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Dr. Drew Pardoll

M.D., Ph.D.
(410) 614-0549 (f)
Drew Pardoll
Interests

Gene and Cell Therapy

Titles

Seraph Professorship in Oncology
Martin D. Abeloff Professorship
Co-Director, Cancer Immunology and Hematopoiesis Program
Professor of Oncology
Professor of Medicine
Professor of Pathology
Professor of Molecular Biology and Genetics

Schools\Degrees

M.D., Johns Hopkins School of Medicine, Baltimore, MD Ph.D., Johns Hopkins School of Medicine, Baltimore, MD

Training

Medical Resident, Osler Medical Service, Johns Hopkins Hospital
Oncology Fellow, Johns Hopkins Hospital
Medical Staff Fellow, Laboratory of Immunology, National Institutes of Allergy and Infectious Disease, National Institutes of Health

Clinical Interests

Cancer

Research Summary

Over the past year, we have completed the initial characterization of a number of interesting dendritic cell-specific genes identified via subtractive hybridization between a dendritic cell cDNA library and an activated macrophage cDNA library. One specific example is a new dendritic cell-specific costimulatory gene termed B7-DC. Another gene, termed MINOR, is an orphan steroid receptor gene that appears to be activated in mature dendritic cells and induces rapid-onset apoptosis. Important reagents will help us further dissect the basic biology of B7-DC as well as evaluate its role in enhancing immunotherapeutic potency. Specifically, we have generated a panel of antibodies against the murine B7-DC molecule and are currently generating antibodies against human B7-DC. We have also made knockout/knockin mice of B7-DC in which the B7-DC gene is replaced with the GFP gene. This will allow us to simultaneously assess expression patterns of B7-DC as well as defects in immune responsiveness in its absence. A second gene that we have identified, termed MINOR, is selectively expressed by mature dendritic cells. MINOR is an orphan steroid receptor gene, and based on homology, we hypothesized that it might be involved as an endogenous activator of dendritic cell apoptosis. 

Indeed, we demonstrated that transfection of the MINOR gene into a dendritic cell line induced active apoptosis. This apoptosis induction was selected for cells of hematopoietic origin, as it did not induce apoptosis in three different nonhematopoietic cell lines. We have currently produced transgenic mice expressing both the wildtype MINOR gene and a dominant negative MINOR gene under control of the MHC class II promoter to generate selective expression in dendritic cells in vivo. These mice should be ready for biologic and immunologic analysis over the next year.

T cell tolerance Using transgenic mouse models, we have developed a number of novel insights into cellular mechanisms of tolerance generation among T cells. Specifically, we have determined that T cells rendered anergic after recognition of self-antigen turn into suppressor cells capable of inhibiting the activation of native T cells in an antigen-specific fashion. This process appears to involve the uncoupling of activation of proliferative and effector cytokines. Thus, proliferative cytokines are not suppressed, allowing for expansion of T cells. However, these T cells are incapable of producing any effector activity because effector cytokines such as IFN are selectively suppressed. We are currently in the process of dissecting signaling pathways and suppressed T cells and have identified a defect in Tibet expression, a factor previously identified as important in induction of IFN.
 

Journal Citations

Anand, S.; Wang, P.; Yoshimura, K.; Choi, I.H.; Hilliard, A.; Chen, Y.H.; Wang, C.R.; Schulick, R.; Flies, A.S.; Flies, D.B.; Zhu, G.; Xu, Y.; Pardoll, D.M.; Chen, L.; Tamada, K. Essential role of TNF family molecule LIGHT as a cytokine in the pathogenesis of hepatitis. J Clin Invest. 2006 Apr;116(4):1045-1051.

Chan, C.W.; Crafton, E.; Fan, H.N.; Flook, J.; Yoshimura, K.; Skarica, M.; Brockstedt, D.; Dubensky, T.W.; Stins, M.F.; Lanier, L.L.; Pardoll, D.M.; Housseau, F. Interferon-producing killer dendritic cells provide a link between innate and adaptive immunity. Nat Med. 2006 Feb;12(2):207-213.

