High-Dose Sirolimus And Immune Selective Pentostatin Plus Cyclophosphamide Conditioning Yields Stable Mixed Chimerism and Insufficient Graft-Versus-Tumor Responses

PURPOSE: We hypothesized that lymphoid-selective host conditioning and subsequent adoptive transfer of sirolimus-resistant allogeneic T cells (T-Rapa), when combined with high-dose sirolimus drug therapy in vivo, would safely achieve anti-tumor effects while avoiding GVHD. EXPERIMENTAL DESIGN: Patients (n=10) with metastatic renal cell carcinoma (RCC) were accrued because this disease is relatively refractory to high-dose conditioning yet may respond to high-dose sirolimus. A 21-day outpatient regimen of weekly pentostatin (P; 4 mg/m2/dose) combined with daily, dose-adjusted cyclophosphamide (C; ≤ 200 mg/day) was designed to deplete and suppress host T cells. After PC conditioning, patients received matched sibling, T cell-replete peripheral blood stem cell allografts and high-dose sirolimus (serum trough target, 20-30 ng/ml). To augment graft-versus-tumor (GVT) effects, multiple T-Rapa donor lymphocyte infusions (DLI) were administered (days 0, 14, and 45 post-transplant) and sirolimus was discontinued early (day 60 post-transplant). RESULTS: PC conditioning depleted host T cells without neutropenia or infection and facilitated donor engraftment (10/10 cases). High-dose sirolimus therapy inhibited multiple T-Rapa DLI, as evidenced by stable mixed donor/host chimerism. No anti-tumor responses were detected by RECIST criteria and no significant classical acute GVHD was observed. CONCLUSIONS: Immune-selective PC conditioning represents a new approach to safely achieve alloengraftment without neutropenia. However, allogeneic T cells generated ex vivo in sirolimus are not resistant to the tolerance-inducing effects of in vivo sirolimus drug therapy, thereby cautioning against use of this intervention in patients with refractory cancer.