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 10 mg/kg i.v.) every 4 weeks 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 8 weeks. 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 7.4 months (95% CI 4.7 to 19.4 months). Median overall survival was 12.3 months (95% CI 9.3 to 15.4 months). 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.

Combination Cancer Immunotherapy in Hepatocellular Carcinoma

“…These locoregional therapies are particularly beneficial when the levels of cancer antigens are negligible because of poor antigen release. The results of combination therapy with an anti-CTLA-4 antibody and locoregional therapy in advanced HCC were recently published [14]. The NCT01853618 study evaluated the efficacy of adjuvant therapy with tremelimumab (anti-CTLA-4 antibody) after RFA or TACE in several, but not all, HCC nodules, with favorable outcomes, including a partial response rate of 26%, time to tumor progression of 7.4 months, and overall survival of 12.3 months.…”

Role of Immune Checkpoint Blockade in the Treatment for Human Hepatocellular Carcinoma

“…It was reported that a phase II study of tremelimumab as a single agent to treat HCC revealed a PR of 17.6%, a median TTP of 6.48 months, and a median overall survival of 8.2 months [25] . On the contrary, Duffy et al have reported the effect of tremelimumab, an anti-CTLA-4 antibody, in combination with RFA or TACE in advanced HCC patients; 26.3% of patients showed a PR, a median TTP of 7.4 months, and an overall survival of 12.3 months [27] . Interestingly, tremelimumab in combination with ablation induced the accumulation of intratumoral CD8 + T cells.…”

“…Interestingly, tremelimumab in combination with ablation induced the accumulation of intratumoral CD8 + T cells. Depending on the treated region, ablation induced a decrease in tumor volume as well, leading to the release of tumor-associated antigens from HCC cells and activated CD8 + T cells, which in turn could have enhanced the antitumor effect of tremelimumab to tumors at a distance [27] . The effectiveness of tremelimumab at lower doses, in combination with RFA or TACE, indicates that immune checkpoint inhibitors are more effective in combination with other conventional treatments, rather than as a single agent.…”

T Cell–Associated Immunotherapy for Hepatocellular Carcinoma

“…The safety profile and antitumor and antiviral effect, have been tested by the usage of antibody, Tremelimumab (CP-675,206) which blocks the binding of CTLA-4, on advanced HCC with HCV-related cirrhosis [53]. The combined treatment of tremelimumab and tumor ablation for advanced HCC patients brings supporting clinical activity and causes expansion of intratumoral CD8 + T cells [54]. Similarly, PD-1 interactions with PD-L1 and PD-L2 inhibits the proliferation of T cells and restrains the release of cytokines [48].…”