title: High-Dose Sirolimus and Immune-Selective Pentostatin plus Cyclophosphamide Conditioning Yields Stable Mixed Chimerism and Insufficient Graft-versus-Tumor Responses.
abstract: OBJECTIVE
  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 antitumor effects while avoiding GVHD.
  
  
  METHODS
  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/m(2)/dose) combined with daily, dose-adjusted cyclophosphamide (C; ≤200 mg/d) 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 posttransplant), and sirolimus was discontinued early (day 60 posttransplant).
  
  
  RESULTS
  PC conditioning depleted host T cells without neutropenia or infection and facilitated donor engraftment (10 of 10 cases). High-dose sirolimus therapy inhibited multiple T-Rapa DLI, as evidenced by stable mixed donor/host chimerism. No antitumor 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.
authors.affiliation: Experimental Transplantation and Immunology Branch, Center for Cancer Research, NIH, Bethesda, Maryland.
authors.forename: Miriam E
authors.initials: ME
authors.lastname: Mossoba
authors.affiliation: Experimental Transplantation and Immunology Branch, Center for Cancer Research, NIH, Bethesda, Maryland.
authors.forename: David C
authors.initials: DC
authors.lastname: Halverson
authors.affiliation: Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, Maryland.
authors.forename: Roger
authors.initials: R
authors.lastname: Kurlander
authors.affiliation: Experimental Transplantation and Immunology Branch, Center for Cancer Research, NIH, Bethesda, Maryland.
authors.forename: Bazetta Blacklock
authors.initials: BB
authors.lastname: Schuver
authors.affiliation: Experimental Transplantation and Immunology Branch, Center for Cancer Research, NIH, Bethesda, Maryland.
authors.forename: Ashley
authors.initials: A
authors.lastname: Carpenter
authors.affiliation: Experimental Transplantation and Immunology Branch, Center for Cancer Research, NIH, Bethesda, Maryland.
authors.forename: Brenna
authors.initials: B
authors.lastname: Hansen
authors.affiliation: Biostatistics and Data Management, NCI, NIH, Bethesda, Maryland.
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.affiliation: Experimental Transplantation and Immunology Branch, Center for Cancer Research, NIH, Bethesda, Maryland.
authors.forename: Syed Abbas
authors.initials: SA
authors.lastname: Ali
authors.affiliation: Experimental Transplantation and Immunology Branch, Center for Cancer Research, NIH, Bethesda, Maryland.
authors.forename: Nishant
authors.initials: N
authors.lastname: Tageja
authors.affiliation: Experimental Transplantation and Immunology Branch, Center for Cancer Research, NIH, Bethesda, Maryland.
authors.forename: Frances T
authors.initials: FT
authors.lastname: Hakim
authors.affiliation: Experimental Transplantation and Immunology Branch, Center for Cancer Research, NIH, Bethesda, Maryland.
authors.forename: Juan
authors.initials: J
authors.lastname: Gea-Banacloche
authors.affiliation: Georgia Regents University Cancer Center, Augusta, Georgia.
authors.forename: Claude
authors.initials: C
authors.lastname: Sportes
authors.affiliation: University of Maryland Greenbaum Cancer Center, Baltimore, Maryland.
authors.forename: Nancy M
authors.initials: NM
authors.lastname: Hardy
authors.affiliation: Experimental Transplantation and Immunology Branch, Center for Cancer Research, NIH, Bethesda, Maryland.
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Hickstein
authors.affiliation: Experimental Transplantation and Immunology Branch, Center for Cancer Research, NIH, Bethesda, Maryland.
authors.forename: Steven Z
authors.initials: SZ
authors.lastname: Pavletic
authors.affiliation: Department of Transfusion Medicine, Clinical Center, NIH, Bethesda, Maryland.
authors.forename: Hanh
authors.initials: H
authors.lastname: Khuu
authors.affiliation: Department of Transfusion Medicine, Clinical Center, NIH, Bethesda, Maryland.
authors.forename: Marianna
authors.initials: M
authors.lastname: Sabatini
authors.affiliation: Department of Transfusion Medicine, Clinical Center, NIH, Bethesda, Maryland.
authors.forename: David
authors.initials: D
authors.lastname: Stroncek
authors.affiliation: University of Pennsylvania, Abramson Family Cancer Research Center, Philadelphia, Pennsylvania.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Levine
authors.affiliation: University of Pennsylvania, Abramson Family Cancer Research Center, Philadelphia, Pennsylvania.
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
authors.affiliation: Fondazione IRCCS Instituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Jacopo
authors.initials: J
authors.lastname: Mariotti
authors.affiliation: University of New Mexico Cancer Center, Albuquerque, New Mexico.
authors.forename: Olivier
authors.initials: O
authors.lastname: Rixe
authors.affiliation: Genitourinary Malignancies Branch, Center for Cancer Research, NIH, Bethesda, Maryland.
authors.forename: Antonio Tito
authors.initials: AT
authors.lastname: Fojo
authors.affiliation: The University of Chicago School of Medicine, Chicago, Illinois.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Bishop
authors.affiliation: Experimental Transplantation and Immunology Branch, Center for Cancer Research, NIH, Bethesda, Maryland.
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Gress
authors.affiliation: Experimental Transplantation and Immunology Branch, Center for Cancer Research, NIH, Bethesda, Maryland. dhfowler@helix.nih.gov.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Fowler
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000473:pathology / Q000628:therapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D005260:Female; D020350:Graft vs Tumor Effect / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D016219:Immunotherapy, Adoptive; D008212:Lymphocyte Depletion; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D015649:Pentostatin / Q000008:administration & dosage; D036102:Peripheral Blood Stem Cell Transplantation; D010641:Phenotype; D020123:Sirolimus / Q000008:administration & dosage; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D018183:Transplantation Chimera; D019172:Transplantation Conditioning / Q000379:methods; D014184:Transplantation, Homologous; D016896:Treatment Outcome
chemical_list: D015649:Pentostatin; D003520:Cyclophosphamide; D020123:Sirolimus