CLINICAL STUDY OF LOCOREGIONAL ADOPTIVE CELLULAR IMMUNOTHERAPY FOR THE CANCER OF DIGESTIVE TRACT

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In first 2 years, to develop a novel tumor-specific adoptive cellular immunotherapy, we conducted a phase I/II clinical trial for patients with refractory advanced or recurrent esophageal cancer. The tumor cell-stimulated T cells (AuTL) were propagated ex vivo by a mixed culture with autologous tumor cell and peripheral blood lymphocytes. In 5 of 11 cases (45%), the AuTLs showed a specific cytotoxicity against autologous tumor cell and other tumor cells lines in an HLA- class I molecular restricted manner tested by ^<51>Cr release assay and IFN-g production assay. These AuTLs were administrated into the tumor locoregionally by repeated direct or endoscopic injections. The clinical response was observed with 1 CR, 3 PRs, 2 SDs and 5 PDs and adverse events were all tolerable. This study also suggested CTL activity in the administrated cells and percentages of CD16^+ cells in the peripheral blood might be laboratory markers for prediction of clinical response. In last year, in order to investigate a new modulator to enhance effects of this immunotherapy, we focused on a synergistic effect in inducing human tumor cell apoptosis between the proteasome inhibitor (PS-341) in combination with the cytotoxic protein TRAIL. High doses of PS-341 alone were toxic to the most human tumor cell lines. However, in presence of TRAIL the apoptosis would be greatly enhanced by intermediate doses of PS-341. Proteasome inhibitor might be a novel modulator for cancer immunotherapy.