European Conference on Interventional Oncology

April 24-27 | Vienna, Austria

April 24-27 | Vienna, Austria

April 24-27 | Vienna, Austria

April 24-27 | Vienna, Austria

April 24-27 | Vienna, Austria

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ProgrammeTopic highlightsCombined immunotherapy and interventional oncology in HCC

Combined immunotherapy and interventional oncology in HCC

We spoke to Dr. Francesco De Cobelli to learn about his presentation at ECIO 2022.

You can now view this session on demand!

A vast array of treatment options is available for hepatocellular carcinoma, ranging from surgical resection or thermal ablation of early disease to intra-arterial and systemic therapies for intermediate and advanced stages with the potential ultimate goal of liver transplant.

The updated ESMO recommendations published in 2021 [1] and the most recent 2022 BCLC update strategy for prognosis prediction and treatment recommendation [2] also acknowledged systemic immunotherapy for first-line treatment of advanced stage HCC (BCLC C). The rationale lies in the biology of HCC, an immunogenic tumor expressing tumor-associated antigens and gene-specific neo-antigens. Drugs currently investigated for systemic immunotherapy of HCC target inhibition of immune checkpoints, i.e. molecules whose physiological function of setting a limit to cell-mediated immune response is exploited by the tumor to escape anti-tumor surveillance. However, response to systemic immunotherapy may be limited in some patients due to the immune suppressive microenvironment observed in the chronically-inflamed liver, particularly in the setting of non-viral hepatitis.

Immunosuppressive factors in the HCC microenvironment provide the rationale for combining systemic immunotherapy and interventional oncology. Both ablative and intra-arterial treatments for HCC trigger release of tumor-associated antigens (TAA) and damage-associated molecular patterns (DAMP) with subsequent activation of antigen presenting cells (APCs) and production of anti-tumor CD8+T cells, a process termed “immunogenic cell death” [3-5]. Response to locoregional treatments and decreased recurrence have been associated to higher frequency of circulating tumor-specific T cells, increased expression and activation of cytotoxic surface markers 4-weeks after RFA [6]; higher AFP-specific CD4+ T-cells following TACE/TAE [7]; and increase in TAA-specific T-cells 2-4 weeks after RFA [8].

The principle of associating systemic immunotherapy with locoregional interventional oncology is to achieve a synergistic effect whereby better tumor response rates and improved survival may be obtained in advanced HCC patients. Currently, a number of ongoing trials are investigating the use of immunotherapy alone or in combination with another biological agent in association with a locoregional treatment in patients with HCC [9].

Available results

A pilot investigation conducted by Duffy et al. [10] on patients with advanced refractory HCC treated with a CTLA-4 inhibitor (tremelimumab) combined with ablation (RFA or Cryoablation) or TACE showed efficacy and safety with a median time to progression of 7.4 months. Only patients with increase in CD8+ T cells at six-week tumor biopsies had a clinical benefit. The IMMUTACE study investigated TACE followed by systemic treatment with an anti-PD 1 (nivolumab) on intermediate stage HCC patients and showed an overall response rate (ORR) of 70% and a median overall survival of nearly 20 months [11].

An additional treatment option in patients with intermediate-to-advanced disease stage HCC due to its ability to induce cell death for as long as 6 months is trans-arterial radioembolisation (TARE), currently of great interest in the setting of combined therapies for HCC. The NASIR-HCC single arm study evaluated transarterial Yttrium-90 radioembolisation (TARE) with resin spheres plus nivolumab in HCC patients in multiple centers in Spain [12] and showed a response rate of 40%. The recent CA 209-678 study also investigated Y90-radioembolisation in patients with advanced HCC followed by nivolumab and resulted in an “encouraging objective response rate [13]. Currently, one study is recruiting patients with unresecatble HCC for treatment with combined systemic therapy plus TARE (NCT04541173); progression free survival will be investigated following TARE alone vs TARE followed by atezolizumab plus bevacizumab. Secondary endpoints include safety, time to progression, overall response and overall survival.

While most ongoing studies are investigating the addition of systemic therapy following interventional oncology techniques in a quasi-“adjuvant” setting, another interesting theoretical application of combined schemes could be to take advantage of the high response rate shown by systemic therapies to downsize the disease and allow local therapy to exert a curative effect.

The steps to providing robust evidence are still numerous and the time needed is long. Particular interest lies in defining the ideal time schedule of combined schemes and biomarkers for selection of ideal candidates. However, the data available point in a promising direction in responding to clinical needs and ameliorating patient outcome.

Fig.1: 77-year-old patient with 6 cm HCC in segment VI and multiple foci of HCC in both liver lobes treated with combination of transarterial Yttrium-90 radioembolization (TARE) plus immunotherapy.

