Graft-versus-tumor effects on murine mammary carcinoma in a model of nonmyeloablative haploidentical stem cell transplantation

Abstract

Despite a slight decrease in mortality over the last decade, breast cancer still remains a leading cause of cancerrelated death in women. Although anti-tumor effects have been observed after allogeneic stem cell transplantation (SCT), this treatment is not standard care owing to graftversus-host disease (GVHD) and scarcity of suitable donors. With the aim of reducing treatment-related mortality and increasing donor availability in clinical situations, we developed a preclinical mouse model that combines nonmyeloablative conditioning with the use of haploidentical donor-recipient pairs. To mimic active disease, CB6F1 mice were inoculated with 5 Â 10 4 4T1 mammary carcinoma cells 10 days before transplantation. Keratinocyte growth factor (KGF) was used as GVHD prophylaxis. Syngeneic (CB6F1) SCT did not cure any of the mice and KGF treatment did not influence tumor development. After transplantation with haploidentical (B6CBAF1) bone marrow and splenocytes, however, tumor outgrowth was reduced and long-term disease-free survival (43 months) was observed in 9/18 (50%) (P ¼ 0.0011) of the animals. We conclude that in a model of murine breast cancer, a graft-versus-tumor effect can be induced by a nonmyeloablative haploidentical SCT procedure.

Elimination of the chemotherapy resistant subpopulation of 4T1 mouse breast cancer by haploidentical NK cells cures the vast majority of mice

“…1, groups b and c.1, respectively). In accordance with our previous results [16], tumor-induced mortality was high (88%) in the negative control group of mice that had either not been treated ( Table 1, exp. 2, group c.2) and a prolonged progression-free survival of the whole group (P = 0.01).…”

“…2b) and in our previous experiments with haploBMST [16], none of the cured mice developed a palpable tumor after infusion of the NK cell-enriched haploidentical SPL cells. Figure 2b also shows that in the four out of ten mice of experimental group c.2 that were ultimately not cured (exp.…”

“…We previously showed that haploidentical BMSPLT from B6CBAF1 donor mice cured *50% of 4T1 breast tumor bearing CB6F1 recipients [16]. Before the hypothesis, if donor alloreactive NK cells are involved can be addressed, it is necessary to functionally show that B6CBAF1 (H-2 b/k ) NK cells are alloreactive toward CB6F1 (H-2 b/d ) cells based on missing H-2 k .…”

“…Based on the observation that alloreactive NK cells can kill AML cells and the previous observation by our group that haploidentical bone marrow (BM) transplantation combined with immune cells from the haploidentical donor spleen (haplo-BMSPLT) after a non-myeloablative conditioning regimen (chemotherapy and radiotherapy) cured mice from 4T1 breast cancer [16], we tested the hypothesis if haploidentical NK cells can cure mice from 4T1 breast cancer. Before showing the results of these experiments, we address the question if the previously described subpopulation of slow-dividing clonogenic cells in the 4T1 breast cancer model [17] represents the chemoresistant fraction, stressing the resemblance of the mouse model with human metastasized breast cancer in this particular respect.…”

Haploidentical hematopoietic SCT increases graft-versus-tumor effect against renal cell carcinoma

“…Haploidentical-SCT (haplo-SCT) could provide an enhanced allogeneic T-cell and natural killer (NK)-cell response and augment GVT effect due to the MHC molecule disparity. Vanclee et al 8 showed in murine breast cancer model that haplo-SCT could successfully induce anti-tumor activity and provide a survival advantage compared with syngeneic transplant. Non-myeloablative haplo-HSCT was reported to induce anti-tumor activity in one patient with advanced RCC after successful engraftment, but the patient eventually developed progression of the disease 1 year after transplant.…”