Clinical Trial Keywords:
Director, Melanoma Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Dr. Topalian's research prior to joining Hopkins revealed the existence of melanoma-associated proteins ("antigens") specifically recognized by human CD8+ killer and CD4+ helper T cells, paving the way for the clinical development of melanoma vaccines. Disappointing results with cancer vaccines in the clinic led to the realization that melanoma and many other human cancers can avoid immune detection and destruction by displaying molecular shields and secreting immune-suppressive factors. Dr. Topalian has led the clinical development of immune-modulating monoclonal antibodies to break through this shield and effectively treat patients with melanoma and other solid tumors. In collaboration with an interdisciplinary research group at Hopkins, Medarex/Bristol Myers-Squibb, and other medical instituions, it was found that patients with treatment-refractory advanced metastatic cancers could respond to blockade of the immune cell inhibitory receptor programmed death-1 (PD-1) or its partner molecule PD-L1 on tumor cells. Research led by Dr. Topalian has characterized the pharmacodynamics of anti-PD-1 and anti-PD-L1 drugs and has explored tumor molecular markers predictive of clinical response. Since animal models suggest that blockade of PD-1 and PD-L1 synergizes with cancer vaccines, Dr. Topalian has continued to search for optimal tumor target antigens, investigating mutated peptides, phosphorylated peptides, and structural interactions between T cell receptors and these antigens in collaboration with Dr. Roy Mariuzza at the University of Maryland. Combination treatment regimens of anti-PD-1/PD-L1 with other immune-modulating antibodies, kinase inhibitors, and epipigenetic therapy are under development.
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.
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.
Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, Chen S, Klein AP, Pardoll DM, Topalian SL, Chen L. Co-localization of inflammatory response with B7-H1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Science Transl Med 2012; 4:127ra37. PMC3568523.
Topalian SL, Hodi FS, Brahmer JR, et al. (30 authors). Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366:2443-54. PMC3544539.
Brahmer JR, Tykodi SS, Chow LQM, Hwu W-J, Topalian, SL et al.(26 authors). Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J. Med 2012; 366:2455-65. PMC3563263
Deng L, Langley RJ, Wang Q, Topalian SL, Mariuzza RA. Structural insights into the editing of germline-encoded interactions between T cell receptor and MHC class II by VaCDR3. Proc Natl Acad Sci USA, 2012; 109:14960-5. PMC3443186.
Lipson EJ, Sharfman WH, Drake CG, Wollner I, Taube JM, Anders RA, Xu H, Yao S, Pons A, Chen L, Pardoll DM, Brahmer JR, Topalian SL. Durable cancer regression off-treatment and effective re-induction therapy with an anti-PD-1 antibody. Clin Cancer Res, 2013; 19:462-468. PMC3548952.
Lyford-Pike S, Pen S, Young GD, Taube JM, Westra WH, Akpeng B, Bruno TC, Richmon JD, Wang H, Bishop JA, Chen L, Drake CG, Topalian SL, Pardoll DM, Pai SI. Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma. Cancer Res, 2013; 73:1733-41. PMC3602406.
Lipson EJ, Vincent JG, Loyo M, Kagohara LT, Luber BS, Wang H, Xu H, Nayar SK, Wang TS, Sidransky D, Anders RA, Topalian SL, Taube JM. PD-L1 expression in the Merkel cell carcinoma microenvironment: Association with inflammation, Merkel cell polyomavirus and overall survival. Cancer Immunol Res, 2013; 1:54-63. PMC3548952.
Chen S, Li Y, Depontieu FR, McMiller TL, English AM, Shabanowitz J, Kos F, Sidney J, Sette A, Rosenberg SA, Hunt DF, Mariuzza RA, Topalian SL. Structure-based design of altered MHC II-restricted peptide ligands with heterogeneous immunogenicity. J Immunol 2013; 191:5097-106. PMC3888030.
Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, Brahmer JR, Lawrence DP, Atkins MB, Powderly JD, Leming PD, Lipson EJ, Puzanov I, Smith DC, Taube JM, Wigginton JM, Kollia GD, Gupta A, Pardoll DM, Sosman JA, Hodi FS. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol 2014;32:1020-30.
Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, Chen L, Pardoll DM, Topalian SL, Anders RA. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res 2014; doi:10.1158/1078-0432.CCR-13-3271.