The ability of allogeneic lymphocytes to target and eradicate leukemia cells has been established as a true biological entity over the past ten (10) years. Whether such effects can be generated against non-hematological """"""""solid"""""""" malignancies remains unexplored. We initiated a clinical trail using a non-myleoablative approach of allogeneic stem cell transplantation in patients with treatment refractory metastatic renal cell carcinoma (RCC). Definition evidence for an allogeneic graft-versus-tumor (GVT) effect has been demonstrated with complete regression of large observed seen in some patients. We have subsequently initiated studies investigating immune reconstitution in those demonstrating a GVT effect in attempts to identify both the effector cell populations mediating these regressions as well as their target antigens. We first analyzed the beta chain of the T-cell receptor by PCR analysis of CDR3 length polymorphisms as well as by monoclonal antibody studies of V-beta family usage. We have identified T-cell subsets (cytotoxic, CD3+, activated), that appear to be mediators of this anti-tumor effect. In one case, we have identified a tumor specific T-cell population which appears to be recognize as an antigen restricted to kidney cancer cells. Through limiting dilution experiments, we are attempting to clone this and other T-cell population in responding patients to use them for the identification of RCC specific tumor antigens. Further, work has been and continues to be done for the development of allogeneic tumor specific T-cells through the transduction of donor dendritic cells with adenovirus encoding tumor antigens. Preliminary data reveals that this approach can result in a dendritic cell population, which is capable of stimulating tumor specific allogeneic T-cells. With the recent ability to grow tumor cell lines in the majority of our RCC patients, we have now initiated studies investigating the optimal approach to generate tumor/dendritic cell fusions to serve as stimulators for an allogeneic tumor specific T-cell population. We have now developed a GFP labeled RCC line from one of our kidney cancer patients to optimize this approach. These studies are being conducted in collaboration with the Urology Oncology Branch and the Surgical Oncology Branch of the National Cancer Institute.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Intramural Research (Z01)
Project #
1Z01HL002345-01
Application #
6414703
Study Section
(HB)
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2000
Total Cost
Indirect Cost
Name
U.S. National Heart Lung and Blood Inst
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Pawelczyk, Edyta; Jordan, Elaine K; Balakumaran, Arun et al. (2009) In vivo transfer of intracellular labels from locally implanted bone marrow stromal cells to resident tissue macrophages. PLoS One 4:e6712
Baskar, Sivasubramanian; Suschak, Jessica M; Samija, Ivan et al. (2009) A human monoclonal antibody drug and target discovery platform for B-cell chronic lymphocytic leukemia based on allogeneic hematopoietic stem cell transplantation and phage display. Blood :
Blum, Arnon; Childs, Richard; Smith, Aleah et al. (2009) Targeted antagonism of CXCR4 mobilizes progenitor cells under investigation for cardiovascular disease. Cytotherapy :1-4
Childs, Richard W; Zerbe, Christa S (2009) Expanding multiviral reactive T cells from cord blood. Blood 114:1725-6
Yong, Agnes S M; Keyvanfar, Keyvan; Hensel, Nancy et al. (2009) Primitive quiescent CD34+ cells in chronic myeloid leukemia are targeted by in vitro expanded natural killer cells, which are functionally enhanced by bortezomib. Blood 113:875-82
Lundqvist, Andreas; Yokoyama, Hisayuki; Smith, Aleah et al. (2009) Bortezomib treatment and regulatory T-cell depletion enhance the antitumor effects of adoptively infused NK cells. Blood 113:6120-7
Yao, Yong-Gang; Childs, Richard W; Kajigaya, Sachiko et al. (2007) Mitochondrial DNA sequence heterogeneity of single CD34+ cells after nonmyeloablative allogeneic stem cell transplantation. Stem Cells 25:2670-6
Lazarus, Hillard M; Stiff, Patrick J; Carreras, Jeanette et al. (2007) Utility of single versus tandem autotransplants for advanced testes/germ cell cancer: a center for international blood and marrow transplant research (CIBMTR) analysis. Biol Blood Marrow Transplant 13:778-89
Sandmaier, Brenda M; Mackinnon, Stephen; Childs, Richard W (2007) Reduced intensity conditioning for allogeneic hematopoietic cell transplantation: current perspectives. Biol Blood Marrow Transplant 13:87-97
Lundqvist, Andreas; McCoy, J Philip; Samsel, Leigh et al. (2007) Reduction of GVHD and enhanced antitumor effects after adoptive infusion of alloreactive Ly49-mismatched NK cells from MHC-matched donors. Blood 109:3603-6

Showing the most recent 10 out of 72 publications