In vitro-activated tumor-bearing host T cells and the effectiveness of tumor vaccine immunotherapy

Vaccination during periods of lymphopenia may facilitate immune responses to weak self-antigens and enhance antitumor immunity. The objective of this study was to determine the effectiveness of tumor vaccine immunotherapy combined with immune reconstruction using tumor-bearing host immune cells in lymphopenia, and to investigate the role of tumor-bearing host T cells activated in vitro during immunotherapy. Animal study conducted in the First Affiliated Hospital of Xi'an Jiaotong University from January 2009 to January 2010. Lymphopenia was induced by cyclophosphamide. A reconstituted immune system with different syngeneic lymphocytes was employed, including lymphocytes from naive rats [unsensitized group], tumor-bearing rats [tumor-bearing group], and tumor-bearing rats activated in vitro [activated group]. All rats were immunized with granulocyte-macrophage colony-stimulating factor [GM-CSF]-modified NuTu-19 ovarian cancer [GM-CSF/NuTu-19] cells. Tumor vaccine-draining lymph nodes [TVDLNs] were harvested, and then stimulated to induce effector T cells [T[E]]. T[E] were then adoptively transferred to rats bearing a 3-day pre-established abdominal tumor [NuTu-19], and the survival rate was calculated. Compared with the unsensitized group, the levels of interleukin-2 [IL-2] were significantly lower in the tumor-bearing group, whereas that of IL-4 were significantly higher [P<.05]. The number of CD4+T cells secreting interferon-gamma and the specific cytotoxicity of CD8+ cytotoxic T lymphocytes were significantly lower [P<.05]. The survival was significantly higher in the activated group compared with the other groups. Lymphocytes from tumor-bearing rats activated in vitro can effectively reverse the immunosuppressive effects of tumor-bearing hosts

Pharmacokinetic/pharmacodynamic relationships of FTY720 in kidney transplant recipients

FTY720 is a new and effective immunosuppressive agent, which produces peripheral blood lymphopenia through a lymphocyte homing effect. We investigated the relationship between the dose of FTY720 or blood concentration (pharmacokinetics, PK) and peripheral lymphopenia (pharmacodynamics, PD) in 23 kidney transplant recipients randomized to receive FTY720 (0.25-2.5 mg/day) or mofetil mycophenolate (2 mg/day) in combination with cyclosporine and steroids. FTY720 dose, blood concentrations and lymphocyte counts were determined weekly before and 4 to 12 weeks after transplantation. The effect of PD was calculated as the absolute lymphocyte count or its reductions. PK/PD modeling was used to find the best-fit model. Mean FTY720 concentrations were 0.36 ± 0.05 (0.25 mg), 0.73 ± 0.12 (0.5 mg), 3.26 ± 0.51 (1 mg), and 7.15 ± 1.41 ng/ml (2.5 mg) between 4 and 12 weeks after transplantation. FTY720 PK was linear with dose (r² = 0.98) and showed low inter- and intra-individual variability. FTY720 produced a dose-dependent increase in mean percent reduction of peripheral lymphocyte counts (38 vs 42 vs 56 vs 77, P < 0.01, respectively). The simple Emax model [E = (Emax * C)/(C + EC50)] was the best-fit PK/PD modeling for FTY720 dose (Emax = 87.8 ± 5.3 percent and ED50 = 0.48 ± 0.08 mg, r² = 0.94) or concentration (Emax = 78.3 ± 2.9 percent and EC50 = 0.59 ± 0.09 ng/ml, r² = 0.89) vs effect ( percent reduction in peripheral lymphocytes). FTY720 PK/PD is dose dependent and follows an Emax model (EC50 = 0.5 mg or 0.6 ng/ml). Using lymphopenia as an FTY720 PD surrogate marker, high percent reductions ( about 80 percent) in peripheral lymphocytes are required to achieve best efficacy to prevent acute allograft rejection.