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Open Access 01-09-2020 | Metastasis | Original Article

Cryoablation combined with transarterial infusion of pembrolizumab (CATAP) for liver metastases of melanoma: an ambispective, proof-of-concept cohort study

Authors: Lujun Shen, Han Qi, Shuanggang Chen, Fei Cao, Lin Xie, Ying Wu, Weimei Ma, Ze Song, Hui Yuan, Tao Zhang, Dandan Li, Xizhi Wen, Qifeng Chen, Wang Li, Xiaoshi Zhang, Weijun Fan

Published in: Cancer Immunology, Immunotherapy | Issue 9/2020

Abstract

Background

The presence of liver metastasis correlates with poor therapeutic response of PD-1 blockade therapy in melanoma. A novel treatment protocol by combining cryoablation with transarterial infusion of pembrolizumab (CATAP) was proposed, and its feasibility and safety was assessed among this group of patients.

Methods

This registered ambispective cohort study enrolled fifteen melanoma patients with multiple hepatic metastases who received planned two-stage CATAP therapy: in the combined stage, subtotal cryoablation on day 1, in which one to two intrahepatic lesions were ablated completely with other lesions left untreated, sequentially combined transarterial infusion of pembrolizumab on day 3, every three weeks, for at least one cycle; in the infusion stage, arterial infusion of pembrolizumab was recommended at three-week interval until disease progression. The primary endpoint was objective response rate by RECIST (version 1.1); secondary end points included progression-free survival (PFS) and safety; exploratory endpoints were changes of cytokines and immune cell compositions in peripheral blood samples.

Results

Of the 15 patients enrolled, no grade 3–4 adverse events or major complications were observed. One patient (6.7%) achieved complete response, and 3 (20.0%) achieved partial response. The overall response rates of CATAP for the entire cohort and patients with cutaneous melanoma were 26.7% (95% confidence interval (CI) 4.3–49.0%) and 33.3% (95% CI 2.5–64.1%), respectively. Clinical response was observed in a proportion of patients (2/6; 33.3%) who failed first-line intravenous pembrolizumab treatment. The median overall PFS time and hepatic PFS time were 4.0 (95% CI 2.5–5.5) and 5.73 (95% CI 1.1–10.4) months, respectively. A significant increase in CD3-CD16 + CD56 + cells (natural killer cells; P = 0.0124) and a marginally significant decrease in CD4 + CD25 + cells (regulatory T cells; P = 0.0546) were observed three weeks after the first cycle of treatment in the combined stage.

Conclusions

The CATAP therapy demonstrated positive clinical activity and a favorable safety profile for melanoma patients with liver metastasis.

Robert C, Ribas A, Schachter J et al (2019) Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. The Lancet Oncol 20:1239–1251. https://doi.org/10.1016/S1470-2045(19)30388-2 CrossRefPubMed

Rodriguez-Cerdeira C, Carnero Gregorio M, Lopez-Barcenas A, Sanchez-Blanco E, Sanchez-Blanco B, Fabbrocini G, Bardhi B, Sinani A, Guzman RA (2017) Advances in immunotherapy for melanoma: a comprehensive review. Mediators Inflamm 2017:3264217. https://doi.org/10.1155/2017/3264217 CrossRefPubMedPubMedCentral

Robert C, Ribas A, Wolchok JD et al (2014) Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet 384:1109–1117. https://doi.org/10.1016/S0140-6736(14)60958-2 CrossRefPubMed

Tumeh PC, Hellmann MD, Hamid O et al (2017) Liver metastasis and treatment outcome with Anti-PD-1 monoclonal antibody in patients with melanoma and NSCLC. Cancer Immunol Res 5:417–424. https://doi.org/10.1158/2326-6066.CIR-16-0325 CrossRefPubMedPubMedCentral

Knolle P, Schlaak J, Uhrig A, Kempf P, Meyer zum Buschenfelde KH, Gerken G (1995) Human Kupffer cells secrete IL-10 in response to lipopolysaccharide (LPS) challenge. J Hepatol 22:226–229CrossRefPubMed

Jenne CN, Kubes P (2013) Immune surveillance by the liver. Nat Immunol 14:996–1006. https://doi.org/10.1038/ni.2691 CrossRefPubMed

John B, Crispe IN (2004) Passive and active mechanisms trap activated CD8+ T cells in the liver. J Immunol 172:5222–5229CrossRefPubMed

Almeida JP, Drezek RA, Foster AE (2014) Controlling melanoma at local and systemic levels: is a combination of ablative therapy and immunotherapy the way forward? Immunotherapy 6:109–111. https://doi.org/10.2217/imt.13.158 CrossRefPubMed

Chu KF, Dupuy DE (2014) Thermal ablation of tumours: biological mechanisms and advances in therapy. Nat Rev Cancer 14:199–208. https://doi.org/10.1038/nrc3672 CrossRefPubMed

10.

