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Department of Immunology
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Phone: 412-383-9737
Fax: 412-383-8098
Lisa.jpg Lisa H. Butterfield , Ph.D.
Professor of Medicine
Hillman Cancer Center Research Pavilion, Room 1.27
5117 Centre Ave.
Pittsburgh, PA 15213
Phone: 412-623-1418
Fax: 412-624-0264
Research Interests
The Butterfield lab focuses on cross-talk between tumor antigens and the immune system in melanoma and hepatocellular cancer (HCC) patients.

We have studied immunodominant and subdominant epitope-specific T cells we identified from alpha fetoprotein (AFP), a self antigen expressed by HCC. Immunodominant epitopes have been tested in HCC patients in the form of both peptides in adjuvant, and as peptide-pulsed dendritic cell (DC) vaccines which resulted in activated and expanded AFP-specific, IFNγ-producing, CD8+ T cells. HCC patients have detectable frequencies of circulating AFP-specific CD8+ T cells to both immunodominant and subdominant epitopes, and these T cells can be differentially expanded with different modes of antigen presentation by DC. Antigen engineered DC (AdVhAFP/DC)-stimulated CD8+ responses are antigenically diverse and not skewed towards subsets of peptides. AFP-specific helper CD4+ T cells, critical for helping effector responses, are only detectable in HCC patients with AdVhAFP/DC stimulation, indicating that an AFP CD4 T cell deficit may exist in patients, but that precursor cells are present and capable of activation.

In melanoma vaccine trials, we find that frequency and function of vaccine induced MART-1-specific T cells is unrelated to clinical outcome, but that broadening of the immune response to include additional antigens expressed by tumor is correlated with clinical outcome. We have created a 3-melanoma-antigen encoding adenovirus, AdVTMM2, and this virus, transduced into DC is being tested clinically to determine whether broader immunity is critical to clinical outcome, and whether systemic IFNa can further promote determined spreading, and improved clinical response.

Most recently, we are investigating methods for incorporating innate effector (NK cell) activation with tumor antigen-specific adaptive immunity. We find that AdV-transduced DC can activate both major subsets of NK cells, as well as secret chemokines to draw NK cells to the DC. By understanding these immune responses, improved vaccines can be rationally designed that specifically initiate antigenically broad immunity, encompassing CD8 and CD4 T cells, as well as innate immunity.
B.S. - Rensselaer Polytechnic Institute (1986)

Ph.D. - University of California at Los Angeles (1993)

Postdoc - University of California at Los Angeles (1993-1997)
Academic Affiliation
Professor, Departments of Medicine, Surgery, and Immunology, University of Pittsburgh School of Medicine

Director, UPCI Immunologic Monitoring and Cellular Products Laboratory
Selected Publications
Butterfield, L.H., Comin-Anduix, B., Vujanovic, L., Lee, Y., Dissette, V.B., Yang, J-Q., Vu, H.T., Seja, E., Oseguera, D.K., Potter, D.M., Glaspy, J.A., Economou, J.S., and Ribas, A. Adenovirus MART-1 engineered autologous dendritic cell vaccine for metastatic melanoma. J. Immunother., 31: 294-309, 2008. PMID: 18317358; PMCID:PMC3651040

Vujanovic, L., Whiteside, T.L., Potter, D.P., Chu, J., Ferrone, S., and Butterfield, L.H. Regulation of antigen presentation machinery in human dendritic cells by recombinant adenovirus. Cancer Immunol. Immunother., 58: 121-133, 2009. PMID: 18488218; PMCID:PMC2726804

Kirkwood, J.M., Lee, S., Moschos, S., Albertini, M., Michalak, J., Sander, C., Whiteside, T.L., Butterfield, L.H., and Weiner, L. Immunogenicity and antitumor effects of vaccination with peptide vaccine +/- granulocyte-monocyte colony-stimulating factor and/or IFN-alpha2b in advanced metastatic melanoma: Eastern Cooperative Oncology Group Phase II Trial E1696. Clin. Cancer Res., 15: 1443-1451, 2009. PMID: 19228745; PCMID:PMC2759898

