Professor of Oncology
Professor of Medicine
Professor of Urology
M.D., The Johns Hopkins University School of Medicine
Hematologic Malignancies, Immunotherapy, Leukemia, Lymphoma, Prostate Cancer
Model systems have been established that enable the fate of tumor-specific T cells to be examined over time. Studies in these models demonstrate the development of tumor-antigen-specific T cell tolerance as an early event in tumor progression, resulting in blunted effector responses to vaccines and other immunotherapies. Most striking is the impairment of CD4+ T cells to differentiate into Th-1 cells capable of making gamma interferon, even in response to otherwise potent immunogens. These findings have critical implications for active immunotherapy, as Th-1 responses are essential for many types of productive host antitumor responses. In contrast to what had been widely believed, these changes in T cell function did not result from the T cell: tumor cell interaction, but rather from T cell recognition of tumor antigen that had been processed and presented by host antigen presenting cells (APCs). This key finding places the APC at the crossroads of the decision leading to either T cell priming or T cell tolerance.
During immune reconstitution, T cells specific for tumor antigen were found to be much less susceptible to the induction of tolerance described above in the immunologically intact host. Furthermore, the adoptive transfer of tumor-tolerant T cells into irradiated recipients led to the rapid conversion of these cells into gamma-interferon-producing effector cells capable of mediating tumor rejection. These findings provide the opportunity to identify which components of T cell repopulation are responsible for restoring previously anergic T cell function, and also highlight the opportunity to integrate active immunization with adoptive T cell therapy in the lymphopenic host. Trainees in the Levitsky laboratory can conduct translational research into the function of APCs in initiating therapeutic anti-cancer immune responses.
Hung, C.F.; Tsai, Y.C.; He, L.; Coukos, G.; Fodor, I.; Qin, L.; Levitsky, H.; Wu, T.C. Vaccinia virus preferentially infects and controls human and murine ovarian tumors in mice. Gene Ther. 2006 Aug 17.
Walczak, P.; Ruiz-Cabello, J.; Kedziorek, D.A.; Gilad, A.A.; Lin, S.; Barnett, B.; Qin, L.; Levitsky, H.; Bulte, J.W. Magnetoelectroporation: improved labeling of neural stem cells and leukocytes for cellular magnetic resonance imaging using a single FDA-approved agent. Nanomedicine. 2006 Jun;2(2):89-94.
Zhou, G.; Drake, C.G.; Levitsky, H.I. Amplification of tumor-specific regulatory T cells following therapeutic cancer vaccines. Blood. 2006 Jan 15;107(2):628-636.
Finke, L.H.; Wentworth, K.; Blumenstein, B.; Rudolph, N.S.; Levitsky, H.; Hoos, A. Lessons from randomized phase III studies with active cancer immunotherapies--outcomes from the 2006 meeting of the Cancer Vaccine Consortium (CVC). Vaccine. 2007 Sep 27;25 Suppl 2:B97-B109.
Hung, C.F.; Tsai, Y.C.; He, L.; Coukos, G.; Fodor, I.; Qin, L.; Levitsky, H.; Wu, T.C. Vaccinia virus preferentially infects and controls human and murine ovarian tumors in mice. Gene Ther. 2007 Jan;14(1):20-29.
Zhou, G.; Levitsky, H.I. Natural regulatory T cells and de novo-induced regulatory T cells contribute independently to tumor-specific tolerance. J Immunol. 2007 Feb 15;178(4):2155-2162.
Mirmonsef, P.; Tan, G.; Zhou, G.; Morino, T.; Noonan, K.; Borrello, I.; Levitsky, H.I. Escape from suppression: tumor-specific effector cells outcompete regulatory T cells following stem-cell transplantation. Blood. 2008 Feb 15;111(4):2112-2121.
Rabinovich, B.A.; Ye, Y.; Etto, T.; Chen, J.Q.; Levitsky, H.I.; Overwijk, W.W.; Cooper, L.J.; Gelovani, J.; Hwu, P. Visualizing fewer than 10 mouse T cells with an enhanced firefly luciferase in immunocompetent mouse models of cancer. Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14342-14346.
