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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010985-05
Application #
8552915
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2012
Total Cost
$2,209,862
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
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
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
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
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
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
Robbins, Paul F; Kassim, Sadik H; Tran, Thai L N et al. (2015) A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T-cell receptor: long-term follow-up and correlates with response. Clin Cancer Res 21:1019-27
Beane, Joal D; Lee, Gary; Zheng, Zhili et al. (2015) Clinical Scale Zinc Finger Nuclease-mediated Gene Editing of PD-1 in Tumor Infiltrating Lymphocytes for the Treatment of Metastatic Melanoma. Mol Ther 23:1380-90
Liu, Li; Patel, Bhavik; Ghanem, Mustafa H et al. (2015) Novel CD4-Based Bispecific Chimeric Antigen Receptor Designed for Enhanced Anti-HIV Potency and Absence of HIV Entry Receptor Activity. J Virol 89:6685-94
Zhang, Ling; Morgan, Richard A; Beane, Joal D et al. (2015) Tumor-infiltrating lymphocytes genetically engineered with an inducible gene encoding interleukin-12 for the immunotherapy of metastatic melanoma. Clin Cancer Res 21:2278-88
Feldman, Steven A; Assadipour, Yasmine; Kriley, Isaac et al. (2015) Adoptive Cell Therapy--Tumor-Infiltrating Lymphocytes, T-Cell Receptors, and Chimeric Antigen Receptors. Semin Oncol 42:626-39

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