Allogeneic hematopoietic cell transplant (HCT) is a widely used therapy for hematologic malignancy. It is important to give the option of HCT to patients without an HLA-matched donor; this is most acute for ethnic minorities. Haploidentical HCT may offer the best or only chance for cure but often fails due to persistant malignancy or fatal toxicity. It is important to improve disease control without increased toxicity of the regimen. We have shown that CD45 radioimmunotherapy (RIT) delivers radiation to leukemic sites, sparing normal organs. We hypothesize haploidentical HCT may be enhanced via CD45 RIT by maximizing delivery to target tissue with minimal toxicity by reducing total-body irradiation (TBI) and chemotherapy. We performed studies to find the maximal intensity of anti-leukemic RIT combined with haploidentical HCT while preserving graft-versus-leukemia effects. We established an HCT regimen in B6SJLF1/J mice (H-2Db haplotype) conditioned with fludarabine (FLU, days -6 to -2), followed by TBI (250, 500, 750 cGy; day -1). Mice received 15 million donor (CB6F1/J, H-2Dd) BM cells (day 0), then cyclophosphamide (CY) for graft-versus-host disease (GvHD) prophylaxis (day +2). Chimerism was TBI dose-dependent; mice receiving ≥500 cGy were fully chimeric 4 weeks post-HCT, persisting ≥8 months. We then treated B6SJLF1/J mice with or without FLU and 200-400 μCi of 90Y-labeled anti-murine CD45 Ab (30F11, day -3), followed by 15 million donor BM cells (day 0) and CY (day +2). All mice receiving 200 or 300 μCi 90Y-CD45 Ab survived 30 days after HCT with no evidence of toxicity or GvHD. Four of 10 mice receiving 400 μCi 90Y-CD45 Ab died by day 25 due to toxicity. At day 25 blood was taken to detect chimerism via flow cytometry. Three of 5 mice that received 200 μCi 90Y-CD45 Ab and FLU showed chimerism with 23-77% CD8+ T-cells expressing H-2Dd. Four of 5 (80%) mice receiving 300 μCi 90Y-30F11 and 2/3 (67%) receiving 400 μCi 90Y-30F11, in the presence of FLU, were chimeric with 22-89% and 25-64% CD8+ donor cells, respectively. Mice receiving 200, 300, or 400 μCi 90Y-CD45 Ab without FLU were chimeric with 10-71% donor cells in 4/5 (80%), 2/5 (40%) and 1/4 (25%) mice, respectively. These data suggest anti-CD45 RIT may be a well-tolerated regimen allowing engraftment of haploidentical marrow without TBI and chemotherapy. Current studies testing pretargeted RIT may improve targeting of malignant CD45+ cells with reduced TBI and FLU, and increased therapeutic index.
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