My laboratory is involved in studies to genetically modify autologous lymphocytes to improve their anti-tumor activity. In 1990 we reported the first studies of gene transfer in humans which involved the adoptive transfer of TIL transduced with a marker gene encoding neomycin phosphotransferase. These studies suggested the possibility that genes could be inserted into lymphocytes to improve their anti-tumor efficacy. We have now made progress in this area by developing techniques for the high efficiency transduction of human lymphocytes. The genes encoding high affinity anti-tumor T cell receptors (TCR) that recognize antigens on melanomas and common epithelial cancers have been identified and clinical trials to use autologous T cells transduced with these TCRs have begun. In recent studies we have shown that up to 30% of patients with metastatic melanoma will achieve objective clinical cancer regressions when treated with their autologous lymphocytes that have been transduced with T cell receptors that recognized the MART-1 or gp100 melanoma antigens. T cell receptors have now been identified that recognize NY-ESO-1, MAGE-A3, and CEA epitopes. Chimeric antigen receptors have been developed that recognize CD19 cell surface antigens on B cell malignancies and the EGFRvIII mutation expressed on glioblastomas. Clinical trials are being performed to study the treatment of patients with a variety of cancer types using these transduced cells. Multiple patients treated with cells transduced with a chimeric receptor targeting CD19 have had substantial responses. 80% of patients treated have had objective responses in the absence of IL-2 administration. Using cells transduced with a TCR reactive with the NY-ESO-1 cancer testes antigen 10 of 19 melanoma patients and 10 of 15 synovial cell sarcoma patients have had objective responses.

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National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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Tseng, Jennifer; Citrin, Deborah E; Waldman, Meryl et al. (2014) Thrombotic microangiopathy in metastatic melanoma patients treated with adoptive cell therapy and total body irradiation. Cancer 120:1426-32
Abate-Daga, Daniel; Speiser, Daniel E; Chinnasamy, Nachimuthu et al. (2014) Development of a T cell receptor targeting an HLA-A*0201 restricted epitope from the cancer-testis antigen SSX2 for adoptive immunotherapy of cancer. PLoS One 9:e93321
Rosenberg, Steven A (2014) Finding suitable targets is the major obstacle to cancer gene therapy. Cancer Gene Ther 21:45-7
Kochenderfer, James N; Feldman, Steven A; Zhao, Yangbing et al. (2009) Construction and preclinical evaluation of an anti-CD19 chimeric antigen receptor. J Immunother 32:689-702
Peng, P D; Cohen, C J; Yang, S et al. (2009) Efficient nonviral Sleeping Beauty transposon-based TCR gene transfer to peripheral blood lymphocytes confers antigen-specific antitumor reactivity. Gene Ther 16:1042-9
Rosenberg, Steven A; Dudley, Mark E (2009) Adoptive cell therapy for the treatment of patients with metastatic melanoma. Curr Opin Immunol 21:233-40
Johnson, Laura A; Morgan, Richard A; Dudley, Mark E et al. (2009) Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood 114:535-46
Parkhurst, Maria R; Joo, Jayne; Riley, John P et al. (2009) Characterization of genetically modified T-cell receptors that recognize the CEA:691-699 peptide in the context of HLA-A2.1 on human colorectal cancer cells. Clin Cancer Res 15:169-80
Burns, William R; Zheng, Zhili; Rosenberg, Steven A et al. (2009) Lack of specific gamma-retroviral vector long terminal repeat promoter silencing in patients receiving genetically engineered lymphocytes and activation upon lymphocyte restimulation. Blood 114:2888-99
Jones, Stephanie; Peng, Peter D; Yang, Shicheng et al. (2009) Lentiviral vector design for optimal T cell receptor gene expression in the transduction of peripheral blood lymphocytes and tumor-infiltrating lymphocytes. Hum Gene Ther 20:630-40

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