Stebbing, J.; Wood, C.; Atkins, M.; Bukowski, R.; Litwin, S.; Bower, M.; Parsa, A.; Levitsky, H. Cancer vaccines: clinical development challenges and proposed regulatory approaches for patient access to promising treatments. Cancer. 2008 Mar 1;112(5):955-961.
Symons, H.J.; Levy, M.Y.; Wang, J.; Zhou, X.; Zhou, G.; Cohen, S.E.; Luznik, L.; Levitsky, H.I.; Fuchs, E.J. The allogeneic effect revisited: exogenous help for endogenous, tumor-specific T cells. Biol Blood Marrow Transplant. 2008 May;14(5):499-509.
Bohana-Kashtan, O.; Morisot, S.; Hildreth, R.; Brayton, C.; Levitsky, H.I.; Civin, C.I. Selective reduction of graft-versus-host disease-mediating human T cells by ex vivo treatment with soluble Fas ligand. J Immunol. 2009 Jul 1;183(1):696-705.
Borrello, I.M.; Levitsky, H.I.; Stock, W.; Sher, D.; Qin, L.; DeAngelo, D.J.; Alyea, E.P.; Stone, R.M.; Damon, L.E.; Linker, C.A.; Maslyar, D.J.; Hege, K.M. Granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting cellular immunotherapy in combination with autologous stem cell transplantation (ASCT) as postremission therapy for acute myeloid leukemia (AML). Blood. 2009 Aug 27;114(9):1736-1745.
Janetzki, S.; Britten, C.M.; Kalos, M.; Levitsky, H.I.; Maecker, H.T.; Melief, C.J.; Old, L.J.; Romero, P.; Hoos, A.; Davis, M.M. "MIATA"-minimal information about T cell assays. Immunity. 2009 Oct 16;31(4):527-528.
Long, C.M.; van Laarhoven, H.W.; Bulte, J.W.; Levitsky, H.I. Magnetovaccination as a novel method to assess and quantify dendritic cell tumor antigen capture and delivery to lymph nodes. Cancer Res. 2009 Apr 1;69(7):3180-3187.
Britten, C.M.; Janetzki, S.; van der Burg, S.H.; Huber, C.; Kalos, M.; Levitsky, H.I.; Maecker, H.T.; Melief, C.J.; O'Donnell-Tormey, J.; Odunsi, K.; Old, L.J.; Pawelec, G.; Roep, B.O.; Romero, P.; Hoos, A.; Davis, M.M. Minimal information about T cell assays: the process of reaching the community of T cell immunologists in cancer and beyond. Cancer Immunol Immunother. 2010 Nov 16.
Kanakry, C.G.; Hess, A.D.; Gocke, C.D.; Thoburn, C.; Kos, F.; Meyer, C.; Briel, J.; Luznik, L.; Smith, B.D.; Levitsky, H.; Karp, J.E. Early lymphocyte recovery following intensive timed sequential chemotherapy for acute myelogenous leukemia: peripheral oligoclonal expansion of regulatory T cells. Blood. 2010 Dec 16.
Luznik, L.; Bolanos-Meade, J.; Zahurak, M.; Chen, A.R.; Smith, B.D.; Brodsky, R.; Huff, C.A.; Borrello, I.; Matsui, W.; Powell, J.D.; Kasamon, Y.; Goodman, S.N.; Hess, A.; Levitsky, H.I.; Ambinder, R.F.; Jones, R.J.; Fuchs, E.J. High-dose cyclophosphamide as single-agent, short-course prophylaxis of graft-versus-host disease. Blood. 2010 Apr 22;115(16):3224-3230.
Smith, B.D.; Kasamon, Y.L.; Kowalski, J.; Gocke, C.; Murphy, K.; Miller, C.B.; Garrett-Mayer, E.; Tsai, H.L.; Qin, L.; Chia, C.; Biedrzycki, B.; Harding, T.C.; Tu, G.H.; Jones, R.; Hege, K.; Levitsky, H.I. K562/GM-CSF immunotherapy reduces tumor burden in chronic myeloid leukemia patients with residual disease on imatinib mesylate. Clin Cancer Res. 2010 Jan 1;16(1):338-347.