Department:
Pathology
Program in Molecular Microbiology and Immunology
UMGCC Research Program:
Tumor Immunology and Immunotherapy
Education/Training:
College Degree:
University of Michigan Literature Science and Arts
Medical Degree:
University of Michigan Medical School
Fellowship:
Surgery Branch, National Cancer Institute (2000-2006)
Contact
Information:
Mailing Address:
University of Maryland School of Medicine
MSTF, 7-34D
Baltimore MD 21201
Email:
pantony@som.umaryland.edu
Phone:
410-706-6555
Fax:
410-706-8414
Research Interests:
Laboratory of Immunology and Tumor Immunotherapy
Because many tumor antigens are self-antigens, T cell responses to tumor antigens may be impaired by previous exposure to the antigens in the host. Ergo, there is a strong need to study authentic self-antigens that are also tumor antigens if preclinical studies are to be translated to humans. Our long-term goal is to understand how to break self-tolerance to tumor antigens and how to maintain tumor immunity through immunological memory.
The Antony lab is interested in developing novel and potent immunotherapies that use the immune system to fight cancer. Specifically, I am interested in how tolerance to cancer can be broken without using lymphodepleting regimens. Although lymphodepletion can enhance the immunotherapy of cancer (see publications below), finding more pragmatic methods to treat cancer is of interest to the immunotherapy community. This will be achieved through adoptive transfer of tumor specific T cells that recognize authentic tumor self-antigens combined with adjuvants that enhance T cell activation, memory formation, and homeostatic proliferation but simultaneously decrease Foxp3+ T regulatory cell function in normal hosts. Another goal of the lab is to understand how CD4+ T cells interact with other cells of the body to fight cancer.
The use of CD4+ T cells in the immunotherapy of cancer is still lacking. MHC class I restricted CD8+ T cells have been the primary focus in the immunotherapy of cancer because most tumors predominantly express MHC class I but not MHC class II molecules and it has been easier to isolate CD8+ T cells. Regardless, it has been shown in mouse models that CD4+ T cells can prevent the growth of class II negative tumors as well as reject MHC class I negative tumors. However, understanding how CD4+ T cells cooperate with other cells such as NK cells, NK T cells, and CD8+ T cells to kill tumor in vivo is still poorly understood, as is the generation of anti-tumor memory CD4+ T cells and their maintenance. Therefore, we developed a T cell receptor transgenic mouse at the National Cancer Institute that produces an MHC class II restricted CD4+ T cell which recognizes a tumor/self-antigen, tyrosinase-related protein-1 (tyrp-1), to directly study the mechanisms of tumor rejection in mice and the formation of immunological memory to a tumor/self-antigen. Using an animal model that mimics the human condition as closely as possible is essential for understanding how to fight cancer in the clinical setting.
Publications:
Kiristioglu I, Antony PA, Fan Y, Forbush B, Mosley RL, Yang H, Teitelbaum DH. Total Parental Nutrition-Associated Changes in Mouse Intestinal Intraepithelial Lymphocytes. Digestive Diseases and Sciences. Vol. 47, No. 5 May 2000.
Yang H, Kiritioglu I, Fan Y, Forbush B, Bishiop DK, Antony PA, Zhou H, Teitelbaum DH. Interferon-gamma expression by intraepithelial lymphocytes results in a loss of epithelial barrier function in a mouse model of total parenteral nutrition. Ann Surg. 2002 Aug;236(2):226-34.
Restifo NP, Antony PA, Finkelstein SE et al. Assumptions of the tumor 'escape' hypothesis. Semin Cancer Biol. 2002 Feb;12(1):81-6.
Antony PA and Restifo NP. Do CD4+CD25+ immunoregulatory T cells hinder tumor immunotherapy? J Immunother. 2002 May-Jun;25(3):202-6.
Overwijk WW, Theoret MR, Finkelstein SE, Surman, DR, Antony PA et al. Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T Cells. J Exp Med. 2003 Aug 18;198(4):569-80.
Diaz LA Jr, Pai R, Endres J, Antony PA, Duzyj C, Bishu S, Morita Y, Fox DA. Xenogeneic cells and superantigen induce human T-cell activation in the absence of T-cell recognition of xenoantigen. J Lab Clin Med. 2003 Sep;142(3):149-57.
