The purpose of this core resource facility is to provide ongoing support for the clinical immunotherapy program in the Surgery Branch of the National Cancer Institute. The laboratory is managed by two co-investigators, Drs. Mark Dudley and John Wunderlich, and each investigator has submitted the same annual report. The major effort in the laboratory is producing, ex vivo, large numbers of human anticancer T lymphocytes that are used in adoptive cell therapy for patients enrolled in Surgery Branch clinical trials. All of the patients have metastatic cancer, primarily melanoma. Commonly, ten to fifty billion cells are used for each treatment. The anticancer cells are generated in vitro from each patient's lymphocytes. The lymphocytes have natural anticancer activity, or anticancer activity induced or enhanced by genetic modification of the cells in vitro. Seventy six patients with metastatic cancer have been treated with anticancer lymphocytes during FY12 through August 1. During part or all of this same period of time, twenty one different clinical trials devoted to these therapies have been active and supported by the core laboratory. The core laboratory has also carried out research activities to improve its services. Thus, efforts have continued 1) to simplify the cell production methodology and make the process easier and more cost effective, 2) to relate characteristics of the anticancer lymphocytes and their parent populations to clinical outcomes following their use for treating patients, and 3) to help translate preclinical adoptive immunotherapy models, developed in the Surgery Branch and elsewhere, into new clinical protocols. Finally, the core laboratory continues to process cells and sera collected from cancer patients for a variety of uses, in addition to generating the anticancer cells described above. The products are routinely analyzed by investigators in the Surgery Branch immunotherapy program to evaluate progress toward the goals of each immunotherapy clinical trial, as well as to address subsequent research questions that help identify changes needed in the clinical trials. The samples are also used by Surgery Branch investigators for specific laboratory research projects that may translate into new patient therapies. These research projects include 1) transducing patients T cells with new genes whose products will provide better tumor recognition or otherwise enhance the cells anticancer functions, 2) evaluating the ability of infused anticancer lymphocytes to survive and function in the patient, 3) identifying new cancer antigens that are recognized by patients anticancer cells, 4) identifying characteristics of infused anticancer T cells that relate to cancer regression as measured by standardized, objective criteria, 5) identifying common characteristics of patients with metastatic cancer who are more likely to respond to adoptive cell therapy, 6) evaluating selected biological response modifiers tested in Surgery Branch clinical trials, and 7) extending adoptive cell therapy to additional types of metastatic cancer (e.g., cancers of the gastrointestinal tract and cancers induced by human papillomavirus).

National Institute of Health (NIH)
National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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Pos, Zoltan; Spivey, Tara L; Liu, Hui et al. (2014) Longitudinal study of recurrent metastatic melanoma cell lines underscores the individuality of cancer biology. J Invest Dermatol 134:1389-96
Bartlett, Edmund K; Fetsch, Patricia A; Filie, Armando C et al. (2014) Human melanoma metastases demonstrate nonstochastic site-specific antigen heterogeneity that correlates with T-cell infiltration. Clin Cancer Res 20:2607-16
Gros, Alena; Robbins, Paul F; Yao, Xin et al. (2014) PD-1 identifies the patient-specific CD8ýýý tumor-reactive repertoire infiltrating human tumors. J Clin Invest 124:2246-59
Turcotte, Simon; Gros, Alena; Tran, Eric et al. (2014) Tumor-reactive CD8+ T cells in metastatic gastrointestinal cancer refractory to chemotherapy. Clin Cancer Res 20:331-43
Dudley, Mark E; Gross, Colin A; Somerville, Robert P T et al. (2013) Randomized selection design trial evaluating CD8+-enriched versus unselected tumor-infiltrating lymphocytes for adoptive cell therapy for patients with melanoma. J Clin Oncol 31:2152-9
Palavalli, Lavanya H; Prickett, Todd D; Wunderlich, John R et al. (2009) Analysis of the matrix metalloproteinase family reveals that MMP8 is often mutated in melanoma. Nat Genet 41:518-20
Prickett, Todd D; Agrawal, Neena S; Wei, Xiaomu et al. (2009) Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4. Nat Genet 41:1127-32
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
Ahmadzadeh, Mojgan; Johnson, Laura A; Heemskerk, Bianca et al. (2009) Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood 114:1537-44
Cronin, Julia C; Wunderlich, John; Loftus, Stacie K et al. (2009) Frequent mutations in the MITF pathway in melanoma. Pigment Cell Melanoma Res 22:435-44

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