CD40ligand-expressing dendritic cells induce regression of hepatocellular carcinoma by activating innate and acquired immunity in vivo

Dendritic cells (DCs) are professional antigen-presenting cells able to prime T-cells against tumor-associated antigens (TAA), but their potential to induce hepatocellular carcinoma (HCC) regression is still limited. CD40/CD40L interaction is essential for DC activation and induction of antigen-specific T-cells. In this study, transduction of TAA-pulsed DC with a CD40L-encoding adenovirus (Ad-CD40L) was used to improve the immune response induced by DC toward HCC. Bone marrow-derived DC from C3H/HeNcrl mice were cultured with granulocyte-macrophage colony-stimulating factor and interleukin-4. On day 6, tumor-lysate pulsed DCs were infected with adenoviruses. HCCs were induced by inoculation of mice with Hepa129-cells subcutaneously. When tumor-volume was 100 to 400 mm(3), DCs were injected intratumorally, subcutaneously, or intravenously. Ad-CD40L transduction exerted CD40/CD40L interactions between DCs, increasing DC immunostimulation with up-regulation of CD80/CD86- and interleukin-12 (IL-12) expression. Intratumoral injection of CD40L-DC was superior to intravenous or subcutaneous treatments, yielding tumor elimination in almost 70% of mice. Moreover, all tumor-free animals were protected against hepatic tumor cell rechallenge. In a preventive setting, subcutaneous injection of CD40L-expressing DCs protected 50% of mice for more than 3 months toward tumor cell challenge. The induced immune response seemed to be dependent on cross-priming with Th1-lymphocytes in the lymph nodes, because transduced DCs were redetected in lymphoid tissues. In addition, immunohistochemistry of tumors indicated a significant tumor infiltration with CD4+, CD8+ T cells and natural killer (NK) cells. Tumor-infiltrating lymphocytes were tumor-specific, as shown in interferon-gamma (IFN-gamma) enzyme-linked immunosorbent spot and T-cell proliferation assays. CONCLUSION: Transduction of DCs with Ad-CD40L increases significantly the stimulatory capacity of DCs. Intratumoral injection of DCs activates both acquired and innate immunity, inducing complete regression of established tumors and long-term immunity against tumor recurrence. This approach improves the antitumoral potential of DCs.     

A systematic review of phase-II trials of thalidomide monotherapy in patients with relapsed or refractory multiple myeloma

The activity of thalidomide in relapsed or refractory multiple myeloma is widely accepted but not yet demonstrated in a randomised-controlled trial. A systematic review of the published clinical trials of these patients could reduce the possible bias of single phase-II studies. A systematic search identified 42 communications reporting on 1674 patients. Thirty-two trials used an escalating dosing regimen and four a fixed dose regimen (one dose with 50 mg/d, three doses with 200 mg/d). The target dose in the dose escalating trials was 800 mg/d in 17 trials, 400-600 mg/d in 10 and 200 mg/d in one trial. The intention-to-treat population for efficacy was 1629 patients with a median age of 62 years. The complete and partial (>50% reduction in monoclonal protein) response rate was 29.4% (95%-confidence interval, 27-32%). The rates for minor responses or stable disease were 13.8% (12-16%) and 11.0% (9-13%). Progressive disease was reported in 9.9% (8-11%). The median overall survival from all trials was reported at 14 months. Severe adverse events (grade III-IV) included somnolence 11%, constipation 16%, neuropathy 6%, rash 3%, thrombo-embolism 3%, cardiac 2%. In conclusion, thalidomide monotherapy achieved complete and partial responses in 29.4% of patients with relapsed or refractory multiple myeloma.     

Clinical trials on CIK cells: first report of the international registry on CIK cells (IRCC)

Purpose  

Recently, a subset of natural killer T lymphocytes termed “cytokine-induced killer (CIK) cells” has been described. To build an international registry, we collected the clinical data and treatment of patients with cancer using CIK cells from the literature and the respective investigators. This registry is expected to set a new set of standards on the reporting of results from clinical trials using CIK cells. A standardized reporting system will accelerate discoveries and allows us to improve treatment to benefit the patients.     

Enhanced CD21 expression and shedding in chronic lymphatic leukemia: a possible pathomechanism in disease progression

CD21 is a 145-kDa membrane glycoprotein mainly expressed on B cells and follicular dendritic cells, and is involved in B-cell activation, survival and proliferation. CD21 can be cleaved to give soluble CD21 (sCD21), which is constantly shed in healthy persons. We show here that plasma sCD21 levels are higher, while B-cell surface CD21 expression levels are lower in B-cell chronic lymphocytic leukemia (B-CLL) patients, but not in multiple myeloma (MM) patients. High sCD21 levels in the blood are positively correlated to the number of cells with high CD21 surface expression and the relative amount of CD21 expressed on the B cells. B-CLL patients with swollen lymph nodes had higher amounts of CD21 high-expressing B cells, as well as CD21 low-expressing B cells, as compared to B-CLL patients without swollen lymph nodes.