This article is sponsored by Guerbet. immunotherapy
Preliminary evidence suggests that combining conventional transarterial chemoembolization (cTACE) with immunotherapy could be beneficial to patients with unresectable liver cancer, writes Rafael Duran. He highlights the role of Vectorio (Guerbet) in standardising the cTACE technique, which he says “is needed for better reproducibility”, and explains how immunotherapy could be given systematically, through locoregional delivery within the Lipiodol-based emulsion, or injected intratumourally. He urges interventional oncologists to watch this space, as he predicts that combined cTACE and immunotherapy will become an increasingly common treatment approach for hepatocellular carcinoma (HCC) patients.
cTACE is the most widely used treatment for unresectable HCC, and has been increasingly utilised in patients with liver metastases. As opposed to surgery, which completely removes the tumour, cTACE achieves tumor cell death in situ. Thus, cTACE-induced necrosis may unmask to the immune system previously shielded tumour antigens and induce antigenspecific T cell responses. cTACE can trigger a cascade of inflammatory and immune responses, induce systemic changes in the levels of cytokines and chemokines, and, notably, has a profound influence on T cell repertoire.
Ayaru and colleagues demonstrated that cTACE could uncover tumour-associated antigens (TAAs), such as alpha-fetoprotein (AFP), and elicit AFP-specific CD4+ T cell responses. Flecken and colleagues showed that the detection of TAAs by CD8+ cytotoxic T cells was increased following cTACE when compared to treatment-naïve HCC patients. A seminal study was conducted by Mizukoshi et al on immune responses in HCC patients treated with several liver-directed locoregional therapies. All the patients demonstrated an increased frequency of TAA specific T cells post therapy, and, intriguingly, T cells from some patients also exhibited novel recognition of TAA peptides that were not recognised prior to treatment, underscoring the importance of these therapies in inducing and enhancing tumour specific T cell responses.
Upon the application of immune checkpoint inhibitors, not only did the number of TAA-specific T cells significantly increase, but also their production of cytokines, suggesting that a combination with immunotherapy is beneficial. In another study by Liao and colleagues, type 17 helper T cells (Th17) cells, which are known to play an important role in inflammation and autoimmunity, were significantly increased in HCC patients treated with cTACE. Interestingly, this increased frequency of circulating Th17 cells following cTACE was predictive of better patient outcomes (improved survival and longer time to progression). Importantly, cTACE is able to significantly decrease the percentage of regulatory T cells (Tregs), which are known to correlate with disease stage (the more advanced disease stage, the more Tregs) and progression, and worse survival outcomes, as they dampen the effector T cell responses against tumours and promote an immunosuppressive tumour microenvironment (Li et al; Liao et al).
Although preliminary, these data highlight the rationale of combining cTACE with immunotherapy. Many trials are ongoing that combine cTACE with systematically delivered immunotherapies to maximise the anticancer efficacy of both therapies. Immunotherapy could be delivered locoregionally within the Lipiodol-based emulsion (i.e. replacing the chemotherapeutic drug or in combination with it), or injected intratumorally. More studies employing combinatorial approaches of cTACE and immunotherapy are expected, and further standardisation of the cTACE technique is needed for better reproducibility. Vectorio will help in the standardisation of the technique by decreasing the current heterogeneity in practices among interventional radiologists. The preparation of the water-in-oil emulsion is improved, and, thus, should be more densely retained within the tumours than the alternative oil-in-water emulsion. For this, it is crucial to have a volume of Lipiodol that is double the volume of the cytotoxic drug, and to adequately mix the chemotherapy with Lipiodol with at least 20 back and forth pumping movements through the stopcock.
To date, interventional oncology (IO) approaches such as cTACE have been highly effective in treating tumours locoregionally, and the effectiveness of these approaches can be augmented to achieve systemic anti-tumour effects by combining with targeted immunotherapies. Although the convergence of IO and immunotherapy is still in its infancy, it presents multitudinous possibilities to be explored, which will be pivotal in improving the standard of patient care.
Rafael Duran is an interventional radiologist at Lausanne University Hospital, Lausanne, Switzerland.