Peng, S.; Trimble, C.; He, L.; Tsai, Y.C.; Lin, C.T.; Boyd, D.A.; Pardoll, D.; Hung, C.F.; Wu, T.C. Characterization of HLA-A2-restricted HPV-16 E7-specific CD8(+) T-cell immune responses induced by DNA vaccines in HLA-A2 transgenic mice. Gene Ther. 2006 Jan;13(1):67-77.

Ravi, R.; Fuchs, E.J.; Jain, A.; Pham, V.; Yoshimura, K.; Prouser, T.; Jalla, S.; Zhou, X.; Garrett-Mayer, E.; Kaufmann, S.H.; Schulick, R.D.; Pardoll, D.M.; Bedi, A. Resistance of cancers to immunologic cytotoxicity and adoptive immunotherapy via X-linked inhibitor of apoptosis protein expression and coexisting defects in mitochondrial death signaling. Cancer Res. 2006 Feb 1;66(3):1730-1739.

Yoshimura, K.; Jain, A.; Allen, H.E.; Laird, L.S.; Chia, C.Y.; Ravi, S.; Brockstedt, D.G.; Giedlin, M.A.; Bahjat, K.S.; Leong, M.L.; Slansky, J.E.; Cook, D.N.; Dubensky, T.W.; Pardoll, D.M.; Schulick, R.D. Selective targeting of antitumor immune responses with engineered live-attenuated Listeria monocytogenes. Cancer Res. 2006 Jan 15;66(2):1096-1104.

Goldberg, M.V.; Maris, C.H.; Hipkiss, E.L.; Flies, A.S.; Zhen, L.; Tuder, R.M.; Grosso, J.F.; Harris, T.J.; Getnet, D.; Whartenby, K.A.; Brockstedt, D.G.; Dubensky, T.W., Jr.; Chen, L.; Pardoll, D.M.; Drake, C.G. Role of PD-1 and its ligand, B7-H1, in early fate decisions of CD8 T cells. Blood. 2007 Jul 1;110(1):186-192.

Grosso, J.F.; Kelleher, C.C.; Harris, T.J.; Maris, C.H.; Hipkiss, E.L.; De Marzo, A.; Anders, R.; Netto, G.; Getnet, D.; Bruno, T.C.; Goldberg, M.V.; Pardoll, D.M.; Drake, C.G. LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems. J Clin Invest. 2007 Nov;117(11):3383-3392.

Harris, T.J.; Grosso, J.F.; Yen, H.R.; Xin, H.; Kortylewski, M.; Albesiano, E.; Hipkiss, E.L.; Getnet, D.; Goldberg, M.V.; Maris, C.H.; Housseau, F.; Yu, H.; Pardoll, D.M.; Drake, C.G. Cutting edge: An in vivo requirement for STAT3 signaling in TH17 development and TH17-dependent autoimmunity. J Immunol. 2007 Oct 1;179(7):4313-4317.

Lin, K.Y.; Lu, D.; Hung, C.F.; Peng, S.; Huang, L.; Jie, C.; Murillo, F.; Rowley, J.; Tsai, Y.C.; He, L.; Kim, D.J.; Jaffee, E.; Pardoll, D.; Wu, T.C. Ectopic expression of vascular cell adhesion molecule-1 as a new mechanism for tumor immune evasion. Cancer Res. 2007 Feb 15;67(4):1832-1841.
Melero, I.; Hervas-Stubbs, S.; Glennie, M.; Pardoll, D.M.; Chen, L. Immunostimulatory monoclonal antibodies for cancer therapy. Nat Rev Cancer. 2007 Feb;7(2):95-106.

Pan, F.; Sun, L.; Kardian, D.B.; Whartenby, K.A.; Pardoll, D.M.; Liu, J.O. Feedback inhibition of calcineurin and Ras by a dual inhibitory protein Carabin. Nature. 2007 Jan 25;445(7126):433-436.

Pardoll, D. Dendritic Cells and Coregulatory Signals: Immune Checkpoint Blockade to Stimulate Immunotherapy. In: Prendergast G, J.E., editor, Cancer Immunotherapy: Immune Suppression and Tumor Growth: Academic Press; 2007. p. 257-276.

Pardoll, D. Cacer-specific vaccines. In: Mendelsohn J, H.P., Israel M, Gray J, Thompson C, editor. 3 ed, The Molecular Basis of Cancer: Elsevier Inc.; 2007. p. 649-669.

