409 Pilot Clinical Trial of Lymphocyte-Selective Pentostatin Plus Cyclophosphamide Conditioning, High Dose Sirolimus and Pre-Emptive DLI with Rapamycin-Resistant Donor CD4+ T Cells

Track: Poster Abstracts
Saturday, February 14, 2015, 6:45 PM-7:45 PM
Grand Hall CD (Manchester Grand Hyatt)
David Halverson, MD , Experimental Transplantation and Immunology Branch, NCI, Bethesda, MD
Miriam Mossoba, PhD , ETIB, NCI, Bethesda, MD
Brenna Hansen, RN , Experimental Transplantation and Immunology Branch, NCI, Bethesda, MD
Bazetta Blacklock Schuver, RN , Experimental Transplantation and Immunology Branch, NCI, Bethesda, MD
Seth M. Steinberg, PhD , Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
Fran Hakim, PhD , Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
Syed Abbas Ali, MD , *, Little Rock, AR
Roger Kurlander, MD , Clinical Center, NIH, Bethesda, MD
Juan Gea-Banacloche, MD , Experimental Transplantation and Immunology Branch, NCI, Bethesda, MD
Dennis Hickstein, MD , Experimental Transplantation and Immunology Branch, NCI, Bethesda, MD
Steven Z. Pavletic, MD , Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
Hanh Khuu, MD , Department of Transfusion Medicine, NIH, Bethesda, MD
David F. Stroncek, MD , Department of Transfusion Medicine, National Institutes of Health, Bethesda, MD
Michael R. Bishop, MD , University of Chicago, Chicago, IL
Ronald Gress, MD , * Co-Senior Experimental Transplantation and Immunology Branch/NCI/NIH, Bethesda, MD
Daniel Fowler, MD , Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
Presentation recording not available for download or distribution as requested by the presenting author.

We recently found that early pre-emptiveDLI with donor CD4+ T-Cells cultured in rapamycin (T-Rapa) allowed  allo-engraftment after low-intensity fludarabine plus cyclophosphamide (Cy) host conditioning (Blood, 2013). To evaluate further reductions in conditioning intensity, we conducted a pilot clinical trial of allogeneic HSCT using a novel regimen of pentostatin and low-dose, daily cyclophosphamide (PC) in patients with refractory renal cell carcinoma (RCC, n=10; Table 1). After PC conditioning, patients received high dose sirolimus, a T-replete matched related donor PBSC graft, and multiple, pre-emptive DLI using T-Rapa cells (schema, Fig. 1).  PC conditioning resulted in profound pre-transplant lymphopenia without a single episode of ANC<1000 cells/ul (Fig. 2) and without any grade 3 or greater toxicity. Donor T cell chimerism was rapidly achieved and remained relatively mixed; in contrast, donor myeloid cell chimerism was initially minimal (<1%) but gradually established by day 100 post-HSCT (Fig. 2). There was no case of classical acute GVHD (0/10); however, no clinical GVT effects were observed by RECIST criteria, thereby activating a protocol stopping rule.  We conclude that the combination of PC conditioning, high-dose sirolimus, and pre-emptive T-Rapa DLI is a very safe method of achieving allo-engraftment without substantial conditioning toxicity or acute GVHD. However, this approach yielded split, mixed chimerism, which was not conducive to GVT effects against refractory RCC.  The remarkable safety and minimal intensity of this platform make it an attractive transplant approach for non-malignant disorders but will require modifications aimed at promoting GVT effects in malignant disorders.

 

Disclosures:
Nothing To Disclose
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