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

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Summary

The current study was designed to evaluate the safety and efficacy of Ex vivo–expanded and highly activated NK cells (MG4101) on patients with malignant lymphoma or advances, recurrent solid tumors. the findings suggest that the 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.

Patients characteristics

20 patients with malignant lymphoma or advanced, recurrent solid tumors who failed to benefit from standard treatment. All patients were at least 18 years old and had histologically or cytologically confirmed malignant lymphoma or solid tumors, Karnofsky Performance Scale >70, or Eastern Cooperative Oncology Group performance status of 0 to 2 with at least 3 months of expected survival.

Methodology

NK-cell preparation
PBMCs were isolated from random healthy donors, and NK cells were expanded. CD3+ T-cell–depleted PBMCs were expanded at a seeding concentration of 2×105 cells/mL in CellGro SCGM serum-free medium with 1% auto-plasma, 1×106 cells/mL irradiated (2,000 rad) autologous PBMCs, 10 ng/mL of monoclonal antibody to CD3 (OKT3 and 500 IU/mL of IL2 in an A-350N culture bag. NK cells were fed fresh medium with 500 IU/mL of IL2 every 2 days until they were harvested on day 14. K562 was obtained from the ATCC and cultured in RPMI-1640 medium supplemented with 10% FBS.

Treatment

MG4101(allogenic NK cells) was administered intravenously one time (step 1) or repeatedly (step 2). Cohort 1 of step 1 was initiated with the infusion dose of 1×106 cells/kg of MG4101, and drug-related toxicities were assessed for 2 weeks. After safety assessment, cohort 3 (1×106 cells/kg, once weekly, triple infusion) and cohort 4 (3×106 cells/ kg, once weekly, triple infusion) were sequentially proceeded. Next, the escalated dose of 1×107 cells/kg was adoptively transferred to cohort 2 of step 1. When the single dose of 1×107 cells/kg was defined as safe, cohort 5 (1×107 cells/kg, once weekly, triple infusion) and cohort 6 (3×107 cells/kg, once weekly, triple infusion) of step 2 proceeded sequentially. In the case of body temperature above 38oC or toxicities greater than grade 2 in absolute neutrophil count, platelet count, hemoglobin, serum creatinine, total bilirubin, or liver aminotransferase, the administration of MG4101 was withheld.

Results

Toxicity
In step 1 (cohort 1 and cohort 2), none of the subjects showed DLTs and all the toxicities were grade 1 or 2. Furthermore, a serial dose increase of MG4101 in step 1 did not seem to cause a proportionate increase in toxicity. The only grade 2 toxicity in our this was chills, which occurred in 1 patient from cohort 2. In step 2, repeated injection of a higher dose of MG4101 correlated with increased incidence of adverse events, but all remained between grades 1 and 2. MG4101-related GVHD was not observed in any of the subjects. As the maximum planned dose of this study was found to be tolerable, the MTD was not determined and 3×107 cells/kg was set as the MFD. Further, toxicity-related suspension of MG4101 injection did not occur during this study.
Clinical response
Responses to the MG4101 were evaluated in 17 patients, including 2 with lymphoma and 15 with advanced solid cancer. Three patients were not evaluable due to incomplete treatment or follow-up loss. As for the lymphoma patients, C1-01 exhibited stable disease (SD) and C4-01 had progressive disease (PD). Of the solid cancer patients, 7 (47%) had SD and 8 (53.0%) had PD. After MG4101 treatment, all of the lymphoma patients and 33% of solid cancer patients received further chemotherapies. The median progression-free survival (PFS) in patients with SD was 4 months (range, 2 to 18 months).

Conclusion

In contrast, administration of MG4101 reduced regulatory T cells and myeloid- derived suppressor cells and suppressed TGFþ 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.

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Scientific article publishing date :1/19/2016

Immucura identifier BSC21_223EN

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