Klebanoff CA, Gattinoni L, Antony PA et al. IL-15 enhances the in vivo anti-tumor activity of tumor-reactive CD8+ T cells. Pro Natl Acad Sci U S A. 2004 Feb 17;101(7):1969-74.
Yang H, Antony PA, Wildhaber BE, Teitelbaum DH. Intestinal Intraepithelial Lymphocyte gd-T Cell-Derived Keratinocyte Growth Factor Modulates Epithelial Growth in the Mouse. J Immunol. 2004 Apr 1;172(7):4151-8.
Finkelstein SE, Heimann DM, Klebanoff CA, Antony PA et al. Bedside to Bench and Back Again: How animal models are guiding the development of new immunotherapies for cancer. J Leukoc Biol. 2004 Aug;76(2):333-7.
Klebanoff CA, Khong H, Antony PA, Palmer D, Restifo NP. Sinks, suppressors and antigen presenters: how lymphphodepletion enhances T cell-mediated tumor immunotherapy. Trends Immunol. 2005 Feb;26(2):111-7.
Antony PA, Piccirillo CA, Akpinarli A et al. CD8+ T cell immunity against a tumor/self-antigen is augmented by CD4+ T helper cells and hindered by naturally occurring T regulatory cells. Cover Article: J Immunol. 2005 Mar 1;174(5):2591-601.
Antony PA, Restifo, NP. CD4+CD25+ T regulatory cells, immunotherapy of cancer, and interleukin-2. J of Immunother. 2005 Mar-Apr;28(2):120-8.
Klebanoff CA, Gattinoni L, Torabi P et al. Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells. Proc Natl Acad Sci U S A. 2005 Jul 5:102(27):9571-6.
Gattinoni L, Klebanoff CA, Finkelstein SE, Antony PA et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J Exp Med. 2005 Oct 3;202(7):907-12.
Antony PA, Paulos C, Ahmadzadeh M, Akpinarli A et al. Interleukin-2-dependent mechanisms of tolerance and immunity in vivo. J Immunol. 2006 May 1;176(9):5255-66.
Gattinoni L, Ranganathan A, Surman DR, Palmer DP, Antony PA et al. CTLA-4 dysregulation of self/tumor-reactive CD8+ T cell function is CD4+ T cell-dependent. Blood. 2006 Aug 1.
Ahmadzadeh MA, Antony PA, Rosenberg SA. IL-2 and IL-15 each mediate de novo induction of FOXP3 expression in human tumor antigen-specific CD8 T cells. J Immunother. 2007 Apr;30(3):294-302.
Paulos CM, Wrzesinski C, Kaiser A, Hinrichs CS, Chieppa M, Cassard L, Palmer DC, Boni A, Muranski P, Yu Z, Gattinoni L, Antony PA, Rosenberg SA, and Restifo NP.Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via Toll-like receptor 4 signaling. JCI. August 2007. In Press.
Paulos, CM, Andrew Kaiser, Claudia Wrzesinski, Christian S. Hinrichs, Lydie Cassard, Andrea Boni, Pawel Muranski, Luis Sanchez-Perez, Douglas C. Palmer, Zhiya Yu, Antony PA, Luca Gattinoni, Steven A Rosenberg and Nicholas P. Restifo. Toll-like Receptors in Tumor Immunotherapy. Submitted.
Muranski PM*, Boni, A*, Antony PA*, Irvine K*, et al. Adoptive Transfer of Tumor-reactive Th17 CD4+ T cells are capable of inducing potent anti-tumor immunity. In revision for Blood.
Xie, Y., Akpinarli, A., Maris, C., Lane, M., Hipkiss, E., Kwon, E-M., Muranski, P., Restifo, NP., Antony, PA. Naïve tumor-specific CD4+ T cells differentiaited in vivo eradicate established melanoma. Journal of Experimental Medicine. 2010.
Quezada, S., Simpson, T., Peggs, K., Mergoub, T, Muranksi, P., Antony, P.A., Restifo, N., Allison, JP. Tumor-reactive CD4+ T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts. Journal of Experimental Medicine. 2010.
