The goal of this research is to use murine models of allogeneic hematopoietic stem cell (HSC) transplantation to identify immunological mechanisms that can be used to design therapies that will reduce the likelihood of leukemia relapse after allogeneic HCS transplant in children with leukemia. In allogeneic HSC transplant the graft versus leukemia (GVL) effect is closely associated with GVHD and clinical attempts to separate the two have not been successful. In the absence of specific immune manipulation the dominant allogeneic immune response that develops after transplant is directed at immunodominant, widely distributed host antigens, and the post-transplant environment does not favor development of immune responses with relative selectively for antigens on minimal residual leukemia. The applicant's laboratory has recently demonstrated that allogeneic HSC transplant recipients treated after transplant with cellular tumor vaccines exhibit prolonged survival but do not experience exacerbations of GVHD. The mechanism of this vaccine effect is under investigation. Hypothesis: Post-transplant tumor vaccines can enhance systemic immune responses that can control minimal residual leukemia without exacerbation of clinically significant graft versus host disease.
Specific Aim 1 : To test the hypothesis that after allogeneic hematopoietic stem cell transplantation moderate affinity T cells specific for subdominant minor histocompatibility antigens can be activated by vaccines to exert antileukemia activity without GVHD.
Specific Aim 2 : To test the hypothesis that allogeneic delayed lymphocyte infusion for acute lymphoblastic malignancies can be made more effective by simultaneous vaccination against leukemia associated antigens.
Specific Aim 3 : To identify the leukemia associated antigenic targets of T cells induced by post-transplant tumor vaccines and to determine if these empirically identified genes correlate with classes of genes predicted to be antigenic based on gene expression analysis.
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| Mullen, Craig A; Campbell, Andrew; Tkachenko, Olena et al. (2011) Evidence of B cell immune responses to acute lymphoblastic leukemia in murine allogeneic hematopoietic stem cell transplantation recipients treated with donor lymphocyte infusion and/or vaccination. Biol Blood Marrow Transplant 17:226-38 |
| Jansson, Johan; Hsu, Yu-Chiao; Kuzin, Igor I et al. (2011) Acute lymphoblastic leukemia cells that survive combination chemotherapy in vivo remain sensitive to allogeneic immune effects. Leuk Res 35:800-7 |
| Young, Faith M; Campbell, Andrew; Emo, Kris Lambert et al. (2008) High-risk acute lymphoblastic leukemia cells with bcr-abl and INK4A/ARF mutations retain susceptibility to alloreactive T cells. Biol Blood Marrow Transplant 14:622-30 |
