Research & Publications +
Dr. Topalian's research prior to joining Hopkins revealed the existence of melanoma proteins and derivative peptides specifically recognized by human CD8+ killer and CD4+ helper T cells, paving the way for the clinical development of antigen-specific melanoma vaccines. Disappointing clinical results with vaccines led to the realization that immunological tolerance mechanisms dominate the interaction between cancer and the tumor-bearing host. Subsequently, Dr. Topalian has led the clinical development of immunomodulatory monoclonal antibodies to treat patients with melanoma and other solid tumors, in collaboration with Medarex/Bristol Myers-Squibb, finding that patients with treatment-refractory advanced metastatic cancers can respond to blockade of the T cell co-receptors programmed death-1 (PD-1) and B7-H1 (Brahmer, J Clin Oncol 2010; Sznol, ASCO Proc 2010). Her laboratory has been responsible for conducting correlative immunological studies in these patients, and has characterized the pharmacodynamics of anti-PD-1 and anti-B7-H1. Since animal models show that blockade of PD-1 and B7-H1 synergizes with cancer vaccines, Dr. Topalian has continued to search for optimal tumor antigens, investigating melanoma-associated mitochondrial mutations (Mithani, Melanoma Res 2008) and recently describing posttranslationally modified phosphopeptides as a new cohort of tumor antigens recognized by human CD4+ T cells (Depontieu, Proc Natl Acad Sci 2009; Li, J Mol Biol 2010). X-ray crystallographic studies of human CD4 T cell receptor interactions with a mutant melanoma antigen, in collaboration with Dr. Roy Mariuzza at the University of Maryland, have demonstrated suboptimal structural features, highlighting the need for enhancing anti-tumor immunity with immunomodulatory antibodies (Deng, Nature Immunol 2007).
Deng, L.; Langley, R.J.; Brown, P.H.; Xu, G.; Teng, L.; Wang, Q.; Gonzales, M.I.; Callender, G.G.; Nishimura, M.I.; Topalian, S.L.; Mariuzza, R.A. Structural basis for the recognition of mutant self by a tumor-specific, MHC class II-restricted T cell receptor. Nat Immunol. 2007 Apr;8(4):398-408.
Yang, J.C.; Hughes, M.; Kammula, U.; Royal, R.; Sherry, R.M.; Topalian, S.L.; Suri, K.B.; Levy, C.; Allen, T.; Mavroukakis, S.; Lowy, I.; White, D.E.; Rosenberg, S.A. Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J Immunother (1997). 2007 Nov-Dec;30(8):825-830.
Lange, J.R.; Fecher, L.; Sharfman, W.H.; Alani, R.M.; Mikkilineni, R.; Topalian, S.L.; Balch, C.M. Melanoma. In: Abeloff MD, A.J., Niederhuber JE, Kastan MB, McKenna WG editor. 4th ed, Abeloffs Clinical Oncology. Philadelphia: Elsevier Inc.; 2008. p. 1229-1252.
Mithani, S.K.; Smith, I.M.; Topalian, S.L.; Califano, J.A. Nonsynonymous somatic mitochondrial mutations occur in the majority of cutaneous melanomas. Melanoma research. 2008 Jun;18(3):214-219.
Depontieu, F.R.; Qian, J.; Zarling, A.L.; McMiller, T.L.; Salay, T.M.; Norris, A.; English, A.M.; Shabanowitz, J.; Engelhard, V.H.; Hunt, D.F.; Topalian, S.L. Identification of tumor-associated, MHC class II-restricted phosphopeptides as targets for immunotherapy. Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):12073-12078.
Brahmer, J.R.; Drake, C.G.; Wollner, I.; Powderly, J.D.; Picus, J.; Sharfman, W.H.; Stankevich, E.; Pons, A.; Salay, T.M.; McMiller, T.L.; Gilson, M.M.; Wang, C.; Selby, M.; Taube, J.M.; Anders, R.; Chen, L.; Korman, A.J.; Pardoll, D.M.; Lowy, I.; Topalian, S.L. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010 Jul 1;28(19):3167-3175.
Li, Y.; Depontieu, F.R.; Sidney, J.; Salay, T.M.; Engelhard, V.H.; Hunt, D.F.; Sette, A.; Topalian, S.L.; Mariuzza, R.A. Structural basis for the presentation of tumor-associated MHC class II-restricted phosphopeptides to CD4+ T cells. J Mol Biol. 2010 Jun 18;399(4):596-603.
Royal, R.E.; Levy, C.; Turner, K.; Mathur, A.; Hughes, M.; Kammula, U.S.; Sherry, R.M.; Topalian, S.L.; Yang, J.C.; Lowy, I.; Rosenberg, S.A. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother. 2010 Oct;33(8):828-833.