Combination immunotherapy using autologous tumor-stimulated lymphocytes and conventional chemotherapy for the patients with refractory recurrent cancer

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Experimental research : Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) induces apoptosis in cancer cells by binding to death receptors DR4/DR5. The expression of functional TRAIL protein appears to be rather restricted to immune cells, including T cells, NK cells, dendric cells (DCs) etc. We examined TRAIL sensitivity in the human cancer cell lines and also assessed TRAIL efficacy with EGFR tyrosine kinase inhibitor Gefitinib, and proteasome inhibitor Bortezomib as possible new approach of combination therapy. Our studies demonstrate that Gefitinib and Bortezomib were useful for enhancement of TRAIL sensitivity in part of cell lines suggesting Akt and NFkB pathways as possible target of combining immuno-chemotherapy.Clinical research : Autologous tumor cells stimulated T lymphocytes (AuTL) were generated ex vivo from peripheral blood lymphocytes over a two week co-culturing process with autologous tumor cells. These AuTLs were capable of lysing established tumor cell l … More ines and may have potential for efficacy as an adoptive immunotherapy (IT) in advanced and metastatic refractory cancer patients (pts). We investigated the feasibility of a combination of AuTL transfer and chemotherapy (ChT) based on conventional conditioning regimen in order to take advantage by both the anticancer effects reconstruction of antitumor immune. 19 patients were enrolled in a pilot clinical trial. The conventional ChT regimen was based on standard dose. The median period of treatment was over 11.5 months and median survival time is 14.8 months. Adverse events related to both of the ChT and AuTL transfer at all doses was minimal. 4 of 13 pts achieved major tumor responses (2 CR : complete regression and 2 PR : partial regression) in this study. 3 pts showed progressive disease and 6 pts had stable disease for over 90 days. Two and one of 4 CR/PR pts had increased IFN-γ and TNF-α production no TGF-β1 responses by their PBMC after 3 treatments, respectively. Two out of 6 pts who experienced stable disease after treatment had high IFN-γ and TNF-α responses and no TGF-β1 or IL-4 response. TGF-β1 and IL-4 secretion increased parallaly in 3/3 pts that experienced progressive disease. These data show that combination therapy of AuTL transfer and non-myeloablative ChT is a feasible option for patients with refractory advanced cancers without reducing Thl cytokine responses in peripheral blood of most pts responded to the treatment. According each mechanism of IT and ChT, a more stringent evaluation of AuTL transfer combined with nonmyeloablative ChT for various cancer should be performed to manage the immunodeficiency in pts. Less