Hy Levitsky M.D.
Professor of Oncology, Medicine, Urology
Scientific Director, George Santos Bone Marrow Transplant Program
Graduate Program in Immunology
Graduate Program in Pathobiology
Graduate Program in Cellular and Molecular Medicine
Room 4M51
Bunting-Blaustein Cancer Research Building
410-614-0552 (phone)
410-614-9705 (fax)
hy@jhmi.edu

 Research Focus.

The Levitsky laboratory is committed to making fundamental discoveries pertaining to the mechanisms that govern host anti-tumor immunity, and exploit these findings to develop novel strategies for cancer therapy. These studies are grounded in basic molecular and cellular immunology as revealed in state of the art mouse models. Such models also support the pre-clinical evaluation of the novel immunotherapies that emerge from these discoveries. The most promising of these are then tested in early phase clinical trials which not only evaluate the impact of a given treatment, but also provide clinical material for in depth analysis of the human anti-tumor immune response. Finally, observations made in the course of human investigation generate hypotheses that are again tested in murine systems.

Examples of relevant discoveries made by this laboratory include:

1. Development of cytokine gene transduced tumor cell based vaccines to augment systemic immune mediated tumor rejection 1,2.

2. Identification of “cross-priming” by host antigen presenting cells as the dominant mechanism responsible for activating tumor-specific MHC class I restricted cytolytic T lymphocytes 3.

3. In vivo demonstration of an endosome to cytosol TAP dependent pathway of antigen processing for cross priming 4.

4. The central role played by tumor-specific CD4 + T cells in regulating anti-tumor immunity 5.

5. Identification of tumor specific T cell tolerance as a major barrier to active immunotherapy 6.

6. Demonstration that “therapeutic cancer vaccines” can also amplify tumor-specific regulatory T cells, potentially deepening the barrier of tolerance 7.

7. The pivotal role played by host antigen presenting cells in regulating the induction of tumor specific T cell tolerance versus priming 8,9.

8. Identification of the period of immune reconstitution following hematopoietic stem cell transplantation as being resistant to tolerance induction and favorable for vaccine induced anti-tumor immunity 10.

Examples of translational clinical studies based on the above discoveries:

1. The clinical development of GM-CSF tumor-cell based vaccines (“GVAX”) now in phase III testing for prostate cancer, and earlier phase testing for several other malignancies. The discovery of “cross-priming” in the response to this vaccine also supported the rationale for using allogeneic tumor cell lines in this platform.

2. The creation of a Universal GM-CSF producing “bystander” cell for therapeutic cancer vaccines, which has been (or is being) tested in multiple myeloma 11, AML 12, lung cancer 13, CLL, Hodgkin disease, and colorectal carcinoma.

3. The integration of cancer vaccines with the adoptive transfer of vaccine primed lymphocytes in the setting of autologous hematopoietic stem cell transplantation. 11,12

4. Strategies seeking to activate host APCs either locally at the vaccine site (using TLR agonists 14), or systemically (e.g. anti-CD40 antibody).

5. Evaluation of vaccine induced eradication of minimal residual disease in CML following cytoreduction with imatinib 14.

6. Evaluation of cancer vaccines in combination with HDAC inhibitors, DNA methyltransferase inhibitors, and iMIDs in the treatment of myelodysplastic syndromes.

New Directions:

Current projects stemming from the above include:

1. Defining the mechanism(s) of regulatory T cell mediated suppression of host anti-tumor immunity.

2. Characterizing homeostatic repopulation of lymphocyte subsets during the re-establishment of regulatory networks following BMT.

3. Modulate Treg function and frequency in vivo and in vitro in the BMT setting.

4. Developing novel molecular imaging techniques to quantify in humans the delivery of antigen by antigen presenting cells from vaccine injection sites to draining lymph nodes (MRI).

