Memory Phenotype CD8+T Cells Are Superior to Naive CD8+T Cells in Separating Graft Anti-Tumor Activity From Gvhd After Bone Marrow Transplantation; Application to DLI.

Abstract

Abstract 2452Poster Board II-429We compared the graft anti-tumor effect and GVHD activities of naturally occurring naive and memory phenotype subsets of C57BL/6 (H-2b) CD8+ T cells after bone marrow transplantation into BALB/c (H-2d) mice. The tumor used for the study was the BCL1 lymphoma, a spontaneously arising non-transfected cell line. We found that naive CD8+ T cells (CD62LhiCD44lo) express higher levels of gut homing molecules a4b7, CCR9 and CD103 compared to memory subsets comprised of both effector (CD62LloCD44hi) and central memory cells (CD62LhiCD44hi). The proliferation of the naive cells was ten-fold higher than memory phenotype cells against BALB/c stimulators and memory cells secreted significantly more IFNg in the MLR. All BALB/c hosts without tumor cells that were given donor memory CD8+T cells along with T cell depleted bone marrow cells (TCD BM) survived over 100 days of transplantation without significant weight loss compared to TCDBM controls. However, 25% of the mice given naive CD8+ T cells and TCD BM died due to GVHD and had significantly greater weight loss compared to TCD BM controls or to hosts given memory CD8+ T cells and TCD BM. BALB/c hosts given 500 BCL1 and TCD BM all died of lymphoma within 28 days of transplantation. Hosts given BCL1 cells, TCD BM and either memory or naive cells cleared the tumor by day 28 but weight loss and survival was significantly improved in the memory versus naive cell groups despite non significant differences in the GVHD scores in the liver and gut at day 100. Ex vivo imaging of mice receiving BCL1 tumor cells, TCD BM, and CD8+T cells from luciferase transgenic donors showed increased accumulation of naive phenotype CD8+T cells in the liver and the gut compared to memory phenotype cells after 6 days of transplantation. We compared the memory and naive CD8+ T cells in a model of donor lymphocyte infusion (DLI) in which BALB/c mice with progressive growth of BCL1 tumor after TCD BM transplantation were given infusion of the CD8+ T cells. Both naive and memory cells are effective in clearing the tumor, and converting the hosts from mixed to complete chimeras. Differences in GVHD are observed. In conclusion, CD8+ memory phenotype T cells are a desirable subset that mediates potent anti-tumor activity without severe GVHD, and can be used in a DLI model. Disclosures:No relevant conflicts of interest to declare.