human T cell biology: mechanisms of lymphocyte costimulation.
Key words: T cells, human, gene therapy, genetic engineering, signal transduction.
Description of Research
There are two themes in the laboratory. One project involves determining mechanisms of lymphocyte activation. A more recent focus is to develop and test novel forms of immunotherapy for cancer and chronic infections. In the area of T cell signal transduction, for the past ten years these studies have been focused on CD28 and CTLA-4. More recently we have also been studying mechanisms that regulate chemokine receptor expression and signal transduction in T cells. In addition, we are studying the role of telomerase expression in telomere maintenance and replicative senescence in T cells. Novel lentiviral expression systems are permitting mechanistic studies of T cell costimulation in primary T cells for the first time.
Over the last decade years my laboratory has been studying the potential use of adoptive immunotherapy for cancer and HIV infection. We have developed a large-scale tissue culture technique that permits the efficient propagation of polyclonal HIV CD4 and CD8 T cell subsets. Several clinical trials involving adoptive immunotherapy of autologous and allogeneic T cells are in process. Four trials are using genetically engineered T cells.
1. mechanisms of T cell costimulation, studies using shRNA and lentiviral vectors and zinc finger nucleases
2. lentiviral vectors to create redirected T cells to study the tumor microenvironment
3. mechanisms of superagonist T cell cell signal transduction
Naoki Kunii, MD, PhD, Post Doc
Chrystal Paulos PhD, Post Doc
Sonia Guedan, PhD, Post Doc
Matthew Frigault, Graduate Student
Carmine Carpenito, PhD, Staff Scientist
John Scholler, Staff Scientist
Yangbing Zhao, MD, PhD, Senior Scientist
Porter David L, Levine Bruce L, Kalos Michael, Bagg Adam, June Carl H: Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. The New England journal of medicine 365 (8): 725-33,2011.
Kalos Michael, Levine Bruce L, Porter David L, Katz Sharyn, Grupp Stephan A, Bagg Adam, June Carl H: T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced Leukemia. Science translational medicine 3 (95): 95ra73,2011.
Rapoport Aaron P, Aqui Nicole A, Stadtmauer Edward A, Vogl Dan T, Fang Hong-Bin, Cai Ling, Janofsky Stephen, Chew Anne, Storek Jan, Akpek Gorgun, Badros Ashraf, Yanovich Saul, Tan Ming T, Veloso Elizabeth, Pasetti Marcela F, Cross Alan, Philip Sunita, Murphy Heather, Bhagat Rita, Zheng Zhaohui, Milliron Todd, Cotte Julio, Cannon Andrea, Levine Bruce L, Vonderheide Robert H, June Carl H: Combination immunotherapy using adoptive T-cell transfer and tumor antigen vaccination on the basis of hTERT and survivin after ASCT for myeloma. Blood 117 (3): 788-97,2011.
Perez EE, Wang J, Miller JC, Jouvenot Y, Kim KA, Liu O, Wang N, Lee G, Bartsevich VV, Lee YL, Guschin DY, Rupniewski I, Waite AJ, Carpenito C, Carroll RG, Orange JS, Urnov FD, Rebar EJ, Ando D, Gregory PD, Riley JL, Holmes MC, June CH.: Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases. Nat Biotechnol. 7 : 808-16,2008.
Paulos Chrystal M, Carpenito Carmine, Plesa Gabriela, Suhoski Megan M, Varela-Rohena Angel, Golovina Tatiana N, Carroll Richard G, Riley James L, June Carl H: The inducible costimulator (ICOS) is critical for the development of human T(H)17 cells. Science translational medicine 2 (55): 55ra78,2010.
Gattinoni Luca, Lugli Enrico, Ji Yun, Pos Zoltan, Paulos Chrystal M, Quigley Máire F, Almeida Jorge R, Gostick Emma, Yu Zhiya, Carpenito Carmine, Wang Ena, Douek Daniel C, Price David A, June Carl H, Marincola Francesco M, Roederer Mario, Restifo Nicholas P: A human memory T cell subset with stem cell-like properties. Nature medicine 17 (10): 1290-7,2011.
June CH, Blazar BR, Riley JL: Engineering lymphocyte subsets: tools, trials and tribulations. Nature Reviews Immunology 9 (10): 704-16,2009.
Carpenito Carmine, Milone Michael C, Hassan Raffit, Simonet Jacqueline C, Lakhal Mehdi, Suhoski Megan M, Varela-Rohena Angel, Haines Kathleen M, Heitjan Daniel F, Albelda Steven M, Carroll Richard G, Riley James L, Pastan Ira, June Carl H: Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proceedings of the National Academy of Sciences of the United States of America 106 (9): 3360-5,2009.
Riley James L, June Carl H, Blazar Bruce R: Human T regulatory cell therapy: take a billion or so and call me in the morning. Immunity 30 (5): 656-65,2009.
Paulos CM, June CH: Putting the brakes on BTLA in T cell-mediated cancer immunotherapy. Journal of Clinical Investigation 120 (1): 76-80,2010.