Interventional Radiology Image-Guided Locoregional Therapies (LRTs) and Immunotherapy for the Treatment of HCC

Abstract

Image-guided locoregional therapies (LRTs) are a crucial asset in the treatment of hepatocellular carcinoma (HCC), which has proven to be characterized by an impaired antitumor immune status. LRTs not only directly destroy tumor cells but also have an immunomodulating role, altering the tumor microenvironment with potential systemic effects. Nevertheless, the immune activation against HCC induced by LRTs is not strong enough on its own to generate a systemic significant antitumor response, and it is incapable of preventing tumor recurrence. Currently, there is great interest in the possibility of combining LRTs with immunotherapy for HCC, as this combination may result in a mutually beneficial and synergistic relationship. On the one hand, immunotherapy could amplify and prolong the antitumoral immune response of LRTs, reducing recurrence cases and improving outcome. On the other hand, LTRs counteract the typical immunosuppressive HCC microenvironment and status and could therefore enhance the efficacy of immunotherapy. Here, after reviewing the current therapeutic options for HCC, we focus on LRTs, describing for each of them the technique and data on its effect on the immune system. Then, we describe the current status of immunotherapy and finally report the recently published and ongoing clinical studies testing this combination.

Rational Nanomedicine Design Enhances Clinically Physical Treatment‐Inspired or Combined Immunotherapy

“…[ 164 ] The electricity‐heat conversion principle depends on the friction motion of ions under the action of high‐frequency oscillation current, and the heat effect can make the temperature at the central region reach above 60 °C. The high temperature leads to the solidification necrosis of tumor tissues around the electrode, [ 165 ] enabling RFA to become the main ablation method for early HCC with a diameter of less than 5 cm. [ 166 , 167 ] Similar to other treatment methods, the eradication of tumor needs the participation of activated autoimmunity or combined therapy‐potentiated immunity.…”

“…[ 180 ] There is lots of evidence that the combination of locoregional treatment (LRT) and ICB can produce synergistic effects on tumor immune response. [ 165 , 181 ] Tremelimumab is a human anti‐CTLA‐4 monoclonal antibody and it can improve its efficacy by combining RFA. In the treatment of local advanced pancreatic cancer, immunotherapy combined with RFA can increase the blocking activity of the checkpoint and the presentation of antigens to the immune system.…”

Interventional oncology of liver tumors: how it all started and where are we now

“…Ablation releases tumor-associated antigens that enhance the immune response against the tumor itself with stimulation to the release of specific CD8+T cells both for HCCs and hepatic metastases, but it also releases inflammatory cytokines that stimulate an antitumor systemic immune response, further enhanced when adjuvant immunotherapy is administered after ablation (thermal ablation as endogenous in situ tumor vaccination). 119–121 This explains the phenomenon called “abscopal effect”, namely tumor regression in untreated lesions and inhibition to develop distant metastases, evidenced after distant thermal ablation. While it is not yet clear which ablative technique has the highest potential for releasing tumor antigens and creating the best immunostimulatory microenvironment, 119 a new ablative technique (histotripsy) seems to have the highest capability to produce the abscopal effect.…”

“… 119–121 This explains the phenomenon called “abscopal effect”, namely tumor regression in untreated lesions and inhibition to develop distant metastases, evidenced after distant thermal ablation. While it is not yet clear which ablative technique has the highest potential for releasing tumor antigens and creating the best immunostimulatory microenvironment, 119 a new ablative technique (histotripsy) seems to have the highest capability to produce the abscopal effect. 122 Generating short, high-amplitude micropulses of focused ultrasound, histotripsy allows to non-invasively treat tumors by cavitation, without thermal injury, inflammation and heat-sink effect and to spare collagen-based structures, like bile ducts, blood vessels, and glissonian capsule.…”

Initiative on Superselective Conventional Transarterial Chemoembolization Results (INSPIRE)

“…According to the recent update of the BCLC staging system, systemic therapy, including immune-oncology, is recommended for patients with intermediate-stage HCC harboring diffuse, infiltrative, extensive bilobar liver involvement [5]. Additionally, TACE might be combined with systemic therapy in an effort of TACE debulking, or TACE as an enhancer of immunotherapy by tumor antigen release [14]. This moving landscape calls for a clear reappraisal of what is an optimal TACE, as well as suitable identification of patients amenable to superselective TACE (ss-TACE).…”