Abdo J, Cornell DL, Mittal SK, Agrawal DK (2018) Immunotherapy plus cryotherapy: potential augmented abscopal effect for advanced cancers. Front Oncol 8:85. https://doi.org/10.3389/fonc.2018.00085 CrossRefPubMedPubMedCentral

11.

Zhang W, Yu H, Guo Z, Li B, Si T, Yang X, Wang H (2014) Percutaneous cryoablation of liver metastases from breast cancer: initial experience in 17 patients. Clin Radiol 69:231–238. https://doi.org/10.1016/j.crad.2013.09.014 CrossRefPubMed

12.

Kim GM, Won JY, Kim MD et al (2016) Cryoablation of hepatocellular carcinoma with high-risk for percutaneous ablation: safety and efficacy. Cardiovasc Interv Radiol 39:1447–1454. https://doi.org/10.1007/s00270-016-1384-4 CrossRef

13.

Xin'an L, Jianying Z, Lizhi N, Fei Y, Xiaohua W, Jibing C, Jialiang L, Kecheng X (2013) Alleviating the pain of unresectable hepatic tumors by percutaneous cryoablation: experience in 73 patients. Cryobiology 67:369–373CrossRefPubMed

14.

Lodh S, Maher R, Guminski A (2014) Intra-arterial infusion and chemo-embolization for melanoma liver metastases. J Surg Oncol 109:376–382. https://doi.org/10.1002/jso.23551 CrossRefPubMed

15.

Munck JN, Riggi M, Rougier P et al (1993) Pharmacokinetic and pharmacodynamic advantages of pirarubicin over adriamycin after intraarterial hepatic administration in the rabbit VX2 tumor model. Cancer Res 53:1550–1554PubMed

16.

Sperling J, Schafer T, Ziemann C, Benz-Weiber A, Kollmar O, Schilling MK, Menger MD (2012) Hepatic arterial infusion of bevacizumab in combination with oxaliplatin reduces tumor growth in a rat model of colorectal liver metastases. Clin Exp Metastasis 29:91–99. https://doi.org/10.1007/s10585-011-9432-6 CrossRefPubMed

17.

Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247. https://doi.org/10.1016/j.ejca.2008.10.026 CrossRefPubMed

18.

Algazi AP, Tsai KK, Shoushtari AN et al (2016) Clinical outcomes in metastatic uveal melanoma treated with PD-1 and PD-L1 antibodies. Cancer 122:3344–3353. https://doi.org/10.1002/cncr.30258 CrossRefPubMed

19.

Wen X, Ding Y, Li J et al (2017) The experience of immune checkpoint inhibitors in Chinese patients with metastatic melanoma: a retrospective case series. Cancer Immunol Immunother CII 66:1153–1162. https://doi.org/10.1007/s00262-017-1989-8 CrossRefPubMed

20.

Wolchok JD, Chiarion-Sileni V, Gonzalez R et al (2017) overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 377:1345–1356. https://doi.org/10.1056/NEJMoa1709684 CrossRefPubMedPubMedCentral

21.

Larkin J, Chiarion-Sileni V, Gonzalez R et al (2015) combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373:23–34. https://doi.org/10.1056/NEJMoa1504030 CrossRefPubMedPubMedCentral

22.

Luke JJ, Callahan MK, Postow MA et al (2013) Clinical activity of ipilimumab for metastatic uveal melanoma: a retrospective review of the Dana-Farber Cancer Institute, Massachusetts General Hospital, Memorial Sloan-Kettering Cancer Center, and University Hospital of Lausanne experience. Cancer 119:3687–3695. https://doi.org/10.1002/cncr.28282 CrossRefPubMed

23.

Johnson DB, Bao R, Ancell KK, Daniels AB, Wallace D, Sosman JA, Luke JJ (2019) Response to anti–PD-1 in uveal melanoma without high-volume liver metastasis. J Natl Compr Cancer Netw 17:114–117. https://doi.org/10.6004/jnccn.2018.7070 CrossRef

24.

