During the past year, in collaboration with Dr. John Barrett (NHLBI), we have analyzed our serial quantitative RT-PCR measurements of BCR-ABL expression in peripheral blood as part of a retropective analysis to identify features in the early post-transplantation period which might predict a favorable outcome after allotransplantation for CML. Using BCR-ABL expression to monitor residual tumor mass, these studies revealed a strong association between early lymphocytes recovery (by day 30 post transplant) and molecular remission of CML. The early molecular findings were a useful predictor for later clinical outcome. Flow cytometry studies surprisingly indicated that NK cells (not T cells) were the lymphoid subset most associated with a favorable outcome. Data analysis also revealed an association between the number CD34 cells infused at the time of transplantation and good clinical outcome. The studies suggest maneuvers to increase CD34 cell dose in donor graft products, and/or manipulations to increase early NK cell recovery may be valuable directions for future clinical investigation. Quantitative BCR-ABL levels measured in this laboratory have also been used in a sophisticated case study to assess the relationship between donor derived anti-tumor CD8 T cell responses and the clinical course in a patient who received an allotransplant and multiple donor lymphocyte transfusions to treat CML. In comparing residual disease (based on serial BCR-ABL expression in blood) with anti-tumor T cell levels (measured by K Rezvani a trainee in Dr. Barrett's laboratory) there was a clear reciprocal relationship between these measures. This was particularly striking during clinical responses to donor lymphocyte infusions and alpha interferon administration. Additional studies of the responsible CD8 cells demonstrated that they were effector T cells expanded in response to antigenic stimulation. In the coming year, I am a co-investigator in a clinical vaccine trial initiated by Dr. Barrett, Rezvani, and associates testing the value of vaccination against tumor antigens (WT-1 and PR1) in suppressing tumor recurrence after allotransplantation for hematologic malignancy. In this setting, we will be using a quantitative RT-PCR assay for measuring WT1 tumor antigen expression to monitor residual disease during serial vaccination
| Rezvani, K; Price, D A; Brenchley, J M et al. (2007) Transfer of PR1-specific T-cell clones from donor to recipient by stem cell transplantation and association with GvL activity. Cytotherapy 9:245-51 |
| Savani, B N; Montero, A; Kurlander, R et al. (2005) Imatinib synergizes with donor lymphocyte infusions to achieve rapid molecular remission of CML relapsing after allogeneic stem cell transplantation. Bone Marrow Transplant 36:1009-15 |
