Director, Johns Hopkins Melanoma Program Professor of Surgery and Oncology
Research Summary: Dr. Topalian received her medical degree from Tufts University School of Medicine in 1979. She completed her residency in general surgery at the Thomas Jefferson University Hospital in Philadelphia and continued to hold two fellowships: the first in Pediatric Surgery Research at the Children’s Hospital of Philadelphia (1982-1983), and the second in Surgical Oncology at the National Cancer Institute, NIH in Bethesda, Maryland (1985-1989). After a 21-year tenure in the Surgery Branch of the National Cancer Institute, Dr. Topalian joined the Johns Hopkins faculty in 2006 to lead the Melanoma Program in the Sidney Kimmel Comprehensive Cancer Center.
Dr. Topalian is a physician-scientist whose research interests focus on cancer immunology and immunotherapy. She has published over 100 original research articles and reviews in this area and is internationally recognized for this work. Dr. Topalian’s basic studies of human anti-tumor immune responses have provided a foundation for the translational development of immunotherapies for melanoma and other cancers, including cancer vaccines, adoptive T cell transfer, and immune-modulating monoclonal antibodies. Her early work established that cytolytic “killer” T lymphocytes in melanoma patients could specifically recognize tumor cells from the same patient. Later studies confirmed the existence of “shared” melanoma antigens (proteins) among tumors from different patients, paving the way for the clinical development of melanoma vaccines. Her seminal investigations into the role of CD4+ T “helper” cells in human anti-tumor immune responses revealed the existence of tumor-specific CD4+ T cells in patients with melanoma and other cancers, and biochemical and molecular methods were devised for identifying the recognized tumor-associated proteins.
As the Director of the Melanoma Program, Dr. Topalian’s current research focuses on modulating immune checkpoints such as PD-1 and PD-L1 in cancer therapy, and discovering biomarkers predicting clinical outcomes following treatment. She continues to work on devising optimal melanoma vaccines, based on biochemical and structural analyses, with the goal of exploring combination treatment regimens of vaccines with PD-1 blocking drugs. These pioneering efforts have opened new avenues of scientific interest and clinical investigation in cancer immunology, and have helped to establish immunotherapy as a treatment modality for cancer.
Selected Literature References
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. 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; 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; 399:596–603.
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.
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M. Safety, activity and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366:2443-54.
Brahmer JR, Tykodi SS, Chow LQM, Hwu W-J, Topalian SL, Hwu P, Drake CG, Camacho LH, Hauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012; 366:2455-65.
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.
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.
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.
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.
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.
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.
Joseph Califano, MD
Associate Professor – Otolaryngology – Head & Neck Surgery and Head and Neck Research Division
Research Summary 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.
Journal Citations 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.
Evan J. Lipson, M.D.
Assistant Professor of Oncology
Research Summary Dr. Lipson's primary research interest is in early-phase clinical trials for melanoma and other skin cancers. As a member of the Johns Hopkins Melanoma and Cancer Immunology Programs, he focuses on evaluating novel therapies for patients with high-risk or advanced disease. In particular, Dr. Lipson is involved in the clinical development of antibodies that block immune regulatory pathways such as PD-1/PD-L1. In 2013, he reported the most prolonged observation of patients with solid tumors responding to anti-PD-1 immunotherapy and the first evidence that re-induction therapy with anti-PD-1 after late tumor recurrence can be effective. (Lipson et al, Clinical Cancer Research, 2013) . Along similar lines, Dr. Lipson described PD-L1 expression in Merkel cell carcinoma and its association with increased tumor-infiltrating lymphocytes, the presence of the causative Merkel cell polyomavirus, and improved overall survival. These findings suggest that an endogenous anti-tumor immune response promotes PD-L1 expression in the MCC microenvironment when polyomavirus is present and provide a rationale for therapies that are now in development for blocking PD-1/PD-L1 in patients with advanced Merkel cell carcinoma. (Lipson et al, Cancer Immunology Research, 2013)
Dr. Lipson received his medical degree from the Mount Sinai School of Medicine in New York City. He completed his internship and residency in Internal Medicine at The Johns Hopkins Hospital, and completed a Medical Oncology fellowship at the Johns Hopkins Kimmel Cancer Center.
Select Journal Citations
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. Clinical Cancer Research. 2013;19(2):462-8.
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 Immunology Research. 2013;1:54-63.
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. Journal of Clinical Oncology. 2014;32(10):1020-1030.
Lipson EJ, Bodell MA, Kraus ES, Sharfman WH. Successful administration of ipilimumab to two kidney transplant patients with metastatic melanoma. Journal of Clinical Oncology. 2014;32(19):e69-e71
Janis Taube, M.D.
Dr. Taube is a board-certified dermatopathologist with a diagnostic and research interest in melanoma and other skin cancers. Her research interests center on the immune evasion by cutaneous neoplasms, specifically studying the PD-L1(B7-H1) / PD-1 axis, and the identification of potential biomarkers that can help pre-select patients with advanced malignancies for novel immunotherapeutic treatment regimens. This requires a focus on immunohistochemical and molecular methods for identifying cell surface antigens and signaling pathways in paraffin-embedded tissue. She was the first to describe the association of melanoma PD-L1 expression with tumor infiltrating lymphocytes (TIL) as an adaptive mechanism of immune resistance by tumor (Taube, et al, Sci Transl Med 2012), a finding which has now been extended to a number of other tumor types, including merkel cell carcinoma (Lipson, et al. Cancer Immunol Res, 2013). The pattern she described of tumor PD-L1 expression associated with TIL provides a rationale for mechanism of action of anti-PD-1 therapies, and also suggests that PD-L1 should be a marker for response to anti-PD-1. Indeed, in collaboration with a number of other members of the Melanoma Program, she went on to demonstrate that PD-L1 expression enriches for response to anti-PD-1 immunotherapies (Topalian, et al NEJM 2012, Taube, et al. Clin Can Res 2014). During this time, her laboratory served as the tissue pathology core for the multi-institutional clinical trials for the first-in-human anti-PD-1 and anti-PD-L1 immunotherapies. Ongoing efforts by her laboratory focus on further characterizing the local melanoma microenvironment with the aim of developing rational treatment combinations.
Dr. Taube received her medical degree from Tulane University in New Orleans, LA. She completed her Pathology residency at The Johns Hopkins Hospital, and completed her Dermatopathology fellowship at Stanford University. She has been faculty at Johns Hopkins since 2009, and the Director of Dermatopathology since 2011.
Selected Journal Citations:
Taube JM, Anders RA, Xu H, Sharma R, Klien A, Topalian SL, Chen L. Colocalization of inflammatory response with B7-H1 [PD-L1] expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 2012;4:127ra37.
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; 19(2):462-8.
Topalian SL, Hodi SF, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal R, Sosman J, Atkins MB, Leming PD, Spigel D, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kokkia GD, Ashok G, Wigginton JM, Sznol M. Safety, Activity and Immune Correlates of Anti-PD-1 Antibody in Cancer Patients. New Engl J Med. 2012;366:2443-54.
Taube JM, Chen L, Xu H, Lipson E, Brahmer J, Drake C, Sharfman W, Topalian S, Anders RA. Association of PD-1, PD-Ls and features of the tumor immune microenvironment with anti-PD-1 therapeutic response. Clin Can Res. 2014 Apr 8. [Epub ahead of print].
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