Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma

Abstract

Background & aims: Tremelimumab is a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on the surface of activated T lymphocytes. Ablative therapies induce a peripheral immune response which may enhance the effect of anti-CTLA4 treatment in patients with advanced hepatocellular carcinoma (HCC). This study aimed to demonstrate whether tremelimumab could be combined safely and feasibly with ablation.

Methods: Thirty-two patients with HCC were enrolled: male:female: 28:4; median age: 62 (range 36-76). Patients were given tremelimumab at two dose levels (3.5 and 10mg/kg i.v.) every 4weeks for 6 doses, followed by 3-monthly infusions until off-treatment criteria were met. On day 36, patients underwent subtotal radiofrequency ablation or chemoablation. Staging was performed by contrast-enhanced CT or MRI scan every 8weeks.

Results: No dose-limiting toxicities were encountered. The most common toxicity was pruritus. Of the 19 evaluable patients, five (26.3%; 95% CI: 9.1-51.2%) achieved a confirmed partial response. Twelve of 14 patients with quantifiable HCV experienced a marked reduction in viral load. Six-week tumor biopsies showed a clear increase in CD8+ T cells in patients showing a clinical benefit only. Six and 12-month probabilities of tumor progression free survival for this refractory HCC population were 57.1% and 33.1% respectively, with median time to tumor progression of 7.4months (95% CI 4.7 to 19.4months). Median overall survival was 12.3months (95% CI 9.3 to 15.4months).

Conclusions: Tremelimumab in combination with tumor ablation is a potential new treatment for patients with advanced HCC, and leads to the accumulation of intratumoral CD8+ T cells. Positive clinical activity was seen, with a possible surrogate reduction in HCV viral load.

Lay summary: Studies have shown that the killing of tumors by direct methods (known as ablation) can result in the immune system being activated or switched on. The immune system could potentially also recognize and kill the cancer that is left behind. There are new drugs available known as immune checkpoint inhibitors which could enhance this effect. Here, we test one of these drugs (tremelimumab) together with ablation.

Clinical trial number: ClinicalTrials.gov: NCT01853618.

Keywords: Hepatocellular carcinoma; Immune; Immune checkpoint; Liver cirrhosis; T-Lymphocytes.

Conflict of interest statement

Conflict of interest

The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

Published by Elsevier B.V.

Figures

Fig. 1. Efficacy data for study population

(A) Swimmer’s plot showing time on study, off-treatment reason, current status and time of response if applicable; the arrow indicates patients still on study; white circle, time of response; blue circle, time of discontinuation due to toxicity. (B) Plot showing magnitude of change in target lesion sum over time as per RECIST; patients evaluable in target lesions not treated by RFA/TACE.

Fig. 2. Example of clinical response

(A) CT scan over 6-month time period for subject 3 showing an increase in the ablated area (denoted A) in addition to changes in tumor size (denoted T) on two separate cuts of the same scan demonstrating worsening appearances at 8 weeks with subsequent improvement and in some cases resolution at 24 weeks. (B) AFP over time for subject 3. (C) CT scan over 6-month time period for subject 10 showing a marked reduction in the tumor area (denoted T) from 10.5 cm at baseline to 4.3 cm after 2 months. Of note, whilst this patient did undergo subtotal TACE the tumor mass shown in the figure was not embolized. (D) AFP over time for subject 10.

Fig. 3. Correlative studies

(A) Percent of live activated CD4+ T cells in peripheral blood of patients during first 4 cycles of tremelimumab. Wilcoxon signed rank test was used to compare T cell subsets at baseline with samples obtained after 4 and 12 weeks. (B) Percent of live activated CD8+ T cells in peripheral blood of patients during first 4 cycles of tremelimumab. Wilcoxon signed rank test was used to compare T cell subsets at baseline with samples obtained after 4 and 12 weeks. (C) Representative tumor biopsy at baseline and post 2 doses of tremelimumab showing marked intratumoral CD3+/CD8+ T cell infiltration (bottom rows: positive pixel count overlay). (D) Quantitative assessment of immunohistochemical staining showing average CD3 and CD8 immune cell tumor infiltration before (N = 6) and after 2 doses of tremelimumab (N = 12). (E) Quantitative assessment of immunohistochemical staining showing average CD3 and CD8 immune cell tumor infiltration after 2 doses of tremelimumab for patients divided into responders (defined as stable/partial response of at least 4 months, N = 5) vs. non-responders (defined as PD/partial response of under 4 months, N = 4).