Vujanović, L.N., Szymkowski, D.E., Alber, S., Watkins, S.C., Vujanović, N.L., and Butterfield, L.H. Virally-infected and matured human dendritic cells activate natural killer cells via cooperative activity of plasma membrane-bound TNF and IL-15. Blood, 116(4): 575-583, 2010. PMID: 20430958; PMCID:PMC3324291

Butterfield, L.H., Palucka, A.K., Britten, C.M., Dhodapkar, M.V., Hakansson, L., Janetzki, S., Kawakami, Y., Kleen, T-O., Lee, P.P., Maccalli, C., Maecker, H.T., Maino, V.C., Maio, M., Malyguine, A., Masucci, G., Pawelec, G., Potter, D.M., Rivoltini, L., Salazar, L.G., Schendel, D.J., Slingluff, C.L., Jr., Song, W., Stroncek, D.F., Tahara, H., Thurin, M., Trinchieri, G., van Der Burg, S.H., Whiteside, T.L., Wigginton, J.M., Marincola, F., Khleif, S., Fox, B.A., and Disis, M.L. Recommendations from the iSBTc-SITC/FDA/NCI Workshop on Immunotherapy Biomarkers. Clin. Cancer Res., 17(10): 3064-3076, 2011. PMID: 21558394; PMCID:PMC3096674

Bray, S.M., Vujanovic, L., and Butterfield, L.H. Dendritic cell-based vaccines positively impact natural killer and regulatory T cells in hepatocellular carcinoma patients. Clin. Dev. Immunol., 2011: 249281, 2011. PMID: 21969837; PMCID:PMC3182577

Butterfield, L.H., Potter, D.M., and Kirkwood, J.M. Multiplex Serum Biomarker Assessments: Technical and Biostatistical Issues. J. Trans. Med., 9: 173, 2011. PMID: 21989127; PMCID:PMC3200183

Blalock, L.T., Landsberg, J., Messmer, M.N., Shi, J., Pardee, A.D., Haskell, R.E., Vujanovic, L., Kirkwood, J.M., and Butterfield, L.H. Human dendritic cells adenovirally-engineered to express three defined tumor antigens promote broad adaptive and innate immunity. OncoImmunol., 1(3): 1-11, 2012. PMID: 22737604; PMCID:PMC3382861

Vujanovic, L., Ballard, W., III, Thorne, S.H., Vujanovic, N., and Butterfield, L.H. Adenovirus-engineered human dendritic cells induce natural killer cell chemotaxis via CXCL8/IL-8 and CXCL10/IP-10. OncoImmunol., 1(4): 448-457, 2012. PMID: 22754763; PMCID:PMC3382881

Kirkwood, J.M., Butterfield, L.H., Tarhini, A.A., Zarour, H., Kalinski, P., and Ferrone, S. Immunotherapy of Cancer in 2011: A Cancer Journal for Clinicians. CA Cancer J Clin., 2012.
Title: Multiple Tumor Antigen-loaded DC Vaccine for Hepatocellular Cancer
RO1 CA138635 (Butterfield, PI)
Agency: NIH/NCI
Role: PI
Funding Period: 07/01/10 - 06/30/15

Title: Multiple Antigen-Engineered DC Immunization and IFNa Boost for Metastatic Melanoma
1P50 CA121973-01A1 (Kirkwood, PI)
Agency: NIH
Role: Skin SPORE Project 2 (Butterfield PI)
Funding Period: 08/01/08 - 07/31/13

Title: Frontier Science and Technology Research Foundation
Agency: ECOG Central Laboratory Support
Role: Co-investigator
Funding Period: 05/01/10 - 04/30/15
Lab Personnel
Postdoctoral Fellows
Lazar Vujanovic, Ph.D.
Angela Pardee, Ph.D.

Jian Shi, M.D.

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