A phase II study of allogeneic natural killer cell therapy to treat patients with recurrent ovarian and breast cancer

Abstract

Background Natural killer (NK) cells derived from patients with cancer exhibit diminished cytotoxicity compared with NK cells from healthy individuals. We evaluated the tumor response and in vivo expansion of allogeneic NK cells in recurrent ovarian and breast cancer. Methods Patients underwent a lymphodepleting preparative regimen: fludarabine 25 mg/m2 × 5 doses, cyclophosphamide 60 mg/kg × 2 doses, and, in seven patients, 200 cGy total body irradiation (TBI) to increase host immune suppression. An NK cell product, from a haplo-identical related donor, was incubated overnight in 1000 U/mL interleukin (IL)-2 prior to infusion. Subcutaneous IL-2 (10 MU) was given three times/week × 6 doses after NK cell infusion to promote expansion, defi ned as detection of ≥ 100 donor-derived NK cells/µL blood 14 days after infusion, based on molecular chimerism and flow cytometry. Results Twenty (14 ovarian, 6 breast) patients were enrolled. The median age was 52 (range 30–65) years. Mean NK cell dose was 2.16 × 107 cells/kg. Donor DNA was detected 7 days after NK cell infusion in 9/13 (69%) patients without TBI and 6/7 (85%) with TBI. T-regulatory cells (Treg) were elevated at day +14 compared with pre-chemotherapy (P = 0.03). Serum IL-15 levels increased after the preparative regimen (P = <0.001). Patients receiving TBI had delayed hematologic recovery (P = 0.014). One patient who was not evaluable had successful in vivo NK cell expansion. Conclusions Adoptive transfer of haplo-identical NK cells after lymphodepleting chemotherapy is associated with transient donor chimerism and may be limited by reconstituting recipient Treg cells. Strategies to augment in vivo NK cell persistence and expansion are needed.

NK cell-based immunotherapy for malignant diseases

“…Strategies to augment in vivo NK cell persistence and expansion might be required to reduce this chimeric effect; Treg reconstitution in the recipient, for example, can repress this chimerism. 179 Additionally, a phase II clinical trial using UCB-derived allogeneic NK cells has been performed in leukemia and myelodysplastic syndrome patients, but was terminated, and no conclusions can be drawn as to its efficacy.…”

Extending the lifespan and efficacies of immune cells used in adoptive transfer for cancer immunotherapies–A review

“…Findings from the trial showed a lack of NK cell expansion and restricted anti-tumor effects in patients with ovarian and breast cancer. 37 This limited response may be due to the immunosuppressive effects of cancer cells on NK cells, as listed above. 28,38 Recently, research has also shown that some NK cells can become NK memory cells, which have a longer life span.…”

Donor Selection for Ex Vivo -Expanded Natural Killer Cells as Adoptive Cancer Immunotherapy

“…Although freshly isolated allogeneic NK cells have been utilized in clinical trials [14][15][16], cell numbers are …”