Pardoll, D. Immunology and Cancer. In: Abeloff M, e.a., editor. 4 ed, Clinical Oncology: Elsevier Inc.; 2007. p. 113-138.

Pardoll, D.M. Building the bionic T cell. Nat Med. 2007 Dec;13(12):1411-1413.
Peng, S.; Trimble, C.; Wu, L.; Pardoll, D.; Roden, R.; Hung, C.F.; Wu, T.C. HLA-DQB1*02-restricted HPV-16 E7 peptide-specific CD4+ T-cell immune responses correlate with regression of HPV-16-associated high-grade squamous intraepithelial lesions. Clin Cancer Res. 2007 Apr 15;13(8):2479-2487.

Pentcheva-Hoang, T.; Chen, L.; Pardoll, D.M.; Allison, J.P. Programmed death-1 concentration at the immunological synapse is determined by ligand affinity and availability. Proc Natl Acad Sci U S A. 2007 Nov 6;104(45):17765-17770.

Tsushima, F.; Yao, S.; Shin, T.; Flies, A.; Flies, S.; Xu, H.; Tamada, K.; Pardoll, D.M.; Chen, L. Interaction between B7-H1 and PD-1 determines initiation and reversal of T-cell anergy. Blood. 2007 Jul 1;110(1):180-185.

Yoshimura, K.; Laird, L.S.; Chia, C.Y.; Meckel, K.F.; Slansky, J.E.; Thompson, J.M.; Jain, A.; Pardoll, D.M.; Schulick, R.D. Live attenuated Listeria monocytogenes effectively treats hepatic colorectal cancer metastases and is strongly enhanced by depletion of regulatory T cells. Cancer Res. 2007 Oct 15;67(20):10058-10066.

Yu, H.; Kortylewski, M.; Pardoll, D. Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol. 2007 Jan;7(1):41-51.

Barnes, E.; Salio, M.; Cerundolo, V.; Francesco, L.; Pardoll, D.; Klenerman, P.; Cox, A. Monocyte derived dendritic cells retain their functional capacity in patients following infection with hepatitis C virus. J Viral Hepat. 2008 Mar;15(3):219-228.

Harris, T.J.; Hipkiss, E.L.; Borzillary, S.; Wada, S.; Grosso, J.F.; Yen, H.R.; Getnet, D.; Bruno, T.C.; Goldberg, M.V.; Pardoll, D.M.; DeWeese, T.L.; Drake, C.G. Radiotherapy augments the immune response to prostate cancer in a time-dependent manner. Prostate. 2008 Sep 1;68(12):1319-1329.

Jordan, K.R.; McMahan, R.H.; Oh, J.Z.; Pipeling, M.R.; Pardoll, D.M.; Kedl, R.M.; Kappler, J.W.; Slansky, J.E. Baculovirus-infected insect cells expressing peptide-MHC complexes elicit protective antitumor immunity. J Immunol. 2008 Jan 1;180(1):188-197.

Rutebemberwa, A.; Ray, S.C.; Astemborski, J.; Levine, J.; Liu, L.; Dowd, K.A.; Clute, S.; Wang, C.; Korman, A.; Sette, A.; Sidney, J.; Pardoll, D.M.; Cox, A.L. High-programmed death-1 levels on hepatitis C virus-specific T cells during acute infection are associated with viral persistence and require preservation of cognate antigen during chronic infection. J Immunol. 2008 Dec 15;181(12):8215-8225.

Wolfl, M.; Rutebemberwa, A.; Mosbruger, T.; Mao, Q.; Li, H.M.; Netski, D.; Ray, S.C.; Pardoll, D.; Sidney, J.; Sette, A.; Allen, T.; Kuntzen, T.; Kavanagh, D.G.; Kuball, J.; Greenberg, P.D.; Cox, A.L. Hepatitis C virus immune escape via exploitation of a hole in the T cell repertoire. J Immunol. 2008 Nov 1;181(9):6435-6446.

Getnet, D.; Maris, C.H.; Hipkiss, E.L.; Grosso, J.F.; Harris, T.J.; Yen, H.R.; Bruno, T.C.; Wada, S.; Adler, A.; Georgantas, R.W.; Jie, C.; Goldberg, M.V.; Pardoll, D.M.; Drake, C.G. Tumor recognition and self-recognition induce distinct transcriptional profiles in antigen-specific CD4 T cells. J Immunol. 2009 Apr 15;182(8):4675-4685.

