2015
DOI: 10.1158/1078-0432.ccr-15-0340
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High-Dose Sirolimus and Immune-Selective Pentostatin plus Cyclophosphamide Conditioning Yields Stable Mixed Chimerism and Insufficient Graft-versus-Tumor Responses

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 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 weekl… Show more

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Cited by 9 publications
(5 citation statements)
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“…The positive selection of CD4 + and CD8 + cells using monoclonal antibodies conjugated to magnetic particles is another technique that would likely be effective for enriching the T-cell content of PBMC concentrates. T cells isolated by both elutriation and antibody selection have been used for adoptive cell therapy [1618]. For some patients, the expansion of T cells may, however, be limited by other factors such as prior chemotherapy, the patients’ disease or patients’ genetics.…”
Section: Discussionmentioning
confidence: 99%
“…The positive selection of CD4 + and CD8 + cells using monoclonal antibodies conjugated to magnetic particles is another technique that would likely be effective for enriching the T-cell content of PBMC concentrates. T cells isolated by both elutriation and antibody selection have been used for adoptive cell therapy [1618]. For some patients, the expansion of T cells may, however, be limited by other factors such as prior chemotherapy, the patients’ disease or patients’ genetics.…”
Section: Discussionmentioning
confidence: 99%
“…We sought to evaluate a novel, reduced-intensity conditioning (RIC) approach to BMT for PIDs, a platform designed with the goals of reducing regimen-related toxicities and complications such as GVHD, using alternative donors, and achieving successful engraftment and robust immune reconstitution. An approach to lymphodepletion-centered RIC developed at the National Institutes of Health (NIH) [6,7] was integrated with post-transplantation cyclophosphamide (PTCy) for GVHD prophylaxis, given the low rates of severe acute and chronic GVHD and the comparable outcomes between alternative donors and HLA-matched sibling donors (MSDs) observed with PTCy-based platforms [8][9][10][11][12][13]. Pentostatin with low-dose cyclophosphamide was used as the T-cell-suppressing backbone of conditioning, based on data demonstrating pentostatin plus cyclophosphamide to result in greater T cell functional impairment compared wth fludarabine plus cyclophosphamide, with similar levels of host T cell lymphodepletion [7].…”
Section: Introductionmentioning
confidence: 99%
“…However, although sirolimus has several pro-tolerogenic mechanistic advantages, it is still not understood how best to deploy this agent, and it currently remains a second line therapy that is not clinically superior to CNI (5, 6). This lack of clinical superiority is due to a number of factors: First, post-transplant monotherapy with sirolimus, in the absence of adjunctive pre-transplant GVHD prevention (7, 8) is unable to sufficiently control Teff activation and, thus cannot in itself prevent GVHD (3, 9). Further, combination strategies that pair sirolimus with CNI or inhibitors of proliferation (such as mycophenolate mofetil (MMF) or methotrexate) have not improved rates of GVHD (6, 10, 11), likely due to the antagonistic impact of these agents on Treg function.…”
Section: Introductionmentioning
confidence: 99%