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, p53, and CEA epitopes. Chimeric antigen receptors have been developed that recognize the HER-2 or CD19 cell surface antigens. Clinical trials are being performed to study the treatment of patients with a variety of cancer types using these transduced cells. The first patient treated with cells transduced with a chimeric receptor targeting CD19 has had a substantial (>90%) partial response. Using cells transduced with a TCR reactive with the NY-ESO-1 cancer testes antigen 5 of 11 melanoma patients and 7 of 9 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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Parkhurst, Maria; Gros, Alena; Pasetto, Anna et al. (2017) Isolation of T-Cell Receptors Specifically Reactive with Mutated Tumor-Associated Antigens from Tumor-Infiltrating Lymphocytes Based on CD137 Expression. Clin Cancer Res 23:2491-2505
Rosenberg, Steven A; Tran, Eric; Robbins, Paul F (2017) T-Cell Transfer Therapy Targeting Mutant KRAS. N Engl J Med 376:e11
Lu, Tangying Lily; Pugach, Omar; Somerville, Robert et al. (2016) A Rapid Cell Expansion Process for Production of Engineered Autologous CAR-T Cell Therapies. Hum Gene Ther Methods 27:209-218
Kalaora, Shelly; Barnea, Eilon; Merhavi-Shoham, Efrat et al. (2016) Use of HLA peptidomics and whole exome sequencing to identify human immunogenic neo-antigens. Oncotarget 7:5110-7
Yao, Xin; Lu, Yong-Chen; Parker, Linda L et al. (2016) Isolation and Characterization of an HLA-DPB1*04: 01-restricted MAGE-A3 T-Cell Receptor for Cancer Immunotherapy. J Immunother 39:191-201
Klebanoff, Christopher A; Rosenberg, Steven A; Restifo, Nicholas P (2016) Prospects for gene-engineered T cell immunotherapy for solid cancers. Nat Med 22:26-36
Pasetto, Anna; Gros, Alena; Robbins, Paul F et al. (2016) Tumor- and Neoantigen-Reactive T-cell Receptors Can Be Identified Based on Their Frequency in Fresh Tumor. Cancer Immunol Res 4:734-43
Tran, Eric; Robbins, Paul F; Lu, Yong-Chen et al. (2016) T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer. N Engl J Med 375:2255-2262
Deniger, Drew C; Pasetto, Anna; Tran, Eric et al. (2016) Stable, Nonviral Expression of Mutated Tumor Neoantigen-specific T-cell Receptors Using the Sleeping Beauty Transposon/Transposase System. Mol Ther 24:1078-89
Jaigirdar, Adnan; Rosenberg, Steven A; Parkhurst, Maria (2016) A High-avidity WT1-reactive T-Cell Receptor Mediates Recognition of Peptide and Processed Antigen but not Naturally Occurring WT1-positive Tumor Cells. J Immunother 39:105-16

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