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

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.

An Exploratory Analysis of Changes in Circulating Plasma Protein Profiles Following Image-Guided Ablation of Renal Tumours Provides Evidence for Effects on Multiple Biological Processes

“…With the development of ICIs targeting CTLA-4 and PD-1 to enhance antitumour T cell activity, these immunotherapies are the current first-line treatments [ 7 , 28 , 29 ]. Based on a knowledge of the relative impacts of the treatments on both the cancer itself and the tumour microenvironment, combination therapies are also now being explored involving single-agent TKIs and ICIs [ 7 , 29 ] and more recently a pilot study of anti-CTLA-4 (tremelimumab) in combination with CRYO, which showed a significant increase in CD3+ and CD8+ T cell infiltration) in the tumour microenvironment compared with tremelimumab monotherapy [ 31 ]. Interestingly, these effects were restricted to the clear cell RCC histological subtype.…”

Synergetic Thermal Therapy for Cancer: State-of-the-Art and the Future

“…Shao qi et al have demonstrated that cryoablation (−80 °C, 30 min) on B16 cancer cells resulted in an 8.25 times release of natural proteins and activated a stronger T-cell immune response, which is 1.6 times more than the heating treatment group (50 °C, 30 min) [ 112 ]. Combining cryoablation, IFN- and VEGF signaling pathways are activated and further enhanced, providing a good induction pathway for immune cell infiltration in the tumor microenvironment [ 113 ]. In addition to the ability to increase the killing activity of immune cells such as T cells and NK cells, the underlying mechanism may contribute to the modulation of immune responses by promoting a release of Hsp70 and reducing Ki67 activity [ 114 , 115 , 116 ].…”

“…Recently, Campbell, M.T. et al conducted a preliminary study using Tremelimumab immunotherapy with and without cryoablation in 29 patients with metastatic renal cell carcinoma [ 113 ]. They found a significant increase in T-cell infiltration in the tumor microenvironment of patients after cryo-trimethoprim combination therapy and laid an important foundation for subsequent combination therapy for patients with mccRCC.…”

Techniques for Profiling the Cellular Immune Response and Their Implications for Interventional Oncology

“…There are compelling preclinical and early clinical data to suggest that interventions such as thermal ablation and transarterial embolization can augment local and systemic tumor immunity [ 26 , 27 , 28 , 298 , 299 , 300 , 301 , 302 , 303 , 304 ]. The thermal ablation modalities such as radiofrequency ablation and microwave ablation cause the destruction of the tumor cells by causing necrosis, whereas cryoablation cause tumor destruction via both necrosis and apoptosis.…”