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T-Rapa6 and T-Rapa12 Cells Differentially Mediate Acute Gvhd after Low-Intensity Allogeneic HCT

Track: Poster Abstracts
Wednesday, February 26, 2014, 6:45 PM-7:45 PM
Longhorn Hall E (Exhibit Level 1) (Gaylord Texan)
David Halverson, MD , Experimental Transplantation and Immunology Branch, NCI, Bethesda, MD
Scott Rowley, MD , John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ
Brenna Hansen, RN , Experimental Transplantation and Immunology Branch, NCI, Bethesda, MD
Bazetta Blacklock Schuver, RN , Experimental Transplantation and Immunology Branch, NCI, Bethesda, MD
Miriam Mossoba, PhD , ETIB, NCI, Bethesda, MD
Seth Steinberg, PhD , Biostatistics and Data Management Section, National Cancer Institute, NIH, Bethesda, MD
Fran Hakim, PhD , Experimental Transplantation and Immunology Branch, NCI, Bethesda, MD
Roger Kurlander, MD , Clinical Center, NIH, Bethesda, MD
Juan Gea-Banacloche, MD , Experimental Transplantation and Immunology Branch, NCI, Bethesda, MD
Claude Sportes, MD , Georgia Regents University Cancer Center, Augusta, GA
Nancy Hardy, MD, , Experimental Transplantation and Immunology, 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, Bethesda, MD
Hanh Khuu, MD , Department of Transfusion Medicine, NIH, Bethesda, MD
Luciano Castiello , Department of Transfusion Medicine, NIH, Bethesda, MD
Marianna Sabatino, PhD , Department of Transfusion Medicine, NIH, Bethesda, MD
David F. Stroncek, MD , Hematology Branch, National Heart, Lung and Blood Institute NHLBI, Bethesda, MD
Bruce Levine, PhD , Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
Carl H. June, MD , Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
Michele L. Donato, MD , John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ
Andre Goy, MD , John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ
Robert Korngold, PhD , John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ
Andrew Pecora, MD , John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ
Michael R. Bishop, MD , University of Chicago, Chicago, IL
Ronald Gress, MD , Experimental Transplantation and Immunology Branch, NCI, Bethesda, MD
Daniel Fowler, MD , Experimental Transplantation and Immunology Branch, NCI, Bethesda, MD

In a phase II clinical trial, pre-emptive DLI using rapamycin-resistant donor CD4+ T cells manufactured in 12-days (T-Rapa12 cells) was associated with conversion of mixed chimerism, GVL effects in patients with refractory hematologic malignancy, and a moderate rate and severity of GVHD (Blood, 2013). We recently found that culture interval truncation to 6-days yielded T-Rapa6 cells with a unique gene expression profile (~6% of genes differentially expressed relative to T-Rapa12 cells; Cytotherapy, 2013). To assess whether T-Rapa6 cells mediate distinct clinical effects relative to T-Rapa12 cells, we conducted a sequential phase II clinical trial (NCT0074490) at the NIH and Hackensack University Medical Center using the exact same low-intensity transplant platform. T-Rapa6 cells were manufactured by ex vivo culture of donor CD4+ T cells using CD3/CD28 co-stimulation and IL-4, IL-2, and rapamycin. Differential in gene expression profile was confirmed during trial implementation (n=39 T-Rapa12 and T-Rapa6 products evaluated).  As in the initial trial, T-Rapa6 cells were infused at d14 post-HCT (2.5 x 107 cells/kg). Patients (pts; n=44) received outpatient chemotherapy (until CD4 < 200 cells/µl) and then received an HLA-matched sibling mobilized allograft. GVHD prophylaxis was cyclosporine plus short-course sirolimus (to d14 post-HCT); low-intensity conditioning was fludarabine (120 mg/m2) and cyclophosphamide (1200 mg/m2). Relative to T-Rapa12 pts, T-Rapa6 pts had similar characteristics (Table I): 36/44 (81.8%) of T-Rapa6 pts had a diagnosis at highest risk for disease progression (Kahl III) and/or were chemotherapy refractory (stable or progressive disease to last regimen). Similar to T-Rapa12 pts, mixed chimerism existed prior to T-Rapa6 DLI (median T and myeloid chimerism at d14 post-HCT: 44% and 35%, respectively). Similar to T-Rapa12 pts, T-Rapa6 pts had a rapid increase in donor chimerism by d28 post-HCT with continued advancement towards full donor chimerism by d100 post-HCT. Relative to T-Rapa12 pts, T-Rapa6 pts had an increased frequency of acute GVHD at days 100 and 180 post-HCT; this increase was primarily attributable to steroid-responsive gut disease. Chronic GVHD incidence did not appear to be substantially increased in T-Rapa6 pts. T-Rapa6 and T-Rapa12 pts had similar survival probabilities and frequency of sustained complete remission; in each cohort, deaths were primarily due to progressive disease. These data provide further support for evaluation of T-Rapa cell pre-emptive DLI after low-intensity allogeneic HCT as this approach associates with consistent alloengraftment, sustained complete remissions, and low transplant-related mortality. The differential gene expression profile existent between T-Rapa12 and T-Rapa6 cells is sufficient to drive differential acute GVHD effects.

Disclosures:
Nothing To Disclose
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