Mike Milone, MD
The ability of adoptively transferred T cells to mediate anti-tumor and anti-viral effects in vivo is now well documented, particularly in the setting of chronic viral infections such as Epstein Barr virus and cytomegalovirus infections. However, reproducibly harnessing this activity for cancer therapy requires that several technical barriers be solved including overcoming self-tolerance and immunosuppression related to cancer and its treatment. My laboratory is addressing these challenges through development of adoptive T cell therapies (see Fig 1). The adoptive immunotherapy approach overcomes many of the obstacles that limit vaccine strategies by permitting control over the antigenic specificity of the T cells through antigen-specific culture systems and/or genetic engineering. Ex vivo T cell culture also affords the ability to generate large numbers of T cells in the face of T cell deficiencies in cancer as well as control the phenotype and function of the adoptively transferred T cells. Strategies being pursued in my laboratory include:
1. Artificial (so called “T-bodies”, see Fig. 2) and natural T cell antigen receptors that can be efficiently delivered to T cells via lentiviral gene transfer or RNA transfection.
Michael Milone is an Assistant Professor of Pathology and Laboratory Medicine at the Hospital of the University of Pennsylvania and the School of Medicine. He earned his MD and PhD in 1999 from the University of Medicine and Dentistry of New Jersey. His doctoral work focused upon the unique interactions between plasmacytoid dendritic cells and viruses that stimulate abundant type I interferon production by this dendritic cell subset. He went on to post-graduate medical training in internal medicine, laboratory medicine and transfusion medicine at the University of Pennsylvania. Dr. Milone continued his scientific research studies during a post-doctoral fellowing pursuing adoptive immunotherapy of cancer with Dr. Carl June at the University of Pennsylvania. This work has lead to an open Phase I study of artificial antigen receptors in patients with B cell leukemia and lympohma. Joining the faculty in 2007, Dr. Milone’s laboratory continues to focus upon genetic engineering and adoptive immunotherapy of cancer with new approaches based upon work within the NCMDIR that began in 2008 when he joined the nanomedicine initiative as the center’s clinical collaborator.
Milone MC, Tsai DE, Hodinka R, Silverman LB, Stadtmauer EA, Malbran A, Wasik M, Nichols KE: Treatment of primary Epstein-Barr virus infection in patients with X-linked lymphoproliferative disease using B-cell directed therapy. Blood 105((3)): 994-6, 2005.
Suhoski MC, Golovina TN, Aqui NA, Tai VC, Varela-Rohena A, Milone MC, Carroll RG, Riley JL, June CH: Engineering Artificial Antigen Presenting Cells to Express a Diverse Array of Costimulatory Molecules. Mol Ther 15(5): 981-8, May 2007.
Christian NA, Milone MC, Ranka SS, Li G, Frail PR, Davis KP, Bates FS, Therien MJ, Ghoroghchain PP, June CH, Hammer DA: Tat-Functionalized Near-Infrared Emissive polymersomes for Dendritic Cell labeling. Bioconjugate Chemistry 18((1)): 31-40, 2007.
Huang X, Guo H, Kang JT, Choi S, Zhou TC,Tammana S, Lees CJ, Li Z, Milone M, Levine BL, Tolar J, June CH, McIvor RS, Wagner JE, Blazar BR, Zhou X: Sleeping Beauty transposon mediated engineering of human primary T cells for therapy of CD19+ lymphoid malignancies. Mol Ther 16(3): 580-589, 2008.
Christian NA, Benencia F, Milone MC, Li G, Frail PR, Therien MJ, Coukos G, Hammer DA: In Vivo Dendritic Cell Tracking Using Fluorescence Lifetime Imaging and Near-Infrared-Emissive Polymersomes. Molecular imaging and biology 11(3): 167-177, Jun 2009.
Milone MC, Fish JD, Carpenito C, Carroll RG, Binder GK, Teachey D, Samanta M, Lakhal M, Gloss G, Danet-Desnoyers G, Campana D, Riley JL, Grupp SA, June CH: Chimeric antigen receptors containing the CD137 signal transduction domain mediate enhanced survival of T cells and increased anti-leukemic efficacy in vivo. Mol Ther 17(8): 1453-64, Aug 2009.
Carpenito C, Milone MC, Hassan R, Simonet JC, Lakhal M, Suhoski MM, Varela-Rohena A, Haines DM, Heitjan DF, Albelda SM, Carroll RG,Riley JL, Pastan I, June CH: Eradication of large established tumor xenografts with genetically re-targeted human T cells containing CD28 and CD137 domains. Proc Nat Acad Sci 106(9): 3360-3365, 2009.
Zhang Qian, Wang Hong Y, Bhutani Gauri, Liu Xiaobin, Paessler Michele, Tobias John W, Baldwin Donald, Swaminathan Kunchithapadam, Milone Michael C, Wasik Mariusz A: Lack of TNFalpha expression protects anaplastic lymphoma kinase-positive T-cell lymphoma (ALK+ TCL) cells from apoptosis. Proceedings of the National Academy of Sciences of the United States of America 106(37): 15843-8, Sep 2009.
Tammana S, Huang X, Wong M, Milone MC, Ma L, Levine BL, June CH, Wagner JE, Blazar BR, Zhou X: 4-1BB and CD28 signaling plays a synergistic role in redirecting umbilical cord blood T cells against B-Cell malignancies. Hum Gene Ther 21(1): 75-86, 2010.