, PD-L1 = programmed cell death ligand 1, PTK-2 = protein tyrosine kinase 2, Tregs = regulatory T cells.

Figure 2:

Diagram summarizes the synergistic relationship between locoregional therapy and immunotherapy. (1) The tumor undergoes either ablation or chemoembolization, resulting in direct tumor cell death and the subsequent disruption of the tumor microenvironment and the provision of tumor neoantigens for antigen-presenting cells. (2) The antigen-presenting cells travel to lymphatic structures to activate naive cytotoxic T cells. (3) The activated T cells can then attack tumor cells with supplemental immunotherapy to synergistically optimize antitumor response. (4) Furthermore, the combination of immunotherapy with activated T cells may increase the efficacy of immunotherapy on nonablated or nonembolized tumors. CLTA4 = cytotoxic T-lymphocyte–associated protein 4, PD-1 = programmed cell death protein 1, PD-L1 = programmed cell death ligand 1, TCR = T-cell receptor, VEGF = vascular endothelial growth factor.

Figure 3:

Chart shows various locoregional therapy (LRT) plus immunotherapy treatment regimens that may be considered in future trials to optimize the synergistic antitumor activity between both treatment strategies. The sequential schedule (adjuvant) is the initiation of one cycle of locoregional therapy followed by immunotherapy without additional locoregional therapy planned. The interrupted schedule (adjuvant and neoadjuvant) is the administration of a priming dose of immunotherapy followed by locoregional therapy. The patient will then continue systemic therapy without additional locoregional therapy planned. The continuous schedule (overlapping) is the initiation of immunotherapy, and the patient may then be treated with several locoregional therapy sessions depending on recurrence while continuing systemic therapy. IRE = irreversible electroporation, TACE= transarterial chemoembolization, TME = tumor microenvironment. Figure outline adapted, with permission, from reference .

Figure 4:

(A) Coronal and (B) axial contrast-enhanced MRI scans of the abdomen in a 74-year-old male patient show left liver–predominant biopsy-proven poorly differentiated hepatocellular carcinoma. Portal venous thrombus and a left retroperitoneal nodule concerning for metastasis (arrow) are also seen. The patient underwent transarterial radioembolization with yttrium 90. (C) Coronal and (D) axial follow-up MRI scans demonstrate near-complete resolution of the hepatic primary along with resolution of the metastatic retroperitoneal nodule, indicative of abscopal reaction (arrow). The patient became a candidate for and successfully underwent left hepatectomy for residual disease.

Figure 5:

(A) Contrast-enhanced abdominal MRI scan in a 72-year-old male patient with hepatitis C and alcohol-induced cirrhosis shows two arterially enhancing lesions (arrows) on axial section with portal venous washout (not shown), concordant with Liver Imaging Reporting and Data System 5 (LR 5) lesions smaller than 3.0 cm. (B) Axial CT image acquired during CT-guided microwave ablation shows the ablation probes positioned within the tumors (arrows). (C) Follow-up axial abdominal MRI scan demonstrates absence of enhancement within the ablation zone (arrows) consistent with nonviable tumor; (D) however, surveillance MRI scan shows that the patient developed two new arterially enhancing lesions (arrows) with portal venous washout (not shown) larger than 3.0 cm, both indicative of LR 5 lesions. The patient underwent transarterial chemoembolization of both new lesions, with (E) transcatheter subtraction angiogram demonstrating arterial blush of the tumor in comparison with the liver background (arrow). (F) Subsequent abdominal axial MRI scan demonstrates absence of enhancement within the tumor (arrows), indicative of nonviable tumor. The patient eventually developed additional lesions requiring initiation of bevacizumab and atezolizumab. The patient’s disease remained stable up until his death, likely from sequelae of decompensated cirrhosis.

Figure 6:

