Nonmyeloablative allogeneic bone marrow transplantation as immunotherapy for hematologic malignancies and metastatic solid tumors in preclinical models.
OBJECTIVE
We previously demonstrated that a combination of mild total lymphoid irradiation (TLI) with selective depletion of the host's donor-reactive cells allows for stable and graft-vs-host disease (GVHD)-free engraftment of allogeneic bone marrow (BM). In this study, we investigated the efficacy of this nonmyeloablative strategy for BM transplantation (BMT) as immunotherapy for minimal residual disease.


METHODS
BALB/c mice inoculated with leukemia (BCL1) or breast carcinoma (4T1) cells were conditioned for BMT with TLI (200 cGy) followed by priming with donor (C57BL/6) BM cells on day 1, and by injection with 200 mg/kg cyclophosphamide on day 2. After conditioning (day 3), recipients were transplanted with BM cells from the same donor. Treated animals were monitored for 230 days for survival, development of leukemia/solid tumor, and GVHD.


RESULTS
BMT converted the mice to complete chimeras and prevented development of leukemia in 90% of recipients and locally growing breast carcinoma in 40% of the mice. Immunization of donors of the second BM with 4T1 cells prevented development of breast carcinoma in 80% of 4T1 inoculated mice. Fewer animals treated for malignancy by nonmyeloablative BMT died of GVHD than those treated by myeloablative BMT. However, late GVHD-related mortality in mice treated for leukemia was higher than after nonmyeloablative BMT to naive recipients (p < 0.00001). Infusion of host-type anti-donor immune lymphocytes 8 days after BMT improved the survival of recipients treated for leukemia without affecting engraftment and the graft-vs-leukemia potential of donor BM.


CONCLUSIONS
Effective eradication of malignant cells can be achieved following allogeneic BMT after nonmyeloablative conditioning.
Prigozhina
Tatyana B
TB
Department of Bone Marrow Transplantation, The Cancer Immunotherapy & Cancer Immunobiology Research Center, Hadassah University Hospital, Jerusalem, Israel.
Gurevitch
Olga
O
Morecki
Shoshana
S
Yakovlev
Elena
E
Elkin
Gregory
G
Slavin
Shimon
S
D000818:Animals; D016026:Bone Marrow Transplantation; D003520:Cyclophosphamide / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control; D007167:Immunotherapy; D007942:Leukemia, Experimental / Q000276:immunology / Q000473:pathology / Q000532:radiotherapy / Q000628:therapy*; D008198:Lymph Nodes / Q000528:radiation effects; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000532:radiotherapy / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D018365:Neoplasm, Residual / Q000628:therapy; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous
D003520:Cyclophosphamide