Grosso, J.F.; Goldberg, M.V.; Getnet, D.; Bruno, T.C.; Yen, H.R.; Pyle, K.J.; Hipkiss, E.; Vignali, D.A.; Pardoll, D.M.; Drake, C.G. Functionally distinct LAG-3 and PD-1 subsets on activated and chronically stimulated CD8 T cells. J Immunol. 2009 Jun 1;182(11):6659-6669.

Kortylewski, M.; Swiderski, P.; Herrmann, A.; Wang, L.; Kowolik, C.; Kujawski, M.; Lee, H.; Scuto, A.; Liu, Y.; Yang, C.; Deng, J.; Soifer, H.S.; Raubitschek, A.; Forman, S.; Rossi, J.J.; Pardoll, D.M.; Jove, R.; Yu, H. In vivo delivery of siRNA to immune cells by conjugation to a TLR9 agonist enhances antitumor immune responses. Nat Biotechnol. 2009 Oct;27(10):925-932.

Kortylewski, M.; Xin, H.; Kujawski, M.; Lee, H.; Liu, Y.; Harris, T.; Drake, C.; Pardoll, D.; Yu, H. Regulation of the IL-23 and IL-12 balance by Stat3 signaling in the tumor microenvironment. Cancer Cell. 2009 Feb 3;15(2):114-123.
Lee, H.; Herrmann, A.; Deng, J.H.; Kujawski, M.; Niu, G.; Li, Z.; Forman, S.; Jove, R.; Pardoll, D.M.; Yu, H. Persistently activated Stat3 maintains constitutive NF-kappaB activity in tumors. Cancer Cell. 2009 Apr 7;15(4):283-293.

Pan, F.; Yu, H.; Dang, E.V.; Barbi, J.; Pan, X.; Grosso, J.F.; Jinasena, D.; Sharma, S.M.; McCadden, E.M.; Getnet, D.; Drake, C.G.; Liu, J.O.; Ostrowski, M.C.; Pardoll, D.M. Eos mediates Foxp3-dependent gene silencing in CD4+ regulatory T cells. Science. 2009 Aug 28;325(5944):1142-1146.

Pardoll, D. Metastasis-promoting immunity: when T cells turn to the dark side. Cancer Cell. 2009 Aug 4;16(2):81-82.

Pletneva, M.; Fan, H.; Park, J.J.; Radojcic, V.; Jie, C.; Yu, Y.; Chan, C.; Redwood, A.; Pardoll, D.; Housseau, F. IFN-producing killer dendritic cells are antigen-presenting cells endowed with T-cell cross-priming capacity. Cancer Res. 2009 Aug 15;69(16):6607-6614.

Trimble, C.L.; Peng, S.; Kos, F.; Gravitt, P.; Viscidi, R.; Sugar, E.; Pardoll, D.; Wu, T.C. A phase I trial of a human papillomavirus DNA vaccine for HPV16+ cervical intraepithelial neoplasia 2/3. Clin Cancer Res. 2009 Jan 1;15(1):361-367.

Wada, S.; Yoshimura, K.; Hipkiss, E.L.; Harris, T.J.; Yen, H.R.; Goldberg, M.V.; Grosso, J.F.; Getnet, D.; Demarzo, A.M.; Netto, G.J.; Anders, R.; Pardoll, D.M.; Drake, C.G. Cyclophosphamide augments antitumor immunity: studies in an autochthonous prostate cancer model. Cancer Res. 2009 May 15;69(10):4309-4318.

Wang, L.; Yi, T.; Kortylewski, M.; Pardoll, D.M.; Zeng, D.; Yu, H. IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway. J Exp Med. 2009 Jul 6;206(7):1457-1464.

Wang, T.; Jiang, Q.; Chan, C.; Gorski, K.S.; McCadden, E.; Kardian, D.; Pardoll, D.; Whartenby, K.A. Inhibition of activation-induced death of dendritic cells and enhancement of vaccine efficacy via blockade of MINOR. Blood. 2009 Mar 26;113(13):2906-2913.

