Abstract
PurposeAdministration of 5 million alloreactive natural killer (NK) cells after low-dose chemo-irradiation cured mice of 4T1 breast cancer, supposedly dose dependent. We now explored the efficacy of bone marrow as alternative in vivo source of NK cells for anti-breast cancer treatment, as methods for in vitro clinical scale NK cell expansion are still in developmental phases.MethodsProgression-free survival (PFS) after treatment with different doses of spleen-derived alloreactive NK cells to 4T1-bearing Balb/c mice was measured to determine a dose–response relation. The potential of bone marrow as source of alloreactive NK cells was explored using MHC-mismatched mice as recipients of 4T1. Chemo-irradiation consisted of 2× 2 Gy total body irradiation and 200 mg/kg cyclophosphamide. Antibody-mediated in vivo NK cell depletion was applied to demonstrate the NK cell’s role.ResultsAdministration of 2.5 instead of 5 million alloreactive NK cells significantly reduced PFS, evidencing dose responsiveness. Compared to MHC-matched receivers of subcutaneous 4T1, fewer MHC-mismatched mice developed tumors, which was due to NK cell alloreactivity because in vivo NK cell depletion facilitated tumor growth. Application of low-dose chemo-irradiation increased plasma levels of NK cell-activating cytokines, NK cell activity and enhanced NK cell-dependent elimination of subcutaneous tumors. Intravenously injected 4T1 was eliminated by alloreactive NK cells in MHC-mismatched recipients without the need for chemo-irradiation.ConclusionsBone marrow is a suitable source of sufficient alloreactive NK cells for the cure of 4T1 breast cancer. These results prompt clinical exploration of bone marrow transplantation from NK-alloreactive MHC-mismatched donors in patients with metastasized breast cancer.
Highlights
Mice with 4T1 breast cancer can be cured by transfer of 5 million alloreactive natural killer (NK) cells after a non-myeloablative dose of total body irradiation and cyclophosphamide (‘‘chemo-irradiation’’) [1]
To demonstrate dose dependency of the anti-4T1 breast cancer effect by transferred alloreactive NK cells, 4T1bearing Balb/c mice were treated with chemo-irradiation at 8 and 9 days after 4T1 injection followed by i.v. injection of 5 million NK cells from various donors that differed with respect to the percentage of NK cell alloreactivity toward Balb/c-type cells
Long-lasting breast cancer-free survival resulted in the vast majority (19 out of 20) of mice that received 5 million NK cells from full-alloreactive B6 or B6CBAF1 donors or 10 million NK cells from half-alloreactive CB6F1 mice (9 out of 10), while 90% of the untreated mice died from tumor progression (p \ 0.001 for each treatment group, Fig. 1a)
Summary
Mice with 4T1 breast cancer can be cured by transfer of 5 million alloreactive NK cells after a non-myeloablative dose of total body irradiation and cyclophosphamide (‘‘chemo-irradiation’’) [1]. Unequivocal evidence that transfer of Breast Cancer Res Treat (2017) 161:421–433 alloreactive NK cells exerts an anti-cancer effect in patients does not exist, either because the chemotherapy and/or irradiation applied before the administration may have resulted in increased progression-free survival or because transferred NK cells are not, transiently or only in limited numbers detectable in recipients [10]. It is for this reason that many efforts are currently performed to produce large amounts of NK cells for clinical application, and the success of these approaches is yet to be awaited. As a dose– response relation of the number of transferred alloreactive NK cells and the anti-4T1 breast cancer effect had not been demonstrated yet, we wanted to proof this formally in the current study
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
