Director, Johns Hopkins Melanoma Program
Professor of Surgery and Oncology
Dr. Topalian's research prior to joining Johns 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).
Topalian SL, Gonzales MI, Parkhurst M, Li YF, Southwood S, Sette A, Rosenberg SA, and Robbins PF. Melanoma-specific CD4+ T cells recognize nonmutated HLA-DR-restricted tyrosinase epitopes. J Exp Med 1996; 183:1965-71.
Pieper R, Christian R, Gonzales MI, Nishimura MI, Gupta G, Settlage RE, Shabanowitz J, Rosenberg SA, Hunt DF, and Topalian SL. Biochemical identification of a mutated human melanoma antigen recognized by CD4+ T cells. J Exp Med 1999; 189:757-65.
Wang R-F, Wang X, Atwood AC, Topalian SL, and Rosenberg SA. Cloning genes encoding MHC class II-restricted antigens: Mutated CDC27 as a tumor antigen. Science 1999;1351-4.
Lindsey KR, Gritz L, Sherry R, Abati A, Fetsch PA, Goldfeder LC, Gonzales MI, Zinnack KA, Rogers-Freezer L, Haworth L, Mavroukakis SA, White DE, Steinberg SM, Restifo NP, Panicali DL, Rosenberg SA, and Topalian SL. Evaluation of prime/boost regimens using recombinant poxvirus/tyrosinase vaccines for the treatment of patients with metastatic melanoma. Clin Cancer Res 2006; 12:2526-37.
Deng L, Langley RL, Brown PH, Xu G, Teng L, Wang Q, Gonzales MI, Calender GG, Nishimura M, Topalian SL and Mariuzza RA. Structural basis for recognition of mutant self by a tumor-specific, MHC class II-restricted TCR. Nat Immunol 2007; 8:398-408.
Mithani SK, Smith IM, Topalian SL, Califano JA. Non-synonymous somatic mitochondrial mutations occur in the majority of cutaneous melanomas. Mel Research 2008; 18:214-219.
Depontieu F, Qian J, Zarling AL, McMiller TL, Salay TM, Norris A, English AM, Shabanowitz J, Engelhard VH, Hunt DF, Topalian SL. Identification of tumor-associated MHC class II-restricted phosphopeptides as targets for immunotherapy. Proc Natl Acad Sci U S A. 2009;106:12073-8.
Brahmer JR, Drake CG, Wollner I, Powderly J, Picus J, Sharfman W, Stankevich E, Pons A, Salay TM, McMiller TL, Gilson MM, Wang C, Selby M, Taube JM, Anders R, Chen L, Korman AJ, Pardoll DM, Lowy I, and Topalian SL. A phase I study of single-agent anti-PD-1 (MDX-1106) in refractory solid tumors: Safety, clinical activity, pharmacodynamics and immunological correlates. J Clin Oncol 2010; 28:3167-75.
Li Y, Depontieu FR, Sidney J, Salay TM, Engelhard VH, Hunt DF, Sette L, Topalian SL, Mariuzza R. Structural basis for the presentation of tumor-associated MHC class II-restricted phosphopeptides to CD4+ T cells. J Mol Biol 2010; 399:596603.
Associate Professor – Otolaryngology – Head & Neck Surgery and Head and Neck Research Division
Dr. Califano’s current research interests include the molecular biologic basis of head and neck cancer development, with a particular interest in molecular alterations in premalignant lesions, genetic instability, mitochondrial dysregulation, as well as molecular detection and surveillance.
Masayesva, B. G., Ha, P., Garrett-Mayer, E., Pilkington, T., Mao, R., Pevsner, J., Speed, T., Benoit, N., Moon, C. S., Sidransky, D., Westra, W. H., & Califano, J. 2004. Gene expression alterations over large chromosomal regions in cancers include multiple genes unrelated to malignant progression. Proc. Natl. Acad. Sci. U S A, E-pub. 101(23):8715-8720.
Tong, B. C., Ha, P. K., Dhir, K., Xing, M., Westra, W. H., Sidransky, D., Califano J. 2003. Mitochondrial DNA Alterations in Thryoid Cancer. J. Surg. Oncol. 82(3):170-173.
Earnest, L., Byrne, P., Califano J. 2003. Massive facial angiofibroma in a patient with tuberous sclerosis. Otolaryngol. Head Neck Surg. 128(1):151-153.
Wu, G., Nomoto, S., Hoque, M. O., Dracheva, T., Osada, M., Lee, C. C., Dong, S. M., Guo, Z., Benoit, N., Cohen, Y., Rechthand, P., Califano, J., Moon, C. S., Ratovitski, E., Jen, J., Sidransky, D., & Trink, B. 2003. DeltaNp63alpha and TAp63alpha regulate transcription of genes with distinct biological functions in cancer and development. Cancer Res. 63(10):2351-2357.
Xing, M., Usadel, H., Cohen, Y., Tokumaru, Y., Guo, Z., Westra, W. B., Tong, B. C., Tallini, G., Udelsman, R., Califano, J. A., Ladenson, P. W., & Sidransky, D. 2003. Methylation of the thyroid-stimulating hormone receptor gene in epithelial thyroid tumors: a marker of malignancy and a cause of gene silencing. Cancer Res. 63(9):2316-2321.