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High-Dose Sirolimus and Immune-Selective Pentostatin Plus Published OnlineFirst June 12, 2015; DOI: 10.1158/1078-0432.CCR-15-0340 Cancer Therapy: Clinical Clinical Cancer Research High-Dose Sirolimus and Immune-Selective Pentostatin plus Cyclophosphamide Conditioning Yields Stable Mixed Chimerism and Insufficient Graft-versus-Tumor Responses Miriam E. Mossoba1, David C. Halverson1, Roger Kurlander2, Bazetta Blacklock Schuver1, Ashley Carpenter1, Brenna Hansen1, Seth M. Steinberg3, Syed Abbas Ali1, Nishant Tageja1, Frances T. Hakim1, Juan Gea-Banacloche1, Claude Sportes4, Nancy M. Hardy5, Dennis D. Hickstein1, Steven Z. Pavletic1, Hanh Khuu6, Marianna Sabatini6, David Stroncek6, Bruce L. Levine7, Carl H. June7, Jacopo Mariotti8, Olivier Rixe9, Antonio Tito Fojo10, Michael R. Bishop11, Ronald E. Gress1, and Daniel H. Fowler1 Abstract Purpose: We hypothesized that lymphoid-selective host con- (days 0, 14, and 45 posttransplant), and sirolimus was discon- ditioning and subsequent adoptive transfer of sirolimus-resistant tinued early (day 60 posttransplant). allogeneic T cells (T-Rapa), when combined with high-dose Results: PC conditioning depleted host T cells without sirolimus drug therapy in vivo, would safely achieve antitumor neutropenia or infection and facilitated donor engraftment effects while avoiding GVHD. (10 of 10 cases). High-dose sirolimus therapy inhibited Experimental Design: Patients (n ¼ 10) with metastatic renal multiple T-Rapa DLI, as evidenced by stable mixed donor/ cell carcinoma (RCC) were accrued because this disease is rela- host chimerism. No antitumor responses were detected by tively refractory to high-dose conditioning yet may respond to RECISTcriteriaandnosignificant classical acute GVHD was high-dose sirolimus. A 21-day outpatient regimen of weekly observed. pentostatin (P; 4 mg/m2/dose) combined with daily, dose-adjust- Conclusions: Immune-selective PC conditioning represents a ed cyclophosphamide (C; 200 mg/d) was designed to deplete new approach to safely achieve alloengraftment without neutro- and suppress host T cells. After PC conditioning, patients received penia. However, allogeneic T cells generated ex vivo in sirolimus matched sibling, T-cell–replete peripheral blood stem cell are not resistant to the tolerance-inducing effects of in vivo sir- allografts, and high-dose sirolimus (serum trough target, 20–30 olimus drug therapy, thereby cautioning against use of this ng/mL). To augment graft-versus-tumor (GVT) effects, multiple intervention in patients with refractory cancer. Clin Cancer Res; T-Rapa donor lymphocyte infusions (DLI) were administered 21(19); 4312–20. Ó2015 AACR. Introduction graft-versus-tumor (GVT) effects. Reduced intensity conditioning decreases toxicity but promotes mixed chimerism (1) and graft Allogeneic hematopoietic cell transplantation (HCT) is limited rejection or tumor progression (2). Intensified post-HCT immune by conditioning toxicity, graft rejection, GVHD, and insufficient suppression or graft T-cell depletion reduces GVHD but can decrease GVT effects (3); furthermore, donor lymphocyte infusion (DLI) using unmanipulated T cells can mediate GVT effects but 1Experimental Transplantation and Immunology Branch, Center for Cancer Research, NIH, Bethesda, Maryland. 2Department of Labora- also mediate GVHD (4). To address these limitations, we con- tory Medicine, Clinical Center, NIH, Bethesda, Maryland. 3Biostatistics ducted a pilot clinical trial of immune-selective conditioning, in and Data Management, NCI, NIH, Bethesda, Maryland. 4Georgia vivo 5 sirolimus GVHD prophylaxis, and multiple infusions of DLI Regents University Cancer Center, Augusta, Georgia. University of ex vivo Maryland Greenbaum Cancer Center, Baltimore, Maryland. 6Depart- products manufactured in sirolimus. ment of Transfusion Medicine, Clinical Center, NIH, Bethesda, Mary- Conditioning varies from myeloablative to reduced intensity to 7 land. University of Pennsylvania, Abramson Family Cancer Research nonmyeloablative (5). However, an ultra–low-intensity platform Center, Philadelphia, Pennsylvania. 8Fondazione IRCCS Instituto Nazionale dei Tumori, Milan, Italy. 9University of New Mexico Cancer that avoids any neutropenia has not been fully explored. Stem cell Center, Albuquerque, New Mexico. 