(A, B) Axial abdominal MRI scans in a 65-year-old female patient with hepatitis C–induced cirrhosis decompensated by hepatocellular carcinoma show (A) an arterially enhancing lesion with portal venous washout with (B) pseudocapsule appearance consistent with Liver Imaging Reporting and Data System 5 lesion larger than 3.0 cm in segment IVb (arrows). (C–E) After the patient underwent conventional transarterial chemoembolization (with ethiodized oil) of this lesion, axial sections from a subsequent MRI examination demonstrate (C) involution of the lesion, along with lack of enhancement (arrow) indicative of no residual tumor; however, (D) a new arterially enhancing lesion with (E) restricted diffusion smaller than 0.3 cm was discovered, concerning for recurrent viable tumor (arrows). (F) Axial CT image shows gas formation during active hyperthermal ablation at the distal end of the probe (arrow) when the patient underwent CT-guided microwave ablation. (G–I) Axial sections from a subsequent MRI examination demonstrate lack of enhancement within the ablation zone. Notably, the presence of postprocedural hemorrhagic products at noncontrast T1-weighted MRI (not shown) make it critical to confirm on enhancement subtraction images that any signal on the (G) contrast-enhanced MRI scan is attributable to true enhancement within the ablation zone (arrow), which could reflect recurrence. Further follow-up images show (H) a new large central arterially enhancing lesion (arrow) with (I) washout overlying the portal vein (arrow), consistent with tumor-in-vein or macrovascular invasion, a poor prognostic indicator requiring the patient to undergo atezolizumab and bevacizumab. The patient eventually died of ascending cholangitis complicated by Klebsiella bacteremia likely attributable to biliary obstruction.

Figure 7:

(A, B) Initial multiphase axial CT images in a 65-year-old male patient with presumed metabolic dysfunction–associated fatty liver disease–induced cirrhosis decompensated by biopsy-proven moderately differentiated hepatocellular carcinoma show a central hepatic mass with (A) heterogeneous arterial enhancement and (B) portal venous washout consistent with Liver Imaging Reporting and Data System 5 (arrows). The patient underwent repeated conventional transarterial chemoembolization procedures with ethiodized oil; however, despite multiple procedures, (C, D) axial sections from a follow-up abdominal MRI examination show persistent arterial enhancement and tumor size indicative of viable tumor with extension into the portal veins, hepatic veins, and inferior vena cava (arrows). The patient was initiated on atezolizumab and bevacizumab. (E, F) Axial sections from subsequent MRI examinations demonstrate decrease in size of tumor burden along with decreased arterial enhancement indicative of tumor response (arrows). The tumor venous thrombus eventually progressed, and the patient is currently undergoing a new clinical trial treatment regimen.

Figure 8:

(A, B) Baseline axial abdominal MRI scans in a 76-year-old male patient with hepatitis C–induced cirrhosis complicated by hepatocellular carcinoma show (A) an arterially enhancing lesion in segment VIII (arrow), with (B) washout and pseudocapsule on portal venous phase image (arrow) consistent with a Liver Imaging Reporting and Data System 5 (LR 5) lesion. (C) Axial chest CT image shows pulmonary nodules concerning for metastatic disease (arrowheads). The patient underwent systemic therapy with atezolizumab and bevacizumab. The patient’s initial LR 5 lesion (arrows) decreased in size and degree of enhancement over the course of (D, E, G, H) two subsequent surveillance abdominal MRI examinations. (F, I) Tandem surveillance chest CT examinations demonstrate resolution of the patient’s initial pulmonary nodules (arrowheads). (Findings are consistent with partial response as per immune Response Evaluation Criteria in Solid Tumors.)

Figure 9:

Axial images in a 61-year-old female patient without history of underlying liver disease presented with multifocal hepatocellular carcinoma with peritoneal metastases at abdominal CT (not shown) with a serum α-fetoprotein level of 404 584 ng/mL. The patient was started on sorafenib; however, due to bowel perforation, systemic chemotherapy was halted. The patient was started on the programmed cell death protein 1, or PD-1, inhibitor nivolumab. (A) Baseline abdominal MRI scan acquired before first dose of nivolumab shows multiple arterial-enhancing lesions (arrows). Subsequent follow-up images from (B) CT at 6 months, (C) CT at 12 months, (D) MRI at 24 months, (E) MRI at 3 years, and (F) MRI at 5 years show decrease in size of the intrahepatic lesions along with complete loss of arterial enhancement (arrows), representing nonviable tumor. The patient’s peritoneal metastases also resolved (not shown), consistent with complete response per modified Response Evaluation Criteria in Solid Tumors, or mRECIST. The patient currently remains on immunotherapy and maintains negligible α-fetoprotein levels.

Figure 10:

Diagram shows various tumor response types observed in patients undergoing immunotherapy. In addition to the classic appearance of decrease in tumor size indicative of tumor response, additional atypical response patterns can be observed upon the initiation of immunotherapy. To avoid inaccurate conclusions and improper treatment regimen changes, radiologists must be aware of these infrequent phenomena and the clinical implications behind them.