IMPROVED EXPERIMENTAL CANCER-THERAPY BY RADIOANTIBODY DOSE INTENSIFICATION AS A RESULT OF SYNGENEIC BONE-MARROW TRANSPLANTATION

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 radioant ibody-induced leukopenia and thrombocytopenia (J. Natl. Cancer Inst. 8 4:399, 1992; Cancer 73:1073, 1994). As an alternative to the use of cy tokines, we investigated the effect of syngeneic bone marrow transplan tation 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 36 0-mu Ci dose of radioantibody (LD(100/28))-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 wi thin 21 days of therapy (normal recovery after 275 mu Ci 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 mole effective than that from cytokine-primed mice whose marrow cells were actively c ycling 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 (2x10( 3) U/d) and GM-CSF (1 mu g/d) intervention, provided a greater stimula tion of peripheral WBC counts than either approach alone; however, fur ther dose escalation under these conditions was not feasible. The 30% intensification in radioantibody dose offers a therapeutic advantage f or both bulky disease (GW-39 subcutaneous nude mouse model) and microm etastatic disease (GW-39 intrapulmonary model). In the bulky tumor mod el, the increase in administered dose resulting from BMT extends the 8 -week growth delay observed at 275 mu Ci I-131-MN-14 IgG by an additio nal 7 weeks. In the metastatic model, dose intensification increased m edian animal survival from 15 to 23 weeks. Therefore, by optimizing th e use of BMT, a greater therapeutic benefit can be derived from radioa ntibody therapy in a solid tumor model. This study represents a proof of principle, that BMT can be effective for low-dose-rate therapy as i t has been for short-duration intense chemotherapy and radiation thera py. It also highlights several important issues to consider when attem pting to apply the method in the clinic.