Development of the therapy with an intratumoral administration of dendritic cells in combination with radiation or anti-cancer drugs against oral cancer : Application to clinical trial.

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Dendritic cells (DCs) are professional antigen-presenting cells. Adequately matured DCs can stimulate T cells to induce tumor-specific cytotoxic T lymphocytes (CTLs). A streptococcal anticancer immunotherapeutic agent OK-432 can strongly mature DCs. In tumor-bearing mouse model, radiation therapy (RT) or oral administration of anticancer drug TS-1 followed by an intratumoral injection of syngeneic bone-marrow-derived DCs and of OK-432 resulted in inducing CTLs and in inhibiting tumor growth. The therapy did not elicit any significant effects in tumor-bearing mice in which Toll-like receptor (TLR) 4 is mutated. We have already succeeded in isolating an active component of OK-432 (lipoteichoic acid-related molecule OK-PSA). OK-PSA matured DCs far better, than original OK-432 in vitro, and OK-PSA-treated DCs stimulated allogeneic T cells to produce IFN-γ, and to induce allo-antigen specific CTLs. In in vivo model, TS-1+DCs+OK-PSA therapy exhibited anticancer effect stronger than the therapy using TS-1, DCs and OK-432. Based on these basic data, we have started an early stage clinical trial, "the therapy with an intratumoral administration of DCs in combination with TS-1 and OK-432", in oral cancer patients in which the standard therapies were not effective. Of 5 cases, complete remission (CR) was observed in one case, partial remission (PR) in 3 cases, and stable desease (SD) in one case. No significant toxicity over grade 3 was observed. It was strongly suggested that an intratumoral administration in combination with TS-1 and OK-432 is safety and effective in oral cancer patients.