Workman, C.J.; Wang, Y.; El Kasmi, K.C.; Pardoll, D.M.; Murray, P.J.; Drake, C.G.; Vignali, D.A. LAG-3 regulates plasmacytoid dendritic cell homeostasis. J Immunol. 2009 Feb 15;182(4):1885-1891.

Wu, S.; Rhee, K.J.; Albesiano, E.; Rabizadeh, S.; Wu, X.; Yen, H.R.; Huso, D.L.; Brancati, F.L.; Wick, E.; McAllister, F.; Housseau, F.; Pardoll, D.M.; Sears, C.L. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med. 2009 Sep;15(9):1016-1022.

Yen, H.R.; Harris, T.J.; Wada, S.; Grosso, J.F.; Getnet, D.; Goldberg, M.V.; Liang, K.L.; Bruno, T.C.; Pyle, K.J.; Chan, S.L.; Anders, R.A.; Trimble, C.L.; Adler, A.J.; Lin, T.Y.; Pardoll, D.M.; Huang, C.T.; Drake, C.G. Tc17 CD8 T cells: functional plasticity and subset diversity. J Immunol. 2009 Dec 1;183(11):7161-7168.

Yoshimura, K.; Meckel, K.F.; Laird, L.S.; Chia, C.Y.; Park, J.J.; Olino, K.L.; Tsunedomi, R.; Harada, T.; Iizuka, N.; Hazama, S.; Kato, Y.; Keller, J.W.; Thompson, J.M.; Chang, F.; Romer, L.H.; Jain, A.; Iacobuzio-Donahue, C.; Oka, M.; Pardoll, D.M.; Schulick, R.D. Integrin alpha2 mediates selective metastasis to the liver. Cancer Res. 2009 Sep 15;69(18):7320-7328.

Yu, H.; Pardoll, D.; Jove, R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer. 2009 Nov;9(11):798-809.

Albesiano, E.; Davis, M.; See, A.P.; Han, J.E.; Lim, M.; Pardoll, D.M.; Kim, Y. Immunologic consequences of signal transducers and activators of transcription 3 activation in human squamous cell carcinoma. Cancer Res. 2010 Aug 15;70(16):6467-6476.

Brahmer, J.R.; Drake, C.G.; Wollner, I.; Powderly, J.D.; Picus, J.; Sharfman, W.H.; Stankevich, E.; Pons, A.; Salay, T.M.; McMiller, T.L.; Gilson, M.M.; Wang, C.; Selby, M.; Taube, J.M.; Anders, R.; Chen, L.; Korman, A.J.; Pardoll, D.M.; Lowy, I.; Topalian, S.L. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010 Jul 1;28(19):3167-3175.

Getnet, D.; Grosso, J.F.; Goldberg, M.V.; Harris, T.J.; Yen, H.R.; Bruno, T.C.; Durham, N.M.; Hipkiss, E.L.; Pyle, K.J.; Wada, S.; Pan, F.; Pardoll, D.M.; Drake, C.G. A role for the transcription factor Helios in human CD4(+)CD25(+) regulatory T cells. Mol Immunol. 2010 Apr;47(7-8):1595-1600.

Ishiwata, K.; Watanabe, N.; Guo, M.; Tomihara, K.; Brumlik, M.J.; Yagita, H.; Pardoll, D.; Chen, L.; Shin, T. Costimulator B7-DC attenuates strong Th2 responses induced by Nippostrongylus brasiliensis. J Immunol. 2010 Feb 15;184(4):2086-2094.

Le, D.T.; Pardoll, D.M.; Jaffee, E.M. Cellular vaccine approaches. Cancer J. 2010 Jul-Aug;16(4):304-310.
Noonan, K.; Marchionni, L.; Anderson, J.; Pardoll, D.; Roodman, G.D.; Borrello, I. A novel role of IL-17-producing lymphocytes in mediating lytic bone disease in multiple myeloma. Blood. 2010 Nov 4;116(18):3554-3563.

Wang, L.; Yi, T.; Zhang, W.; Pardoll, D.M.; Yu, H. IL-17 Enhances Tumor Development in Carcinogen-Induced Skin Cancer. Cancer Res. 2010 Dec 15;70(24):10112-10120.

 

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