Lisa H. Butterfield, PhD
Campus: 5117 Centre Ave.
Office: Hillman Cancer Center, Research Pavilion Suite 1.26
Lab: Hillman Cancer Center, Research Pavilion 1.33
Pittsburgh PA 15213
- BS - Rensselaer Polytechnic Institute (1986)
- PhD - University of California at Los Angeles (1993)
- Postdoc - University of California at Los Angeles (1993-1997)
- Professor of Medicine, Surgery and Immunology
- Director, UPCI Immunologic Monitoring and Cellular Products Laboratory
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. We are now testing different approaches to AFP and additional HCC antigen loading of antigen presenting cells to better promote effective anti-HCC tumor immunity.
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.
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., May 1;1(3):287-357, 2012. PMID: 22737604; PMCID: 3382861
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: 3382881
Naveh, H.P., Vujanovic L., and Butterfield, L.H. Cellular immunity induced by a recombinant adenovirus-human dendritic cell vaccine for melanoma. J. Immunother. Cancer. Nov 18;1:19, 2013.
Butterfield, L.H., Economou, J.S., Gamblin, T.C., Geller, D.A. Alpha Fetoprotein DNA Prime and Adenovirus Boost Immunization of Two Hepatocellular Cancer Patients. J. Trans. Med. Apr 5;12:86, 2014. PMID:24708667.
Hodi, F.S., Lee, S., McDermott, D.F., Rao, U.N., Butterfield, L.H., Tarhini, A.A., Leming, P., Puzanov, I., Shin, D.,Kirkwood, J.M. Ipilimumab plus sargramostim vs Ipilimumab Alone for Treatment of Metastatic Melanoma: A Randomized Clinical Trial. JAMA. Nov 5;312(17);1744-53, 2014. doi: 10.1001/jama.2014.13943. PMID:25369488
Pardee, A.D., Shi, J., and Butterfield, L.H. Tumor-derived alpha-fetoprotein impairs the differentiation and T cell stimulatory activity of human dendritic cells. J Immunol. 2014 Dec 1;193(11):5723-32. doi: 10.4049/jimmunol.1400725. Epub 2014 Oct 29. PMID:25355916; PMCID: PMC4239186
Vujanovic, L., Shi, J,, Kirkwood, J.M., Storkus, W.J. and Butterfield, L.H.. Molecular mimicry of MAGE-A6 and Mycoplasma penetrans HF-2 in the induction of anti-tumor CD8+ T cell responses. Oncoimmunology. 2014 Nov 14;3(8):e954501. eCollection 2014. PMID:25960935; PMCID: PMC4368152
Pardee, A.D., Yano, H., Weinstein, A.M., Ponce, A.A.K., Ethridge, A.D., Normolle, D.P., Vujanovic, L., Mizejewski, G.J., Watkins, S.C., and Butterfield, L.H. Route of antigen delivery impacts the immunostimulatory activity of dendritic cell-based vaccines for hepatocellular carcinoma. J Immunother Cancer. 2015 Jul 21;3:32. doi: 10.1186/s40425-015-0077-x. eCollection 2015. PMID: 26199728; PMCID: PMC4509479
Butterfield, L.H. Cancer vaccines. BMJ. 2015 Apr 22;350:h988. doi: 0.1136/bmj.h988. PMID:25904595
Butterfield, LH. Lessons learned from cancer vaccine trials and target antigen choice. Cancer Immunol Immunother. 2016 Feb 3. [Epub ahead of print] PMID:26842127
Click here for a complete list of publications.
- Immunotherapy of melanoma and hepatocellular cancer, dendritic cells, adenovirus, immunologic monitoring