Additive antitumour response to the rabbit VX2 hepatoma by combined radio frequency ablation and toll like receptor 9 stimulation

Behm, Barbara; Fazio, Pietro Di; Michl, Patrick; Neureiter, Daniel; Kemmerling, Ralf; Hahn, Eckhart G.; Strobel, D; Gress, Thomas M.; Schuppan, Detlef; Wissniowski, TT

doi:10.1136/gutjnl-2014-308286

Cited by 55 publications

(47 citation statements)

References 49 publications

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“…26 The combination of RFA and TLR9 stimulation was tested in a VX2 hepatoma model and the combination was shown to prevent subsequent tumour spread. 27 Similar results have been obtained in a B16-OVA model. Combination treatment with cryoablation plus TLR9 stimulation via CpGoligodeoxynucleotides was very effective in the eradication of local and systemic tumours due to enhanced dendritic cell maturation leading to more efficient cross-presentation in tumourbearing mice.…”

Section: B Asupporting

confidence: 77%

Combined locoregional-immunotherapy for liver cancer

Greten

Mauda-Havakuk

Heinrich

et al. 2019

Journal of Hepatology

160

123

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Locoregional therapies are commonly used to treat patients with hepatocellular carcinoma. It has been noted for many years that locoregional therapies may have additional systemic effects other than simple tumour elimination. Immunological ''side effects" have been described in response to locoregional therapies in animal studies and in patients. With the advent of immunotherapy for hepatocellular carcinoma, there is increasing interest in determining the best way to combine immunotherapy with locoregional therapies. Herein, we provide a compact summary of answered and unanswered questions in the field, including: What animal model is best suited to test combined immune-locoregional treatments? How does tumour cell death affect immune responses? What type of immune responses have been observed in patients treated with different types of locoregional therapies? What can be surmised from the results of the first study testing the combination of locoregional therapy with immune checkpoint blockade? Finally, we discuss the outlook for this rapidly growing area of research, focussing on the issues which must be overcome to bridge the gap between interventional radiology and cancer immunology. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.

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Section: B Asupporting

confidence: 77%

Combined locoregional-immunotherapy for liver cancer

Greten

Mauda-Havakuk

Heinrich

et al. 2019

Journal of Hepatology

160

123

View full text Add to dashboard Cite

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“…Accordingly, these remote and/or systemic effects could have substantial influence on overall clinical efficacy. On the other hand, many researchers (19)(20)(21) have reported potentially beneficial immunologic effects after RF ablation, including an abscopal effect that can be enhanced with adjuvant therapies.…”

Section: Mice and Ablation Protocolmentioning

confidence: 99%

Irreversible Electroporation versus Radiofrequency Ablation: A Comparison of Local and Systemic Effects in a Small-Animal Model

Bulvik¹,

Rozenblum²,

Gourevich³

et al. 2016

Radiology

105

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Purpose To compare both periablational and systemic effects of two mechanistically different types of ablation: thermal radiofrequency (RF) ablation and electroporative ablation with irreversible electroporation (IRE) in appropriately selected animal models. Materials and Methods Animal experiments were performed according to a protocol approved by the Animal Care Committee of Hebrew University. Female C57BL/6 mice (n = 165) were randomized to undergo either RF or IRE ablation of noncancerous normal liver. The inflammatory response, cell proliferation, interleukin 6 (IL-6) levels, and intactness of vessels in the liver were assessed at 6, 12, and 24 hours and at 3, 7, and 14 days after ablation (n = 122 for mechanistic experiments). Systemic effects were then assessed by comparing tumor formation in an Mdr2-knockout (KO) mouse model (n = 15) and tumor growth in a remote BNL 1ME hepatoma xenograft tumor (n = 28). Results were averaged and evaluated by using two-tailed t tests. Results Although RF ablation was associated with a well-defined periablational inflammatory rim, for IRE, the infiltrate penetrated the ablation zone, largely along persistently patent vessels. Peak IL-6 levels (6 hours after ablation) were 10 and three times higher than at baseline for IRE and RF, respectively (P < .03). Mdr2-KO mice that were treated with IRE ablation had more tumors that were 3 mm or larger than mice treated with RF ablation or sham operation (mean, 3.6 ± 1.3 [standard deviation] vs 2.4 ± 1.1 and 2.2 ± 0.8, respectively; P < .05 for IRE vs both RF ablation and sham operation). For BNL 1ME tumors, both RF and IRE liver ablation reduced tumor growth, with a greater effect noted for IRE (1329 mm(3) ± 586 and 819 mm(3) ± 327 vs 2241 mm(3) ± 548 for sham operation; P < .05) that was accompanied by more infiltrating lymphocytes compared with sham operation (7.6 cells per frame ± 1.9 vs 11.2 ± 2.1 vs 0.3 ± 0.1; P < .05). Conclusion Persistent patency of vasculature within the coagulated zone from IRE increases the area and accumulation of infiltrative cells that is associated with a higher serum IL-6 level than RF ablation. These local changes of IRE induce more robust systemic effects, including both tumorigenic and immunogenic effects. (©) RSNA, 2016 Online supplemental material is available for this article.