Bastianpillai C, Petrides N, Shah T, Guillaumier S, Ahmed HU, Arya M (2015) Harnessing the immunomodulatory effect of thermal and non-thermal ablative therapies for cancer treatment. Tumour Biol 36:9137–9146. https://doi.org/10.1007/s13277-015-4126-3 CrossRefPubMed

25.

Lee H, Quek C, Silva I et al (2019) Integrated molecular and immunophenotypic analysis of NK cells in anti–PD-1 treated metastatic melanoma patients. Oncoimmunology 8:e1537581. https://doi.org/10.1080/2162402X.2018.1537581 CrossRefPubMed

26.

Barry KC, Hsu J, Broz ML et al (2018) A natural killer-dendritic cell axis defines checkpoint therapy-responsive tumor microenvironments. Nat Med 24:1178–1191. https://doi.org/10.1038/s41591-018-0085-8 CrossRefPubMedPubMedCentral

27.

Gambichler T, Schroter U, Hoxtermann S, Susok L, Stockfleth E, Becker JC (2019) Decline of PD-1 positive circulating T regulatory cells predicting more favorable clinical outcome of melanoma patients under immune checkpoint blockade. Br J Dermatol. https://doi.org/10.1111/bjd.18379 CrossRefPubMed

28.

Gambichler T, Schroter U, Hoxtermann S, Susok L, Stockfleth E, Becker JC (2019) A brief communication on circulating PD-1-positive T-regulatory lymphocytes in melanoma patients undergoing adjuvant immunotherapy with nivolumab. J Immunother 42:265–268. https://doi.org/10.1097/CJI.0000000000000277 CrossRefPubMed

29.

Joseph RW, Elassaiss-Schaap J, Kefford R et al (2018) Baseline tumor size is an independent prognostic factor for overall survival in patients with melanoma treated with pembrolizumab. Clin Cancer Res 24:4960–4967. https://doi.org/10.1158/1078-0432.CCR-17-2386 CrossRefPubMedPubMedCentral

30.

Zaretsky JM, Garcia-Diaz A, Shin DS et al (2016) Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med 375:819–829. https://doi.org/10.1056/NEJMoa1604958 CrossRefPubMedPubMedCentral

31.

Hugo W, Zaretsky JM, Sun L et al (2017) Genomic and transcriptomic features of response to anti–PD-1 therapy in metastatic melanoma. Cell 168:542. https://doi.org/10.1016/j.cell.2017.01.010 CrossRefPubMed

32.

Forschner A, Battke F, Hadaschik D et al (2019) Tumor mutation burden and circulating tumor DNA in combined CTLA-4 and PD-1 antibody therapy in metastatic melanoma—results of a prospective biomarker study. J Immunother Cancer. https://doi.org/10.1186/s40425-019-0659-0 CrossRefPubMedPubMedCentral

33.

Seto T, Sam D, Pan M (2019) Mechanisms of primary and secondary resistance to immune checkpoint inhibitors in cancer. Med Sci (Basel). https://doi.org/10.3390/medsci7020014 CrossRef

34.

Robert C, Schachter J, Long GV et al (2015) Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 372:2521–2532. https://doi.org/10.1056/NEJMoa1503093 CrossRefPubMed

35.

Ng KK, Lam CM, Poon RT, Ai V, Tso WK, Fan ST (2003) Thermal ablative therapy for malignant liver tumors: a critical appraisal. J Gastroenterol Hepatol 18:616–629. https://doi.org/10.1046/j.1440-1746.2003.02991.x CrossRefPubMed

Title: Cryoablation combined with transarterial infusion of pembrolizumab (CATAP) for liver metastases of melanoma: an ambispective, proof-of-concept cohort study
Authors: Lujun Shen
Han Qi
Shuanggang Chen
Fei Cao
Lin Xie
Ying Wu
Weimei Ma
Ze Song
Hui Yuan
Tao Zhang
Dandan Li
Xizhi Wen
Qifeng Chen
Wang Li
Xiaoshi Zhang
Weijun Fan
Publication date: 01-09-2020
Publisher: Springer Berlin Heidelberg
Keywords: Metastasis
Melanoma
Melanoma
Published in: Cancer Immunology, Immunotherapy / Issue 9/2020
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-020-02566-z

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Abstract

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