5. Developing novel imaging techniques to evaluate tumor-specific T cell trafficking in humans (PET).

6. Utilizing a screening method of combinatorial libraries altering primary amino acid sequences of candidate tumor antigens as a means to augment vaccine responses and circumvent tolerance.

7. Develop novel vaccine strategies that systemically target APCs in vivo, and allow for simultaneous manipulation of APC activation and function.

References:

1. Dranoff G, Jaffee E, Lazenby A, et al. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci U S A. 1993;90:3539-3543.

2. Levitsky HI, Montgomery J, Ahmadzadeh M, et al. Immunization with granulocyte-macrophage colony-stimulating factor- transduced, but not B7-1-transduced, lymphoma cells primes idiotype- specific T cells and generates potent systemic antitumor immunity. J Immunol. 1996;156:3858-3865.

3. Huang AY, Golumbek P, Ahmadzadeh M, Jaffee E, Pardoll D, Levitsky H. Role of bone marrow-derived cells in presenting MHC class I-restricted tumor antigens. Science. 1994;264:961-965.

4. Huang AY, Bruce AT, Pardoll DM, Levitsky HI. In vivo cross-priming of MHC class I-restricted antigens requires the TAP transporter. Immunity. 1996;4:349-355.

5. Hung K, Hayashi R, Lafond-Walker A, Lowenstein C, Pardoll D, Levitsky H. The Central Role of CD4(+) T Cells in the Antitumor Immune Response. J Exp Med. 1998;188:2357-2368.

6. Staveley-O' Carroll K, Sotomayor E, Montgomery J, et al. Induction of antigen-specific T cell anergy: An early event in the course of tumor progression. Proc Natl Acad Sci U S A. 1998;95:1178-1183.

7. Zhou G, Drake CG, Levitsky HI. Amplification of tumor-specific regulatory T cells following therapeutic cancer vaccines. Blood. 2006;107:628-636.

8. Sotomayor EM, Borrello, I., Tubb, E., Rattis, F.M., Bien, H., Lu, Z., Fein, S., Schoenberger, S., and Levitsky, H.I. Conversion of tumor-specific CD4+ T-cell tolerance to T-cell priming through in vivo ligation of CD40. Nature Medicine. 1999;5:780-787.

9. Sotomayor EM, Borrello I, Rattis FM, et al. Cross-presentation of tumor antigens by bone marrow-derived antigen-presenting cells is the dominant mechanism in the induction of T-cell tolerance during B-cell lymphoma progression. Blood. 2001;98:1070-1077.

10. Borrello I, Sotomayor EM, Rattis FM, Cooke SK, Gu L, Levitsky HI. Sustaining the graft-versus-tumor effect through posttransplant immunization with granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing tumor vaccines. Blood. 2000;95:3011-3019.

11. Borrello I, Biedrzycki B, Sheets K, Donnelly A, Hege K, Levitsky H. Autologous tumor combined with a GM-CSF secreting cell line vaccine (GVAX) following autologous stem cell transplant (ASCT) in multiple myeloma. BLOOD. 2004;104:129a.

12. DeAngelo DJ, Alyea EP, Borrello I, et al. Posttransplant immunotherapy with a GM-CSF based tumor vaccine (GVAX) following autologous stem cell transplant (ASCT) for acute myeloid leukemia (AML). Blood. 2004;104:129a.

13. Nemunaitis J, Jahan T, Ross H, et al. Phase 1/2 trial of autologous tumor mixed with an allogeneic GVAX vaccine in advanced-stage non-small-cell lung cancer. Cancer Gene Ther. 2006;13:555-562.

14. B. Smith YLK, C. B. Miller, C. Chia, C. Gocke, J. Kowalski, I. Tartakovsky, B. Biedrzycki, R. J. Jones, K. Hege, H. I. Levitsky. K562/GM-CSF vaccination reduces tumor burden, including achieving molecular remissions, in chronic myeloid leukemia (CML) patients with residual disease on imatinib mesylate.

Journal of Clinical Oncology. 2006;24 (18S):6509.