Pathology and Microbiology

James E. Talmadge, Ph.D.

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ACADEMIC DEGREES:
Ph.D., Veterinary Science (Veterinary Microbiology and Pathology), Washington State University, Pullman, 1979.
M.S., Bacteriology, Washington State University, Pullman, 1975.
B.S., Biology, Virginia Polytechnic Institute and State University, Blacksburg, VA, 1973.

Post-Degree Training:
Postdoctoral Fellow, Cancer Metastasis and Treatment Laboratory, (Dr. I.J. Fidler), Frederick Cancer Research Facility, 1980-1981.

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Contact Name:	James E. Talmadge, Ph.D. Pathology and Microbiology University of Nebraska Medical Center 987660 Nebraska Medical Center Omaha, NE 68198-7660
Phone Number:	402-559-5639
Fax Number:	402-559-4990
e-mail address:	jtalmadg@unmc.edu

 

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NE LB506 Department of Health and Human Services
"Depletion of T and Dendritic cells in Stem Cell Products."
Principal Investigator: James E. Talmadge
Date: 7/1/05-6/30/06
This goal of this proposal is to identify the potential for an antibody directed against CD52 to deplete T cells and DCs in stem cell products (SCPs) to be used for allogeneic stem cell transplantation.                                       

Nebraska Research Initiative.
Extension of “Program in Molecular Therapeutics.” 
Principal Investigator:  James Talmadge  
Date: 7/01/04-6/31/06
The goal of these studies is to determine the induction of immune responses to tumor antigens or the interruption of the tumor vascular supply, which may not require maximum serum levels of a molecular therapeutic, but rather prolonged levels targeting a specific cellular subset or organ. 

BAA N01-CO-47010-16
Alnis, Inc. “Novel Technologies for Noninvasive Detection, Diagnosis and Treatment of Cancer.”
Principal Investigator: Stephen Barry    
Date: 11/1/04-10/31/07
Role: Co-I

Eppley Cancer Center
“Alemtuzumab Depletion of T cells and DCs in AlloNST.”
Principal Investigator: James Talmadge    
Date: 5/1/05-4/30/07
The goal is to develop nonmyeloablative allogeneic stem cell transplantation (alloNST) with reduced graft versus host disease (GVHD) and retention of graft versus tumor (GVT) activity.

1 RO1 HL070885-01A2
Department of Health and Human Services
“Flt3 Ligand, Immunomodulation and Therapy in Asthma.”
Principal Investigator: Devendra K. Agrawal    
Date: 12/1/04-11/30/08
To determine if Flt3L has therapeutic activity for asthma via cellular immunoregulatory mechanism that are allergen non-specific.
Role: Co-PI

Prior
LB-595 and Cattleman’s Ball
“Immunotherapy for Pancreatic Cancer”
Principal Investigator: Joyce Solheim    
Date: 1/1/03-12/31/05
Role: Co-I 

3 P30 CA036727-19S1
Avon-NCI Progress for Patients
“Adenovirus p53 DC Vaccine for Breast Cancer”
Principal Investigator: James E Talmadge   
Date: 2/1/03-1/31/05

BAA N01-CO-17016-32 with Alnis.
“Determination of the anti-angiogenic and anti-neoplastic activity of nanoparticles with Adriamycin.”
Principal Investigator:  James Talmadge   
Date: 3/10/03-3/9/05

5R21AT001739-02
National Institute of Health
“Prevention of Cancer by Coriolus versicolor Mushroom.”
Principal Investigator:  Bela Toth    
Date: 4/1/03-3/31/05
Role: Co-PI

NOT-AI-02-005
Department of Health and Human Services, SBIR
“Augmenting innate and vaccine immune response with derG.”
Principal Investigator:  Daniel Zimmerman   
Date:  09/30/03-3/31/05
Role: Co-I

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• PUBLICATIONS (last 3 years):

Simon N. Robinson, Jennifer M. Chavez, B.S., Vladimir M., R. Lee Mosley, Gary J. Rosenthal. Joan M. Blonder, Talmadge JE.  2003 Delivery of Flt3 Ligand (Flt3L) Using a Poloxamer-Based Formulation Increases Biological Activity In Mice.  Bone Marrow Transplantation, 31(5):361-9.

