Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer.

BACKGROUND: NK cells can destroy tumor cells without prior sensitization or immunization. Tumors often lose expression of MHC molecules and/or antigens. However, NK cells can lyse tumor cells in a non-MHC-restricted manner and independent of the expression of tumor-associated antigens. NK cells are therefore considered ideal for adoptive cancer immunotherapy; however the difficulty of obtaining large numbers of fully functional NK cells that are safe to administer deters its clinical use. This phase I clinical trial seeks to address this obstacle by first developing a novel system that expands large numbers of highly activated clinical grade NK cells, and second, determining if these cells are safe in a mono-treatment so they can be combined with other reagents in the next round of clinical trials. METHODS: Patients with unresectable, locally advanced and/or metastatic digestive cancer who did not succeed with standard therapy were enrolled. NK cells were expanded ex vivo by stimulating PBMCs with OK432, IL-2, and modified FN-CH296 induced T cells. Patients were administered autologous natural killer cell three times weekly via intravenous infusions in a dose-escalating manner (dose 0.5 × 10(9), 1.0 × 10(9), 2.0 × 10(9) cells/injection, three patients/one cohort). RESULTS: Total cell population had a median expansion of 586-fold (range 95-1102), with a significantly pure (90.96 %) NK cell population. Consequently, NK cells were expanded to approximately 4720-fold (range 1372-14,116) with cells being highly lytic in vitro and strongly expressing functional markers such as NKG2D and CD16. This NK cell therapy was very well tolerated with no severe adverse events. Although no clinical responses were observed, cytotoxicity of peripheral blood was elevated approximately twofolds up to 4 weeks post the last transfer. CONCLUSION: We successfully generated large numbers of activated NK cells from small quantities of blood without prior purification of the cells. We also determined that the expanded cells were safe to administer in a monotherapy and are suitable for the next round of clinical trials where their efficacy will be tested combined with other reagents. TRIAL REGISTRATION: UMIN UMIN000007527.

Inquest results on the aged: comparison between Mie Prefecture and three Medical Examiners' Offices in Japan.

In Japan, the medical examiner system was enforced only in three large cities, Tokyo metropolitan, Osaka and Kobe Cities. In other areas without this system, autopsy rates are much lower than in the areas with the system. Since the population of the aged (>/=65 years old) has been increasing recently, the subjects for medicolegal investigations seem to be also increasing. In the present study, between Mie Prefecture and those three Medical Examiner's Offices in Japan, the inquest results during the 5-year-period from 1996 to 2000, especially on the aged, were compared. The aged accounted for approximately 50% of all inquest cases in those areas. Autopsy rates for the aged were 16, 24 and 75% in Tokyo, Osaka and Kobe, respectively. Seventy-five to eighty percent was classified in deaths due to disease. Seventy to seventy-five percent of death due to disease was subclassified in circulatory diseases. The highest incidence of vascular diseases was observed in Kobe whose autopsy ratio was the highest. On the contrary, ambiguous causes of deaths, e.g. heart failure or unknown, were still frequent in Mie Prefecture.