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 (A‰) T-cells. The application of aBPs to ALT in vivo or ex vivo may be beneficial. A brief overview of aBPs and A‰ T-cells is provided, together with some preliminary results and discussion of the therapeutic potential of ALT in combination with aBPs. Autologous activated lymphocyte therapy (ALT) has been reported to have a beneficial effect for some malignancies. ALT was first introduced by Rosenberg et al. as an adoptive immunotherapy in the late 1980s (1), and has been further developed to date. In this therapy, peripheral blood mononuclear cells (PBMCs) are activated and proliferated by cultivation under stimulation with an immobilized anti- CD3 antibody (OKT3) and interleukin-2 (IL-2), and administered repeatedly to patients. ALT has been applied to patients with refractory cancer in clinical trials or as unconventional cancer therapy. Many university hospitals and cancer centers have actively investigated the use of ALT and some of them carry out ALT as a "highly advanced medical technology" with the approval of the Ministry of Health, Labor and Welfare in Japan. However, its therapeutic efficacy is limited (2); 10 to 20% response rates of this therapy have been reported (3-15). For ALT to be successful, it may be beneficial to administer it in combination with other therapies, such as chemotherapy, since some success with the combined use of ALT and chemotherapy has been reported (16, 17). Encouraging results of ALT in combination with molecularly targeted therapy using imatinib mesylate have previously been shown (18). Metastatic or primary bone tumors cause much suffering to affected patients because of uncontrollable pain, leading to a poor quality of life. Clinical trials of aBPs have established their efficacy against bone pain and complications, such as pathologic fractures in patients with breast cancer, multiple myeloma and other solid tumors (19- 23). ABPs inhibit bone resorption by directly inhibiting osteoclast function (24-26). Recently, some indirect mechanisms have also been shown to exist. ABPs could activate and induce the proliferation of gamma/delta (A‰) T-cells that have cytotoxic activity against some human tumor cells, indicating its possible antitumor activity (27, 28). The application of aBPs to ALT in vivo or ex vivo may provide a new strategy for treating malignant bone diseases. A brief overview of the aBPs and A‰ T-cells is presented. A case of bone cancer metastases successfully treated with the combination of aBPs and ALT is reported, and preliminary results of a cultivation method for ALT by which A‰ T-cells were predominantly proliferated using aBPs are shown. The therapeutic potential of ALT in combination with aBPs is discussed. A‰ T-cells and Aminobisphosphonates