Introduction: Tremelimumab is a fully human monoclonal antibody that binds to CTLA-4 expressed on the surface of activated T lymphocytes and results in inhibition of B7-CTLA-4-mediated downregulation of T-cell activation. Patients with advanced hepatocellular carcinoma, who progressed on standard of care, were treated with tremelimumab and tumor ablation (radiofrequency ablation and transcatheter arterial chemoembolization) to augment anti-tumor immunity. Treatment was safe and feasible. Encouraging clinical activity has been seen with objective confirmed partial responses in 4/12 (33%) evaluable patients and a time to progression of 7.4 months. Here we report first results from immunoanalysis evaluating tumor biopsies, immune cell subsets in peripheral blood and serum viral loads in patients with chronic HBV or HCV infection.
Methods: 20 Patients with HCC were treated with tremelimumab and tumor ablation on clinical trial NCT01853618. Tumor biopsies were taken at the time of ablation and peripheral blood mononuclear cells (PBMC) were collected before and during treatment in a subset of patients. Serum samples were tested for viral load (quantitative HCV RNA). Serum HBsAg titers were measured by chemiluminescent microparticle immunoassay (CMIA) using the ARCHITECT platform (Abbott Laboratories, Chicago, IL), as per the manufacturer's instructions. Tumor biopsies with analyzed by immunohistochemistry for CD3, CD4, CD8, CD20 and Granzyme B. Eleven-color flow cytometry was performed to study PBMC using the following antibodies: CD4, CD3, CD4, CD8, CD11c, CD14, CD19, CD20, CD25, CD38, CD45RA, CD56, CD123, CD127, CCR7, CCR4, CXCR3, PD-1, 4-1BB, TIM3, CTLA4, PD-L1, ICOS, HLA-DR. Statistical analysis was done using the Wilcoxon signed rank test. Results presented are preliminary and update data will be presented at meeting.
Results: Immunohistochemical analysis of tumor biopsies demonstrated an increase in the CD3+CD8+ T cell population in tumors. CD8+ T cells stained positive for Granzyme A. No changes in the number of CD68+ macrophages were seen. Multi-color flow cytotometry PBMC revealed statistically significant changes after the 1st cycle of activated CD4+ and CD8+ T cells. There was a trend towards a reduction in CD4+ Tregs. Activated CD8+ T cells remained elevated for more than three months. Eight of 9 patients with quantifiable HCV experienced a marked reduction in viral load. Four of 4 HBV patients experienced a reduction in quantitative HepBsAg. Analysis of immune cell phenotype and more in depth analysis of tumor samples is ongoing and will be reported.
Conclusions: Tremelimumab in combination with subtotal TACE or RFA leads to an accumulation of intratumoral CD8+ T cells, an activation of CD4+ and CD8+ T cells in peripheral blood and reductions in HCV viral load and HBsAg.
Citation Format: Firouzeh Korangy, Mei ElGindi, Drew Pratt, David Venzon, Austin Duffy, Oxana Makarova-Rusher, Sid Kerkar, David Kleiner, Bradford Wood, Tim Greten. Tremelimimab activates CD4 and CD8+ T cells in patients with hepatocellular carcinoma. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A195.
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