Table 3 Recent applications of cytokine-induced and memory-like NK cells for the treatment of hematological malignancies
Methods | Clinical Trial | Phase | Condition or Disease | Intervention/ Treatment | Response | References |
|---|---|---|---|---|---|---|
Cytokine-induced NK cells | NCT03019666 | I | R/R MM, NHL | NK cells cultured ex vivo with IL-15 and nicotinamide (GDA-201) | The overall response rate was 74% in 19 NHL patients,13 had a CR and 1 had a PR | [205] |
_ | _ | AML | Haploidentical donor NK cells using double immunomagnetic depletion and IL-15 stimulation | Preliminary demonstrated the safety and feasibility of manufactured NK IL15 cells | [206] | |
NCT03050216 NCT01898793 | II I/II | R/R AML, MDS | IL-15 (ALT-803) activated, haploidentical donor NK cells IL-12 (Aldesleukin) induced NK cells | IL-15 enhanced responder CD8 T cell activation and proliferation, compared with IL-2 alone, demonstrating that additional IL-15 can hasten donor NK cell elimination. These results indicated that stimulating patient CD8 T-cell allo-rejection responses may critically limit allogeneic cellular therapy supported with IL-15 | [207] | |
_ | _ | High-risk R/R AML | Double-bright (CD56bright/CD16bright) NK cells from HLA-haploidentical donors modified to express membrane-bound IL-21 | Among 13 involved patients, 7 were observed with intermediate or adverse cytogenetics. No dose-limiting toxicities, infusion-related fever, or CRS were observed. OR was 78.6% and CR was 50.0% | [208] | |
NCT02763475 | II | AML | Haploidentical K562-mb15-41BBL-activated and expanded NK cells administrated with IL-2 | The 3-year OS was 83.3% and the cumulative 3-year relapse rate was 28.6%. There were no conclusions regarding efficacy because the study was terminated early | [209] | |
NCT01385423 NCT02395822 | I II | R/R AML | Intravenous or subcutaneous rhIL-15 after lymphodepleting chemotherapy and haploidentical NK cells | Escalating doses of rhIL-15 (0.3–1.0 ug/kg) were given on 12 consecutive days in a phase 1 trial. Of 26 patients, 36% had robust in vivo NK-cell expansion at day 14, and 32% achieved CR.16 patients received 10 once per day doses of SC rhIL-15 at 2.0 μg/kg on a phase 2 trial. NK-cell expansion at day 14 was seen in 27% of the patients, and 40% achieved remission | [210] | |
AML in first CR1 at high risk for recurrence | CTV-1 leukemia cell line lysate-activated NK cells isolated from related HLA-haploidentical donors | 2 patients remained relapse-free in post-trial follow-up, exceeding 42.5 months. Donor NK cell microchimerism was detected on day 7 in 10 of 12 patients, with 3 patients having evidence of donor cells on day 14 or later | [211] | |||
_ | _ | MDS/AML | IL2-activated haploidentical NK cells | Only transient adverse events were observed in the 16 patients. 6 patients achieved objective responses with CR, marrow CR, or PR | [212] | |
_ | I | AML | IL-2-dependent NK cell line (NK-92) | None of the involved 7 patients experienced dose-limiting toxicities. Cell dose-dependent effects in the plasma levels of several cytokines were observed | [114] | |
_ | I | High-risk myeloid malignancies | Membrane-bound IL-21 expanded donor NK cells | Among 13 involved patients, no infusional reactions or dose-limiting toxicities occurred. 1 patient died of nonrelapse mortality, 1 patient relapsed, all others were alive and in remission at last follow-up | [213] | |
NCT02477787 | II | High-risk AML and MDS | IL-15 and -21-activated NK cells | Intention-to-treat analysis showed a lower disease progression for the NK cell infusion group (30-month cumulative incidence, 35% vs 61%, P = 0.040) | [214] | |
Memory-like NK cells | NCT03068819 | I | Post-HCT relapsed AML | ML NK cells generated by stimulation with IL-12, -15, and -18 | 4 of 8 evaluable patients achieved CR at day 28. 2 maintained a durable remission for > 3 months, with 1 in remission for > 2 years. No significant toxicity was experienced | [215] |
NCT04024761 | I | Myeloid malignancies | Cytokine-induced ML NK cells | In the first 6 enrolled patients, infusion of ML NK cells led to a rapid 10- to 50-fold in vivo expansion that was sustained over months. The infusion was well tolerated, with fever and pancytopenia as the most common adverse events | [216] | |
_ | _ | Cytokine-induced ML NK cells | Clinical responses were observed in 5 of 9 evaluable patients, including 4 CR | [203] | ||
NCT02782546 | II | R/R AML | Cytokine-induced ML NK cells | In 15 patients, donor ML NK cells were well tolerated, and 87% of patients achieved a composite CR at day + 28 | [217] |