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“…Very recently, Wissniowski et al used a VX2 rabbit hepatoma model to assess RFA-mediated antitumor immune response and therapeutic efficacy [27]. Compared with untreated controls, RFA was found to induce a 26-fold increase in antitumor T-cell stimulation and a 16-fold increase in antitumor cytotoxicity.…”

Section: Relationship Of Rfa-mediated Antitumor Immunity With Tumor Smentioning

confidence: 99%

“…Wissniowski et al, tested the antitumor T cell response and cytotoxicity in the rabbit VX2 hepatoma model in response to the combined treatment with TLR9 stimulation and RFA [27]. They demonstrated that only this combination prevented subsequent tumor spread and resulted in a significantly improved survival, justifying the further exploration of the combination of RFA and TLR9 agonists in HCC.…”

Section: Rfa In Combination With Additional Immunotherapeutic Strategmentioning

confidence: 99%

Potential of Radiofrequency Ablation in Combination with Immunotherapy in the Treatment of Hepatocellular Carcinoma

Staveley-O’Carroll

Kimchi

2016

J Clin Trials

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Radiofrequency ablation (RFA) is an important treatment option for patients with early hepatocellular carcinoma (HCC). RFA offers a reliable, reproducible modality to effectively treat hepatic lesions with minimal collateral damage to the surrounding hepatic parenchyma. In addition to traditional open operative techniques, RFA can be performed percutaneously or laparoscopically to minimize the physiologic insult to the patient. Due to the concomitant hepatic damage and dysfunction that often is present in patients with HCC these factors make RFA a frequently utilized therapeutic option. However, RFA is most efficacious in treating smaller tumors (≤ 2 cm), particularly when an ablation margin of ≥ 4–5 mm can be obtained. RFA has diminishing utility in larger tumors, resulting in reduced three and five year overall survival rates when compared to surgical resection. Multimodal approaches to include RFA with other standard and investigational approaches have become a subject of recent interest. RFA capably produces cellular destruction causing liberation of a substantial amount of antigens, many of which are tumor-specific providing a favorable environment for immune recognition. We propose that utilizing an immunotherapeutic approach in conjunction with RFA is the next logical step in the treatment of HCC. In this review, we summarize how RFA modulates antitumor immunity and works in concert with immunotherapy in the treatment of HCC. The information provided is expected to help the future design of novel RFA-integrated immunotherapies which are able to generate durable and powerful antitumor immune response to achieve optimal tumor control.

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Additive antitumour response to the rabbit VX2 hepatoma by combined radio frequency ablation and toll like receptor 9 stimulation

Cited by 55 publications

References 49 publications

Combined locoregional-immunotherapy for liver cancer

Combined locoregional-immunotherapy for liver cancer

Irreversible Electroporation versus Radiofrequency Ablation: A Comparison of Local and Systemic Effects in a Small-Animal Model

Potential of Radiofrequency Ablation in Combination with Immunotherapy in the Treatment of Hepatocellular Carcinoma

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