title: Improved experimental cancer therapy by radioantibody dose intensification as a result of syngeneic bone marrow transplantation.
abstract: Myelosuppressive toxicity is dose-limiting for radioimmunotherapy. We have reported on the use of cytokine intervention (rhIL-1 and rmGM-CSF) to stimulate differentiation of progenitor cells and reduce radioantibody-induced leukopenia and thrombocytopenia (J. Natl. Cancer Inst. 84:399, 1992; Cancer 73:1073, 1994). As an alternative to the use of cytokines, we investigated the effect of syngeneic bone marrow transplantation on the ability to dose-escalate radioantibody. Injection of 10(7) bone marrow cells from a donor mouse 6 to 8 days after a 340- to 360-microCi dose of radioantibody (LD100/28)--a 25 to 30% increase above the maximal tolerated dose--resulted in 100% survival. This observation is associated with a recovery in neutrophil and thrombocyte counts within 21 days of therapy (normal recovery after 275 microCi takes 42 days). None of the mice survived when BMT was done at either 4 or 11 days after radioantibody. Marrow from normal donor mice was more effective than that from cytokine-primed mice whose marrow cells were actively cycling after a 5-day course of IL-1/GM-CSF. The combination of the two myeloprotective approaches, BMT plus a 14-day schedule of IL-1 (2 x 10(3) U/d) and GM-CSF (1 microgram/d) intervention, provided a greater stimulation of peripheral WBC counts than either approach alone; however, further dose escalation under these conditions was not feasible. The 30% intensification in radioantibody dose offers a therapeutic advantage for both bulky disease (GW-39 subcutaneous nude mouse model) and micrometastatic disease (GW-39 intrapulmonary model). In the bulky tumor model, the increase in administered dose resulting from BMT extends the 8-week growth delay observed at 275 microCi 131I-MN-14 IgG by an additional 7 weeks. In the metastatic model, dose intensification increased median animal survival from 15 to 23 weeks. Therefore, by optimizing the use of BMT, a greater therapeutic benefit can be derived from radioantibody therapy in a solid tumor model. This study represents a proof of principle, that BMT can be effective for low-dose-rate therapy as it has been for short-duration intense chemotherapy and radiation therapy. It also highlights several important issues to consider when attempting to apply the method in the clinic.
authors.affiliation: Garden State Cancer Center at the Center for Molecular Medicine and Immunology, Newark, NJ 07103, USA.
authors.forename: R D
authors.initials: RD
authors.lastname: Blumenthal
authors.forename: R M
authors.initials: RM
authors.lastname: Sharkey
authors.forename: D
authors.initials: D
authors.lastname: Forman
authors.forename: G
authors.initials: G
authors.lastname: Wong
authors.forename: J
authors.initials: J
authors.lastname: Hess
authors.forename: D M
authors.initials: DM
authors.lastname: Goldenberg
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D016026:Bone Marrow Transplantation; D003131:Combined Modality Therapy; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use; D006410:Hematopoiesis; D007375:Interleukin-1 / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000532:radiotherapy*; D016499:Radioimmunotherapy / Q000379:methods*; D011879:Radiotherapy Dosage; D016019:Survival Analysis
chemical_list: D000911:Antibodies, Monoclonal; D007375:Interleukin-1; D016178:Granulocyte-Macrophage Colony-Stimulating Factor