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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.

Interleukin-7 (IL-7) is a homeostatic cytokine for resting T cells with increasing serum and tissue levels during T cell depletion. In preclinical studies, IL-7 therapy exerts marked stimulating effects on T cell immune reconstitution in mice and primates. First-in-humanclinical studies of recombinant human IL-7 (rhIL-7) provided the opportunity to investigate the effects of IL-7 therapy on lymphocytes in vivo. rhIL-7 induced in vivo T cell cycling, bcl-2 up-regulation, and a sustained increase in peripheral blood CD4 + and CD8 + T cells. This T cell expansion caused a signifi cant broadening of circulating T cell receptor (TCR) repertoire diversity independent of the subjects ' age as naive T cells, including recent thymic emigrants (RTEs), expanded preferentially, whereas the proportions of regulatory T (T reg) cells and senescent CD8 + effectors diminished. The resulting composition of the circulating T cell pool more closely resembled that seen earlier in life. This profi le, distinctive among cytokines under clinical development, suggests that rhIL-7 therapy could enhance and broaden immune responses, particularly in individuals with limited naive T cells and diminished TCR repertoire diversity, as occurs after physiological (age), pathological (human immunodefi ciency virus), or iatrogenic (chemotherapy) lymphocyte depletion. . Effects of rhIL-7 therapy on circulating T cells and spleen. rhIL-7 was administered every other day on day 1 -14 (8 injections, indicated by tick marks on X axis), at 4 dose levels: 3 μ g/kg/d (dashed line with ᭹ ; n = 3); 10 μ g/kg/d (dotted line with ᭝ ; n = 3); 30 μ g/kg/d (dashed line with ٗ ; n = 5); and 60 μ g/kg/d (solid line with ᭺ ; n = 4). Mean value for each cohort ( ± the SEM) are plotted at the indicated time points. (A) The absolute lymphocyte count from complete blood counts (left) and fl ow cytometry -based frequency were used to determine circulating absolute CD3 + / CD4 + and CD3 + /CD8 + counts, absolute numbers ± the SEM (bottom graphs), and percent change in absolute numbers over baseline (top graphs) of the respective subsets shown on day 1 (total lymphocytes only), 7, 14, 21, and 28 for all treated subjects, as well as day 55 -90 for subjects treated with 30 or 60 μ g/kg/d. Baseline values represent the mean of four separate analyses performed in each subject within 2 wk before initiation of rhIL-7 therapy. (B) Spleen size: bidimensional product by CT scan obtained at the time points shown; percent changes from the pretherapy scan are plotted. (C -F ) Baseline (1 value obtained on day 0) and day 7, 14, 21, and 28 data points were generated for CD3 + /CD4 + (left) and CD3 + /CD8 + subsets (right). augments antitumor responses, leading to improved survival when combined with antitumor vaccines ( 21,22 ). The capacity for supranormal levels of IL-7 to augment T cell cycling in response to antigens with low affi nity for the TCR appears largely responsible for homeostatic peripheral expansion, which involves increased T cell proliferation to self-antigens during...