Phase I Study of Random Healthy Donor–Derived Allogeneic Natural Killer Cell Therapy in Patients with Malignant Lymphoma or Advanced Solid Tumors

Abstract

Natural killer (NK) cells with mismatched killer cell immunoglobulin-like receptor-ligand pairs have shown efficacy and been proven safe in treatment of cancer patients. Ex vivo-expanded and highly activated NK cells (MG4101) had been generated under good manufacturing practice conditions, which demonstrated potent anticancer activity in vitro and in vivo in preclinical studies. The current phase I clinical trial was designed to evaluate safety and possible clinical efficacy of repetitive administrations of MG4101 derived from random unrelated healthy donors into patients with malignant lymphoma or advanced, recurrent solid tumors. The maximum dose (3 × 10(7) cells/kg, triple infusion) was tolerable without significant adverse events. Of 17 evaluable patients, 8 patients (47.1%) showed stable disease and 9 (52.9%) showed progressive disease. We also evaluated the capacity of MG4101 to influence host immune responses. Administration of MG4101 augmented NKG2D expression on CD8(+) T cells and upregulated chemokines that recruit T cells. In contrast, administration of MG4101 reduced regulatory T cells and myeloid-derived suppressor cells and suppressed TGFβ production. In conclusion, administration of a large number of MG4101 cells was not only safe and feasible, but also exhibited efficacy in maintaining the effector arm of the host immune response.

Optimization of Large-Scale Expansion and Cryopreservation of Human Natural Killer Cells for Anti-Tumor Therapy

“…In our previous study, we established an efficient method for large-scale expansion of NK cells from healthy donors under GMP conditions for 2 weeks (12). We also completed a phase I clinical trial for solid tumor patients, administering NK cells produced from the 2 week-manufacturing process (11). However, the expansion of NK cells by the 2 wk-manufacturing process was limited in terms of the number of NK cells in the final products.…”

“…Clinical trials using ex vivo -expanded allogeneic NK cells have been performed in patients with advanced non-small cell lung cancer (phase I) and recurrent ovarian or breast cancers (phase II) (8910). Our group has also performed a phase I clinical trial with ex vivo -expanded allogeneic NK cells derived from random donors in patients with malignant lymphoma or advanced sold tumors (11). These studies have demonstrated the safety of allogeneic NK cell therapy.…”

The Rise of Allogeneic Natural Killer Cells As a Platform for Cancer Immunotherapy: Recent Innovations and Future Developments

“…Though an antitumor effect of the adoptively transferred NK cells could be observed, their persistence in vivo was shorter (between 1 and 4 days) in comparison to other clinical trials. This stresses the potential need for an effective NK cell-promoting conditioning regimen, to increase the life span and migration of NK cells in patients (69). …”

Phase I clinical trial of adoptive transfer of expanded natural killer cells in combination with IgG1 antibody in patients with gastric or colorectal cancer

“…Consistent with this observation, Yang et al recently demonstrated that activated allogeneic NK cell therapy can reduce the Treg population in peripheral blood. 38 Moreover, they demonstrated that adoptive NK therapy reduced not only Tregs, but also myeloid-derived suppressor cells (MDSC) in peripheral blood. These results suggest that ex vivo-activated NK cells have a novel role in overcoming the negative function of immune suppressor cells, through unknown mechanisms.…”