Tremelimumab in combination with microwave ablation in patients with refractory biliary tract cancer

Clinical Question: Does the combined used of microwave ablation and anti-CTLA-4 antibody tremelimumab improve outcomes among patients with refractory biliary tract cancer?

Take-away Points: A 50% disease response rate was observed among patients with refractory biliary tract cancer treated with the checkpoint inhibitor tremelimumab and microwave ablation. Non-dose-limiting adverse events were common.

Reference: Xie C, et al. Tremelimumab in combination with microwave ablation in patients with refractory biliary tract cancer. Hepatology. Epub ahead of print 22 December 2018.

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Study design: Prospective open-label single-arm cohort study

Funding source: National Institutes of Health/National Cancer Institute, AstraZeneca

Setting: Single Institution

Summary

Without surgical intervention, survival with first-line chemotherapy for biliary tract cancer (BTC) is less than one year. No standard second-line regimen exists, and outcomes among patients with treatment-refractory disease are poor. Recently, immunotherapy has shown promise for treatment of hepatocellular carcinoma (HCC), a close histologic relative of BTC. While response rates remain low, preliminary studies have suggested a positive effect of adjuvant treatments such as ablation or radiation therapy, possibly through immune stimulation. In the present investigation, researchers at the National Institutes of Health evaluated outcomes for 20 patients treated with the anti-CTLA4 checkpoint inhibitor tremelimumab combined with subtotal microwave ablation for refractory BTC. Primary outcome measures included progression-free survival (PFS) and overall survival (OS). An analysis of multiple immune response parameters was also performed. Results showed median PFS and OS values (3.4 months and 6.0 months, respectively) comparable to published data using cytotoxic chemotherapy. Overall response and disease control rates were 12.5% and 50.0%, respectively, with two patients achieving partial response and six (37.5%) with stable disease. One or more adverse events were observed in all patients (25.0% grade 4). Immune assays showed a significant increase in a subset of CD8+ cytotoxic T lymphocytes and decreased T cell clonality following initiation of therapy in a pattern different from that previously observed in HCC patients.



Figure: Progression-free survival (A) and overall survival (B) among patients with refractory biliary tract cancer treated with tremelimumab and microwave ablation.

Commentary

The revolution of cancer immunotherapy currently underway has revived interest in the potential immunomodulatory effects of local treatment modalities such as image-guided thermal ablation (IGTA). Spontaneous regressions of distant disease following IGTA—so called “abscopal effects”—have been known to occur since at least the early 2000s, though the phenomenon has proven infrequent and stubbornly unpredictable in routine clinical practice. As with abscopal effects observed following radiation therapy, the mechanism of action has been long been assumed immunologic in nature, and multiple studies have been conducted in an attempt to clarify the manner in which IGTA treatments augment tumoral antigenicity, such as increased levels of circulating pro-inflammatory cytokines and heat shock proteins. With the advent of checkpoint inhibitors and related agents, this paradigm has since shifted toward the investigation of IGTA as a potential immune-stimulatory adjuvant with the goal of optimizing treatment effects among patients receiving systemic immunotherapies. In the present investigation, researcher describe the feasibility of such an approach among patients with refractory biliary tract cancers undergoing treatment with CTLA4 inhibitor tremelimumab. Though clinical response rates were low, combination therapy with subtotal microwave ablation was found to yield significant modulation of T cell subspecies within the tumor microenvironment, and treatment-related adverse events were acceptable. Trials such as these offering compelling proof-of-principle evidence that medicine’s two “IOs”—immuno-oncology and interventional oncology—may together yield sufficiently powerful synergies to significantly impact patient outcomes, particularly for cancers that have proven themselves recalcitrant to conventional cytotoxic chemotherapy treatment regimens.

Post Author:
Aaron W.P. Maxwell, M.D.
Radiology Resident, PGY-5
Department of Diagnostic Imaging
The Warren Alpert Medical School at Brown University
@DoctorAWPM