10Genitourinary Malignancies engraftment may not be fully reliant on conditioning-induced 11 Branch, Center for Cancer Research, NIH, Bethesda, Maryland. The "marrow space" (6); we thus reasoned that nonneutropenic University of Chicago School of Medicine, Chicago, Illinois. conditioning would permit stem cell engraftment if immunologic Corresponding Author: Daniel H. Fowler, NIH, 10 Center Drive, CRC, 3-EAST rejection was prevented. Conditioning also reduces tumor bur- Labs, 3-3330. Bethesda, MD 20892. Phone: 301-435-8641; Fax: 301-480-4354; den, but this rationale is weakened in chemotherapy refractory E-mail: [email protected] settings. Finally, because conditioning reduces graft rejection, it doi: 10.1158/1078-0432.CCR-15-0340 should be directed toward host T cells that primarily mediate Ó2015 American Association for Cancer Research. rejection (7). An immune-selective regimen that avoided 4312 Clin Cancer Res; 21(19) October 1, 2015 Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2015 American Association for Cancer Research. Published OnlineFirst June 12, 2015; DOI: 10.1158/1078-0432.CCR-15-0340 High-Dose Sirolimus and GVT Effects conditioning (26) or with calcineurin inhibitors (27). However, Translational Relevance campath plus high-dose sirolimus (target, 30 ng/mL) after non- Graft rejection, GVHD, and insufficient graft-versus-tumor myeloablative conditioning was safe and effective for GVHD (GVT) effects each limit the therapeutic application of alloge- prevention (28). We thus reasoned that high-dose, single-agent neic hematopoietic cell transplantation (HCT), particularly for sirolimus would be safe after immune selective PC conditioning solid tumors such as metastatic renal cell carcinoma. This trial and represent adequate GVHD prophylaxis after T-cell–replete used three interventions to address these limitations: (i) lym- transplant and multiple T-Rapa DLI. phocyte-selective host conditioning using pentostatin plus We evaluated this therapy in refractory metastatic renal cell dose-adjusted cyclophosphamide (PC regimen), (ii) high- carcinoma (RCC), thereby providing a rationale for lymphocyte- dose sirolimus therapy, and (iii) augmentation of T-cell– specific conditioning intended for rejection abrogation rather replete allogeneic HSCT with additional donor lymphocyte than tumor reduction. Metastatic RCC is susceptible to an allo- þ infusions (DLI) consisting of CD4 T cells manufactured ex geneic GVT effect that is generally associated with GVHD, as vivo in sirolimus (T-Rapa cells). The PC regimen represents a described by the National Heart Lung and Blood Institute (29) new approach to prevent graft rejection, as it selectively mod- and a summation report from 21 European countries (30). ulated host T cells without neutropenia or infection and safely However, GVT effects were not observed in a separate study permitted alloengraftment. High-dose sirolimus effectively (31). Thus, more robust methods of harnessing GVT effects and prevented GVHD but also inhibited multiple T-Rapa DLI, modulating GVHD are required in patients with RCC. Finally, thereby offsetting any potential beneficial direct antitumor metastatic RCC can respond to temsirolimus (32), thus suggesting effect of sirolimus. These results caution against use of high- that high-dose sirolimus might yield an antitumor benefit. dose sirolimus during allogeneic T-cell therapy in patients with refractory cancer. Materials and Methods Clinical trial design and implementation The trial (schema, Fig. 1; ClinicalTrials.gov, NCT00923845) neutropenia would yield direct safety advantages and also reduce was approved by the National Cancer Institute (NCI) institutional conditioning-related induction of GVHD (8). review board and implemented according to an Investigational We used pentostatin plus daily cyclophosphamide (Cy) con- New Drug Application accepted by FDA. All subjects provided ditioning that was personalized on the basis of efficacy [absolute informed consent before participation. On-study dates ranged lymphocyte count (ALC) reduction] and safety [absolute neutro- from June 2008 to June 2010. Subjects were enrolled on the basis phil count (ANC) preservation]. Pentostatin was used as trans- of age (18–75 years), presence of metastatic RCC [any histology; plant conditioning with neutropenia-inducing doses of total active central nervous system (CNS) disease excluded], availabil- body irradiation (9, 10) or busulfan (11). Pentostatin plus bolus ity of an eligible 6 of 6 HLA-matched sibling donor, history of dose Cy (600 mg/m2) caused neutropenia (12); as such, we used nephrectomy, 1 prior systemic therapy, life expectancy 3 low-dose Cy (200 mg/d) and allowed Cy reductions depending months, Karnofsky score 80, and adequate organ function. upon achievement of ALC reduction targets. In a murine model, Patients received a 21-day course of pentostatin (Nipent, Hospira; pentostatin plus daily Cy (PC) depleted and suppressed T cells intravenous infusion on days 1, 8, and 15; 4 mg/m2/dose, and prevented marrow allograft rejection more effectively than adjusted for renal insufficiency) and oral Cy (200 mg flat dose/ fludarabine plus Cy (13). PC therapy also prevented murine day). The protocol stated that the goal of PC therapy was to reduce sensitization to a foreign immunotoxin (14);
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