Drew Pardoll.M.D., Ph.D.

Co-PI Projects 4 and 5

Chair of Scientific Review,

Committee for the Developmental

Research Program

Department Affiliation:

Primary: Oncology,

Secondary: Molecular Biology and Genetics

Degree: M.D., Ph.D., Johns Hopkins University

Rank: Professor

Telephone Number: 410-955-7866

Fax Number: 410-614-0549

E-mail address: dmpardol@welchlink.welch.jhu.edu

School of Medicine Address:

JHU School of Medicine

720 Rutland Ave., 364 Ross

Baltimore, MD 21205

Tumor imunology, T cell tolerance; T cell regulation

Our laboratory focuses on the regulation of antigen specific T cell responses and studies approaches to modify these responses for immunotherapy. Specifically, the interests of the laboratory fall into four areas:

1. Immunologic Tolerance - the major mechanism by which tumors grow unchecked by the immune system is their ability to induce tolerance among mature T cells. Our studies using transgenic mouse models have indicated that the same mechanisms that induce tolerance to peripheral tissue specific antigens likely are responsible for tolerance induction to tumor antigens. In particular, we have developed experimental evidence for the existence of a dedicated bone marrow derived "tolerizing" antigen presenting cell (APC) responsible for processing and presenting cell tissue and tumor antigens to induce tolerance.

2. Antigen Presentation - one of the cancer vaccine approaches that are being actively tested clinically is the vaccination with tumor cells transduced with the GM-CSF gene. These vaccines appear to be particularly potent because of the ability of the locally produced GM-CSF to activate the differentiation of bone marrow progenitors into dendritic cells. Using subtractive library approaches, we have been in the process of mapping out genes unique to dendritic cells that mediate their potent T cell stimulatory capacity.

3. Definition of Immunodominant and Immunorelevant Tumor Antigens - Ultimately, we wish to define the biological and biochemical rules that determine which antigens are dominant targets for immune responses. We are currently using genomic approaches to rapidly screen for genes encoding antigens recognized by tumor specific T cells.

4. Dissection of Immunologic Effector Pathways - Our studies on GM-CSF gene modified tumor vaccines have led to the identification of novel effector pathways in tumor immunity. Besides the classical CTL response, we have found that activation of the eosinophils and activation of macrophages to produce NO and superoxides are critical pathways of tumor killing. Using in vitro systems for the chemical generation of these mediators, we have been defining molecular pathways by which these mediators specifically induce apoptosis in tumor cells.

1.Wang, T.-L., Ling, M., Shih, I.-M., Pham, T., Pai, S.I., Lu, Z., Kurman, R.J., Pardoll, D.M., and Wu, T.-C. (2000) Intramuscular administration E7-transduced dendritic cells generate the most potent E7-specific antitumor immunity. Gene Therapy, 7:726.

2. Ewend M.G., Thompson, R.C., Anderson, R., Sills, A.K., Stavely-O'Carroll, K., Tyler, B.M., Hanes, J., Brat, D., Thoams, M., Jaffee, E.M., Pardoll, D.M., and Brem, H. (2000). Intracranial paracrine IL-2 therapy stimulates prolonged antitumor immunity which extends outside the central nervous system. J Immunotherapy Jul-Aug 23(4):438-448.

3. Chen, C.-H., Wang, T.-L., Hung, C.-F., Yang, Y., Pardoll, D.M., and Wu, T.-C. (2000) Boosting with recombinant vaccinia increased HPV E7-specific T cell precursor frequencies of HPV-16 E7-expressing DNA vaccines. Vaccine, 18(19):2015-2022.

4. Pardoll, D.M. (2000) Therapeutic vaccination for cancer. Clinical Immunology 95:S44-S62.

5. Slansky, J.E., Rattis, F.M., Boyd, L.F., Fahmy, T., Jaffee, E.M., Schneck, J.P., Margulies, D.H., and Pardoll, D.M. (2000) Enhanced antigen-specific antitumor immunity with altered peptide ligands that stabilize the MHC-peptide-TCR complex. Immunity Oct 13:529-538.