Current & Future Immunotherapy of HCC
Immune-based therapy can represent an improvement in outcomes for patients with HCC, as many clinical trials demonstrate. In a historical study, 150 patients were randomized to receive either IL-2 and anti-CD3-activated PBMC, or observation after curative resection. The results were encouraging, both with respect to time to relapse and disease-free survival (p = 0.09). A trial testing the administration of APC in HCC patients who received pulsed DC with autologous tumor lysate showed an increase of 1-year survival (63 vs 10%; p = 0.038). Most recently, murine models have demonstrated that immunotherapy and DC in combination with IL-12 in an adjuvant setting activates T and natural killer cells and reduces HCC recurrence.
DCs could be used as a potential cellular adjuvant for the production of specific tumor vaccines. Recently, El Ansary and colleagues' study evaluated the safety and efficacy of the autologous pulsed DC vaccine in advanced HCC patients in comparison with supportive treatment. Thirty patients with advanced HCC who were not suitable for radical or locoregional therapies were enrolled. Patients were divided into two groups, group I, consisting of 15 patients, received vaccination with mature autologous DCs pulsed ex vivo with a liver tumor cell line lysate. Group II (control group; n = 15) received supportive treatment. To generate DCs, 100 and 4 ml of venous blood were obtained from each patient. DCs were identified by CD80, CD83, CD86 and HLA-DR expressions using flow cytometry. Follow-up at 3 and 6 months postinjection by clinical, radiological and laboratory assessment was carried out. Improvements in OS were observed. Partial radiological response was obtained in two patients (13.3%), stable course in nine patients (60%) and four patients (26.7%) showed progressive disease (died at 4 months postinjection). Both CD8 T cells and serum IFN-γ were elevated after DC injection. The authors conclude that autologous DC vaccination in advanced HCC patients is safe and well tolerated. Ex vivo treatment with CTLA-4 blocking antibodies of T-cell CD8, isolated from patients affected by HCC, showed an expanded antigen-specific T-cell repertoire, alluding that ipilimumab may possess a therapeutic potential in treating hepatocarcinoma. A therapeutic advantage, regarding refractory solid tumors, can be obtained by an antibody-mediated block of PD-1, meanwhile the inhibition of Tim-3 signaling has been demonstrated to restore anti-tumor T-cell action in preclinical models. Another approach has been described to overcome cancer-mediated immunosoppression, involving the reactivation of hyporesponsive tumor-specific T cells by supplying T-cell growth factors (IL-15 and IL-7) or costimulatory agonists (anti-4-1BB and anti-OX40). Other treatment options regarding tumor homing and penetration of T-effector cells are being evaluated because of the correlation between T-cell infiltration of hepatocarcinoma lesions and OS. Strategies are divided into two big groups: restoring the tumor vascularity, and upregulation of chemokines and molecules of adhesion. Monoclonal antibodies against VEGF and its receptors, such as sorafenib or bevacizumab, appear to have a restricted therapeutic effect in clinical trials. In fact a hallmark of new vessel formation in HCC is their structural and functional abnormality; this leads to an abnormal tumor microenvironment characterized by low oxygen tension and low therapeutic agent levels. Preclinical data sustain the idea that angiogenesis and tumor vascularity still represent a potential target that, through the generation of long-lived antivascular T-cell responses via VEGFR2 vaccine, can be suppressed via a T-cell dependent process. Proinflammatory chemokines demonstrated their importance in HCC-specific T-cell immunity, such as IFN-γ- inducible chemokines CXCL9/Mig and CXCL10/IP-10, high levels of which correlated with the presence of CD8 T cell in hepatocarcinoma. It is still unknown if this pattern of chemokine expression is correlated with a positive prognosis, as has been seen in patients with cervical/uterine tumors. Agents that can induce the expression of chemokines and adhesion molecules by vascular activation represent another promising approach.