Pilot study of Tremelimumab with and without cryoablation in patients with metastatic renal cell carcinoma

Matthew T Campbell,Shalini S Yadav,Jiaqi Peng ,Eric Jonasch,Sonali Jindal,James P Allison,Fei Duan,Rahul A Sheth,Alexsandra Espejo ,Jose A Karam,Jianjun Gao,Rebecca S Slack Tidwell ,Hong Chen,Amishi Yogesh Shah ,Alda L Tam,Nizar M Tannir,Sreyashi Basu,Kamran Ahrar,Christopher G Wood,Priya Rao,Amado J Zurita,Padmanee Sharma

doi:10.1038/s41467-021-26415-4

Matthew T Campbell, Shalini S Yadav + Show 20 more

Open Access

https://doi.org/10.1038/s41467-021-26415-4

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Abstract

Cryoablation in combination with immune checkpoint therapy was previously reported to improve anti-tumor immune responses in pre-clinical studies. Here we report a pilot study of anti-CTLA-4 (tremelimumab) with (n = 15) or without (n = 14) cryoablation in patients with metastatic renal cell carcinoma (NCT02626130), 18 patients with clear cell and 11 patients with non-clear cell histologies. The primary endpoint is safety, secondary endpoints include objective response rate, progression-free survival, and immune monitoring studies. Safety data indicate ≥ 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 that treatment with tremelimumab plus cryotherapy is feasible and modulates the immune microenvironment in patients with metastatic clear cell histology.

Highlights

Cryoablation in combination with immune checkpoint therapy was previously reported to improve anti-tumor immune responses in pre-clinical studies
Five of the six patients who received prior treatment with nivolumab were in the cryoablation plus tremelimumab arm
Treatment with tremelimumab with or without cryoablation was associated with immune-mediated toxicities with grade 3 or greater events occurring in 55% of patients

Summary

Introduction

Cryoablation in combination with immune checkpoint therapy was previously reported to improve anti-tumor immune responses in pre-clinical studies. We report a pilot study of anti-CTLA-4 (tremelimumab) with (n = 15) or without (n = 14) cryoablation in patients with metastatic renal cell carcinoma (NCT02626130), 18 patients with clear cell and 11 patients with non-clear cell histologies. Cryoablation plus tremelimumab leads to a significant increase in immune cell infiltration These data highlight that treatment with tremelimumab plus cryotherapy is feasible and modulates the immune microenvironment in patients with metastatic clear cell histology. A phase III study in metastatic melanoma found improved overall survival (OS) for patients who received ipilimumab, an IgG1 monoclonal antibody targeting CTLA-4, which led to FDA approval[3]. A single-phase II study of single-agent ipilimumab in mccRCC found an objective response rate of 9.8% (6 out of 61), with noted highgrade immune-related adverse events in a subset of patients[11]. Cryo has been used to palliate symptoms in patients with painful RCC metastases[13]

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