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Here we report a pilot study of anti-CTLA-4 (tremelimumab) with (n\u2009=\u200915) or without (n\u2009=\u200914) cryoablation in patients with metastatic renal cell carcinoma (NCT02626130), 18 patients with clear cell and 11 patients with\u00a0non-clear cell histologies. The primary endpoint is safety, secondary endpoints include objective response rate, progression-free survival, and immune monitoring studies. Safety data indicate \u2265 grade 3 treatment-related adverse events in 16 of 29 patients (55%) including 6 diarrhea\/colitis, 3 hepatitis, 1 pneumonitis, and 1 glomerulonephritis. Toxicity leading to treatment discontinuation occurs in 5 patients in each arm. 3 patients with clear cell histology experience durable responses. One patient in the tremelimumab arm experiences an objective response, the median progression-free survival for all patients is 3.3 months (95% CI: 2.0, 5.3 months). Exploratory immune monitoring analysis of baseline and post-treatment tumor tissue samples shows that treatment increases immune cell infiltration and tertiary lymphoid structures in clear cell but not in non-clear cell. In clear cell, cryoablation plus tremelimumab leads to a significant increase in immune cell infiltration. These data highlight\u00a0that treatment with tremelimumab plus cryotherapy is feasible and modulates the immune microenvironment in patients with metastatic clear cell histology.<\/jats:p>","DOI":"10.1038\/s41467-021-26415-4","type":"journal-article","created":{"date-parts":[[2021,11,4]],"date-time":"2021-11-04T07:37:43Z","timestamp":1636011463000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":57,"title":["Pilot study of Tremelimumab with and without cryoablation in patients with metastatic renal cell carcinoma"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1915-4491","authenticated-orcid":false,"given":"Matthew T.","family":"Campbell","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1638-1445","authenticated-orcid":false,"given":"Surena F.","family":"Matin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alda L.","family":"Tam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9615-8985","authenticated-orcid":false,"given":"Rahul A.","family":"Sheth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamran","family":"Ahrar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3041-8582","authenticated-orcid":false,"given":"Rebecca S.","family":"Tidwell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priya","family":"Rao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7697-9591","authenticated-orcid":false,"given":"Jose A.","family":"Karam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher G.","family":"Wood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nizar M.","family":"Tannir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0943-2806","authenticated-orcid":false,"given":"Eric","family":"Jonasch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6138-4472","authenticated-orcid":false,"given":"Jianjun","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amado J.","family":"Zurita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9007-0621","authenticated-orcid":false,"given":"Amishi Y.","family":"Shah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonali","family":"Jindal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Duan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5028-3833","authenticated-orcid":false,"given":"Sreyashi","family":"Basu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8841-7219","authenticated-orcid":false,"given":"Alexsandra B.","family":"Espejo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James P.","family":"Allison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shalini S.","family":"Yadav","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4658-055X","authenticated-orcid":false,"given":"Padmanee","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,11,4]]},"reference":[{"key":"26415_CR1","doi-asserted-by":"publisher","first-page":"1734","DOI":"10.1126\/science.271.5256.1734","volume":"271","author":"DR Leach","year":"1996","unstructured":"Leach, D. 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S.F.M. reports consulting\/advisory roles for Johnson and Johnson and Research Funding from QED; Education\u2014Ology education. A.L.T. reports consulting\/advisory roles for Boston Scientific, Cello Therapeutics, Endocare, AstraZeneca; and Research Funding from Boston Scientific, Johnson & Johnson. R.A.S. reports consulting\/advisory roles for Varian, Boston Scientific. J.A.K. reports consulting\/advisory roles for Pfizer, Merck, Roche\/Genentech, and Research Funding from Roche\/Genentech, Mirati, Merck, Elypta; Stock Ownership: Allogene, MedTek, ROM Technologies. N.M.T. reports consulting\/advisory roles for Bristol Myers-Squibb; Pfizer; Nektar Therapeutics; Exelisis, Inc, Eisai Medical Research; Eli Lilly; Oncorena; Calithera Bioscience; Surface Oncology; Novartis, Ipsen; Merck Sharp & Dohme and Research Funding from Bristol Myers-Squibb; Nektar Therapeutics; Calithera Bioscience; Arrowhead Pharmaceuticals, Inc. E.J. reports consulting\/advisory roles for Eisai, Exelixis, Novartis, Merck, Pfizer, Roche. And Research support from Exelixis, Merck, Pfizer. J.G. reports consulting\/advisory roles for Seattle Genetics, Jounce Therapeutics, Pfizer, Janssen, Symphogen, AstraZeneca, ARMO biosciences, CRISPR Therapeutics AG. A.J.Z. reports consulting\/advisory roles for AstraZeneca and Bayer and Research funding to his institution from Infinity Pharma, Honoraria from Pfizer, and Janssen. A.Y.S. reports consulting\/advisory roles for Ad boards, Pfizer, Exelixis, and Research Grant funding from Bristol Myers-Squibb, Eisai, EMD Serono. J.P.A. reports consulting, advisory roles, and\/or stocks\/ownership for Achelois, Apricity Health, BioAtla, Codiak BioSciences, Dragonfly Therapeutics, Forty-Seven Inc., Hummingbird, ImaginAb, Jounce Therapeutics, Lava Therapeutics, Lytix Biopharma, Marker Therapeutics, Polaris, BioNTech, and Adaptive Biotechnologies; and owns a patent licensed to Jounce (61\/247,438; \u201cCombination Immunotherapy for the Treatment of Cancer\u201d). P.S. reports consulting, advisory roles, and\/or stocks\/ownership for Achelois, Apricity Health, BioAlta, Codiak BioSciences, Constellation, Dragonfly Therapeutics, Forty-Seven Inc., Hummingbird, ImaginAb, Jounce Therapeutics, Lava Therapeutics, Lytix Biopharma, Marker Therapeutics, Oncolytics, Infinity Pharma, BioNTech, Adaptive Biotechnologies, and Polaris; and owns a patent licensed to Jounce Therapeutics (61\/247,438; \u201cCombination Immunotherapy for the Treatment of Cancer\u201d). The remaining authors declare no potential competing interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"6375"}}