The therapeutic potential of immuno-cell therapy of cancer in combination with aminobisphosphonates.

Many university hospitals and cancer centers in Japan have actively investigated the use of autologous activated lymphocyte therapy (ALT). However its therapeutic efficacy was found to be quite limited. The efficacy of aminobisphosphonates (aBPs) has been shown for osteolytic bone disease. aBPs could activate and induce the proliferation of gamma/delta (gamma/delta) T-cells. The application of aBPs to ALT in vivo or ex vivo may be beneficial. A brief overview of aBPs and gamma/delta T-cells is provided, together with some preliminary results and discussion of the therapeutic potential of ALT in combination with aBPs.

Combination therapy with dendritic cell vaccine and IL-2 encapsulating polymeric micelles enhances intra-tumoral accumulation of antigen-specific CTLs.

Dendritic cell (DC) vaccine is a promising immunotherapy for cancer due to its ability to induce antigen-specific CTLs efficiently. However, a number of clinical studies have implied insufficient therapeutic benefits with the use of MHC class 1 restricted peptide-pulsed DC vaccine. To enhance the clinical efficacy, we examined combination therapy of DC vaccine pulsed with OVA peptide and intravenous low dose unmodified IL-2 (IL-2 solution) administration against EG7 tumor-bearing mice. Unexpectedly, no additional effects of IL-2 solution were observed on CTL induction and the therapeutic effects of DC vaccine, possibly because of the short half-life of IL-2 in plasma. Therefore, we generated IL-2-encapsulating polymeric micelles (IL-2 micelle), which showed prolonged IL-2 retention in the circulation after intravenous administration compared with IL-2 solution. When mice were treated with OVA peptide-pulsed DCs in combination with IL-2 micelle, OVA-specific CTLs were efficiently induced in the spleen in comparison with DC vaccine combined with IL-2 solution or DC vaccine alone. In addition, combination therapy of DC vaccine and IL-2 micelle against EG7 tumor-bearing mice induced the efficient accumulation of antigen-specific CTLs into the tumor and marked anti-tumor effects. Thus, the administration of IL-2 micelle can significantly enhance DC vaccine efficacy against tumors.

Cell behavior analysis to evaluate proliferative potentials of human lymphocytes expanded and activated for therapeutic use.

The cluster designation 3-lymphokine activated killer (CD3-LAK) culture was conducted using human lymphocytes obtained from different donors. It was found that donor-dependent variances existed in terms of lag time and minimum doubling time, which were process parameters for comprehending the proliferative potentials of cells in an early phase with weak growth and in a subsequent phase with active growth, respectively. To correlate these variances with culture performances, cellular behaviors were estimated by constructing a custom-made observation tool that can capture and process images of culture surfaces. The tool enabled us to determine time-lapse changes in an average projected cell area and the frequency of cell aggregates during the culture in a noninvasive manner. It was found that linear relationships were obtained both between lag time and average projected cell area, and between minimum doubling time and formation rate of cell aggregates, irrespective of culture performance fluctuation depending on each donor state. It is concluded that the developed tool is helpful for operating CD3-LAK culture while monitoring the state of human lymphocytes.