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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Jin, Benjamin Y; Campbell, Tracy E; Draper, Lindsey M et al. (2018) Engineered T cells targeting E7 mediate regression of human papillomavirus cancers in a murine model. JCI Insight 3:
Rossi, John; Paczkowski, Patrick; Shen, Yueh-Wei et al. (2018) Preinfusion polyfunctional anti-CD19 chimeric antigen receptor T cells are associated with clinical outcomes in NHL. Blood 132:804-814
Qutob, Nouar; Masuho, Ikuo; Alon, Michal et al. (2018) RGS7 is recurrently mutated in melanoma and promotes migration and invasion of human cancer cells. Sci Rep 8:653
Kochenderfer, James N; Somerville, Robert P T; Lu, Tangying et al. (2017) Long-Duration Complete Remissions of Diffuse Large B Cell Lymphoma after Anti-CD19 Chimeric Antigen Receptor T Cell Therapy. Mol Ther 25:2245-2253
Qiao, Guilin; Qin, Jianzhong; Kunda, Nicholas et al. (2017) LIGHT Elevation Enhances Immune Eradication of Colon Cancer Metastases. Cancer Res 77:1880-1891
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

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