References

  1. Vogel A, Martinelli E for ESMO Guidelines Committee. Updated treatment recommendations for hepatocellular carcinoma (HCC) from the ESMO Clinical Practice Guidelines. Ann Oncol. 2021 Jun;32(6):801-805. doi: 10.1016/j.annonc.2021.02.014
  2. Reig M, Forner A, Rimola J, et al. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update, Journal of Hepatology 2022 March 1; 73(3):681-693. doi:10.1016/j.jhep.2021.11.018.
  3. Fabian KP, Wolfson B, Hodge JW. From Immunogenic Cell Death to Immunogenic Modulation: Select Chemotherapy Regimens Induce a Spectrum of Immune-Enhancing Activities in the Tumor Microenvironment. Front Oncol. 2021 Aug 23;11:728018. doi: 10.3389/fonc.2021.728018 .
  4. Kepp O, Marabelle A, Zitvogel L, Kroemer G. Oncolysis without viruses – inducing systemic anticancer immune responses with local therapies. Nat Rev Clin Oncol. 2020 Jan;17(1):49-64. doi: 10.1038/s41571-019-0272-7 .
  5. Yilmaz MT, Elmali A, Yazici G. Abscopal Effect, From Myth to Reality: From Radiation Oncologists’ Perspective. Cureus. 2019 Jan 9;11(1):e3860. doi: 10.7759/cureus.3860.
  6. Zerbini A, Pilli M, Penna A et al. Radiofrequency thermal ablation of hepatocellular carcinoma liver nodules can activate and enhance tumor-specific T-cell responses. Cancer Res. 2006 Jan 15;66(2):1139-46. doi: 10.1158/0008-5472.CAN-05-2244 .
  7. Ayaru L, Pereira SP, Alisa A et al. Unmasking of alpha-fetoprotein-specific CD4(+) T cell responses in hepatocellular carcinoma patients undergoing embolization. J Immunol. 2007 Feb 1;178(3):1914-22. doi: 10.4049/jimmunol.178.3.1914. PMID: 17237442.
  8. Mizukoshi E, Yamashita T, Arai K et al. Enhancement of tumor-associated antigen-specific T cell responses by radiofrequency ablation of hepatocellular carcinoma. Hepatology. 2013 Apr;57(4):1448-57. doi: 10.1002/hep.26153.
  9. gov, studies identified as NCT03397654, NCT03572582, NCT03638141, NCT04652492, NCT04981665, NCT04268888, NCT04340193, NCT04997850, NCT04472767, NCT03937830, NCT04814043, NCT04992143, NCT04803994, NCT04246177, NCT04712643. https://clinicaltrials.gov/ . Accessed February 1, 2022.
  10. Duffy AG, Ulahannan SV, Makorova-Rusher O, et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J Hepatol. 2017 Mar;66(3):545-551. doi: 10.1016/j.jhep.2016.10.029.
  11. Vogel A, Saborowski A, Hinrichs J, et al. IMMUTACE: A biomarker-orientated, multicenter phase II AIO study of transarterial chemoembolization (TACE) in combination with nivolumab performed for intermediate stage hepatocellular carcinoma (HCC). Ann Oncol. 2021;32(5):S1312. doi: 10.1016/j.annonc.2021.08.2114
  12. De La Torre M, Matilla A, Varela M, et al. Nivolumab after selective internal radiation therapy using sir spheres resin microspheres in patients with hepatocellular carcinoma: the NASIR HCC trial. Presented at: International Liver Cancer Association 2020 Virtual Conference; September 11-13, 2020.
  13. Tai D, Loke K, Gogna A, et al. Radioembolisation with Y90-resin microspheres followed by nivolumab for advanced hepatocellular carcinoma (CA 209-678): a single arm, single centre, phase 2 trial. Lancet Gastroenterol Hepatol. 2021 Dec;6(12):1025-1035. doi: 10.1016/S2468-1253(21)00305-8.

Fig.1a: Contrast-enhanced CT scan at diagnosis.

Fig.1b: Superselective angiography.

Fig.1c: PET-CT scan obtained after infusion of Yttrium-90 resin microspheres.

Fig.1d: Contrast-enhanced CT obtained after 9 months shows tumor necrosis with complete response.

Francesco De Cobelli

Prof. Francesco De Cobelli is full professor of radiology and currently the chair of the Department of Radiology at the San Raffaele Vita-Salute University Hospital in Milan, Italy. He is also the director of the postgraduate school of radiology and co-director of the international PhD course in clinical and experimental medicine at the same University.

In recent years, his clinical and research activity has been primarily focused on interventional oncology and oncologic imaging, in particular image-guided treatment of hepatic lesions and kidney tumors, as well as promoting multimodality and multidisciplinary treatments. He is currently the Vice-President of the Italian College of Interventional Radiology (ICIR) of the Italian Society of Medical and Interventional Radiology (SIRM). Prof. De Cobelli is the author or co-author of 314 publications with an h-index 46 and more than 9,800 citations (Scopus).