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

Abstract

BackgroundNK 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.MethodsPatients 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 × 109, 1.0 × 109, 2.0 × 109 cells/injection, three patients/one cohort).ResultsTotal 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.ConclusionWe 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 UMIN000007527Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0632-8) contains supplementary material, which is available to authorized users.

Clinical Applications of Natural Killer Cells

“…Clinical trials using autologous NK cells have been performed targeting solid tumors such as colorectal cancer, non-small cell lung cancer, melanoma, kidney cancer and esophageal cancer [87][88][89]. In general, autologous NK cell therapy is safe without side effects such as GvHD [87], but its therapeutic effect is limited to some cancer types [74].…”

“…In general, autologous NK cell therapy is safe without side effects such as GvHD [87], but its therapeutic effect is limited to some cancer types [74]. An activation culture with IL-2 and OKT3 or Hsp70 has been reported to be able to efficiently induce the proliferation of NK cells [74], in particular, the retronectin culture method of Sakamoto et al showed a high amplification efficiency (about 4720-fold) [89].…”

Cancer Immunotherapy: New Technology to Target Cancer Cells

“…These immuno ligands have demonstrated antitumour activity both in vitro and in vivo. In phase I clinical trial study conducted on advanced digestive cancer patient, NK cells infusion was well tolerated by all patients with no adverse events [17]. However, there was no clinical response was reported but nevertheless, there is still an area of improvement within the context of genetic modification for developing NK-cells based effective cancer immunotherapies as shown in Figure 1.…”

Recombinant Antibodies to Arm Cytotoxic Lymphocytes in Cancer Immunotherapy

“…Indeed, ex vivo cytokine activated and expanded autologous NK cells were shown to be safe; however, no clinical responses in cancer patients with metastatic melanoma, renal cell carcinoma or advance gastrointestinal cancer were seen [133,134,135]. These limitations could potentially be overcome by combination of autologous NK cells (either the patients' endogenous NK cells or reinfused autologous cells after ex vivo stimulation/expansion) in combination with a bispecific immuno-engager and optional IL-15.…”