High-Dose Sirolimus and Immune-Selective Pentostatin plus Cyclophosphamide Conditioning Yields Stable Mixed Chimerism and Insufficient Graft-versus-Tumor Responses

Miriam E. Mossoba, David C. Halverson, Roger Kurlander, Bazetta Blacklock Schuver, Ashley Carpenter, Brenna Hansen, Seth M. Steinberg, Syed Abbas Ali, Nishant Tageja, Frances T. Hakim, Juan Gea-Banacloche, Claude Sportes, Nancy M. Hardy, Dennis D. Hickstein, Steven Z. Pavletic, Hanh Khuu, Marianna Sabatini, David Stroncek, Bruce L. Levine, Carl H. JuneJacopo Mariotti, Olivier Rixe, Antonio Tito Fojo, Michael R. Bishop, Ronald E. Gress, Daniel H. Fowler

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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 antitumor 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/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.

Original languageEnglish (US)
Pages (from-to)4312-4320
Number of pages9
JournalClinical Cancer Research
Volume21
Issue number19
DOIs
StatePublished - Oct 1 2015

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Pentostatin
Chimerism
Sirolimus
Cyclophosphamide
Transplants
Neoplasms
T-Lymphocytes
Tissue Donors
Neutropenia
Lymphocytes
Drug Therapy
Adoptive Transfer
Conditioning (Psychology)
Renal Cell Carcinoma
Allografts
Siblings
Research Design
Outpatients

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

High-Dose Sirolimus and Immune-Selective Pentostatin plus Cyclophosphamide Conditioning Yields Stable Mixed Chimerism and Insufficient Graft-versus-Tumor Responses. / Mossoba, Miriam E.; Halverson, David C.; Kurlander, Roger; Schuver, Bazetta Blacklock; Carpenter, Ashley; Hansen, Brenna; Steinberg, Seth M.; Ali, Syed Abbas; Tageja, Nishant; Hakim, Frances T.; Gea-Banacloche, Juan; Sportes, Claude; Hardy, Nancy M.; Hickstein, Dennis D.; Pavletic, Steven Z.; Khuu, Hanh; Sabatini, Marianna; Stroncek, David; Levine, Bruce L.; June, Carl H.; Mariotti, Jacopo; Rixe, Olivier; Fojo, Antonio Tito; Bishop, Michael R.; Gress, Ronald E.; Fowler, Daniel H.

In: Clinical Cancer Research, Vol. 21, No. 19, 01.10.2015, p. 4312-4320.

Research output: Contribution to journalArticle

Mossoba, ME, Halverson, DC, Kurlander, R, Schuver, BB, Carpenter, A, Hansen, B, Steinberg, SM, Ali, SA, Tageja, N, Hakim, FT, Gea-Banacloche, J, Sportes, C, Hardy, NM, Hickstein, DD, Pavletic, SZ, Khuu, H, Sabatini, M, Stroncek, D, Levine, BL, June, CH, Mariotti, J, Rixe, O, Fojo, AT, Bishop, MR, Gress, RE & Fowler, DH 2015, 'High-Dose Sirolimus and Immune-Selective Pentostatin plus Cyclophosphamide Conditioning Yields Stable Mixed Chimerism and Insufficient Graft-versus-Tumor Responses', Clinical Cancer Research, vol. 21, no. 19, pp. 4312-4320. https://doi.org/10.1158/1078-0432.CCR-15-0340
Mossoba, Miriam E. ; Halverson, David C. ; Kurlander, Roger ; Schuver, Bazetta Blacklock ; Carpenter, Ashley ; Hansen, Brenna ; Steinberg, Seth M. ; Ali, Syed Abbas ; Tageja, Nishant ; Hakim, Frances T. ; Gea-Banacloche, Juan ; Sportes, Claude ; Hardy, Nancy M. ; Hickstein, Dennis D. ; Pavletic, Steven Z. ; Khuu, Hanh ; Sabatini, Marianna ; Stroncek, David ; Levine, Bruce L. ; June, Carl H. ; Mariotti, Jacopo ; Rixe, Olivier ; Fojo, Antonio Tito ; Bishop, Michael R. ; Gress, Ronald E. ; Fowler, Daniel H. / High-Dose Sirolimus and Immune-Selective Pentostatin plus Cyclophosphamide Conditioning Yields Stable Mixed Chimerism and Insufficient Graft-versus-Tumor Responses. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 19. pp. 4312-4320.
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abstract = "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 antitumor 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/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.",
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T1 - High-Dose Sirolimus and Immune-Selective Pentostatin plus Cyclophosphamide Conditioning Yields Stable Mixed Chimerism and Insufficient Graft-versus-Tumor Responses

AU - Mossoba, Miriam E.

AU - Halverson, David C.

AU - Kurlander, Roger

AU - Schuver, Bazetta Blacklock

AU - Carpenter, Ashley

AU - Hansen, Brenna

AU - Steinberg, Seth M.

AU - Ali, Syed Abbas

AU - Tageja, Nishant

AU - Hakim, Frances T.

AU - Gea-Banacloche, Juan

AU - Sportes, Claude

AU - Hardy, Nancy M.

AU - Hickstein, Dennis D.

AU - Pavletic, Steven Z.

AU - Khuu, Hanh

AU - Sabatini, Marianna

AU - Stroncek, David

AU - Levine, Bruce L.

AU - June, Carl H.

AU - Mariotti, Jacopo

AU - Rixe, Olivier

AU - Fojo, Antonio Tito

AU - Bishop, Michael R.

AU - Gress, Ronald E.

AU - Fowler, Daniel H.

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N2 - 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 antitumor 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/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.

AB - 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 antitumor 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/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.

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