Simon N. Robinson, Vladimir M. Pisarev, Jennifer M. Chavez, Rakesh K. Singh, Talmadge JE. 2003 Matrix Metalloproteinase (MMP)-9 activity is not required for G-CSF or Flt3 ligand-induced hematopoietic progenitor cell mobilization or engraftment., Stem Cells, 2003 Mar;31(5):361-9

H. Sang, V. M. Pisarev, C. Munger, S. Robinson, J. Chavez, L. Hatcher, P. Parajuli, Y. Guo, and Talmadge JE.  2003.  Regional, but not Systemic Recruitment/Expansion of Dendritic Cells by a Pluronic-formulated Flt3-Ligand Plasmid with Vaccine Adjuvant Activity. Vaccine, 21(21-22):3019-3029.

Steven Z. Pavletic, R.Gregory Bociek, James M. Foran, Ronald J. Rubocki, Charles A. Kuszynski, James L. Wisecarver, Lori Hatcher, David M. Lucas, John C. Byrd, Michael   R. Grever,  Shantaram S. Joshi,  Penny Hardiman, Lynette M. Hock, Timothy R. McGuire, Philip J. Bierman, Julie M.Vose, James O. Armitage, and Talmadge JE. 2003. Lymphodepleting Effects and Safety of Pentostatin for Nonmyeloablative Allogeneic Stem Cell Transplantation. Transplantation, 76(5).

Reber AJ, Ashour AE, Robinson SN, Talmadge JE, Solheim JC. 2004. Flt3 ligand bioactivity and pharmacology in neoplasia. Current Drug Targets – Immune, Endocrine and Metabolic Disorders. 4(2):149-56.

Gilroy RK, Coccia PF, Talmadge JE, Hatcher LI, Pirruccello SJ, Shaw Jr. BJ, Rubocki, RJ, Sudan DL, Langnas AL, Horslen SP. 2004. Donor Immune Reconstitution after Liver-Small Bowel Transplantation for Multiple Intestinal Atresia with Immunodeficiency.  Blood. Feb 1;103(3):1171-4.

Reber AJ, Ashour AE, Robinson SN, Talmadge JE, Solheim JC.  ²⁰⁰⁴ Flt3 ligand bioactivity and pharmacology in neoplasia. Current Drug Targets – Immune, Endocrine and Metabolic Disorders. Current Drug Targets - Immune, Endocrine & Metabolic Disorders, 4, 149-157.

Talmadge JE. 2004. Gene Therapy of Cancer - 12^th International Conference Review. IDrugs. 7(2):100-04.

Edwan JH, Perry G, Talmadge JE, Agrawal DK.  2004 Flt-3 Ligand Reverses Late Allergic Response and Airway Hyper-Responsiveness in a Mouse Model of Allergic Inflammation, J of Immunology. 172: 5016-5023.

Talmadge JE and KH Cowan. 2004 Gene Therapy in Oncology. In: Clinical Oncology, 3^rd Edition.  Editors: M Abeloff, J Armitage, M Kastan, J Niederhuber, D Meloni. Elsevier Science. Philadelphia, PA.

Singh RK and Talmadge JE. 2004 The Evolution of Diversity within Tumors and Metastases.  In: Fundamental Aspects of Cancer, vol. 1 CAGP series. Editor: RH Goldfarb.  Kluwer Academic Publishers. The Netherlands. Talmadge JE. 2004 Immunostimulants in Cancer Therapy. In: Textbook Principles of Immunopharmacology. Second Edition. Editors: RP Nijkamp and M Parnham. Birkhauser Publishing.

Talmadge JE, Chavez J, Jacobs L, Munger C, Chinnah T, Williamson D, Yates K. 2004 Fractionation of Aloe vera L. inner gel, purification and molecular profiling of activity. IASC Aloe Special Issue. International Immunopharmacology. 14(4): 1757-1773.

Edwan JH, Talmadge JE, Agrawal DK.  2005. Treatment with Flt3 ligand plasmid reverses allergic airway inflammation in ovalbumin-sensitized and -challenged mice. International Immunopharmacology.  5(2):345-357.

Bibby DC, Talmadge JE, Dalal MK, Kurz SG, Chytil KM, Barry SE, Shand DG, Steiert M. 2005. Pharmacokinetics and Biodistribution of RGD-Targeted Doxorubicin-Loaded Nanoparticles in Tumor-Bearing Mice. International Journal of Pharmaceutics. 293(1-2):281-90. 

Sang H, Pisarev VM, Chavez J, Robinson SN, Guo Y, Hatcher L, Munger C, Solheim JC, Singh RK, Talmadge JE. 2005. Murine Mammary Adenocarcinoma Cells Transfected with p53 and/or Flt3L Induce Antitumor Immune Responses. Cancer Gene Therapy. 12(4):427-37.

Chen ZT, Varney ML, Backora MW, Cowan KH, Solheim JC, Talmadge JE, Singh RK. 2005. Down-regulation of VEGF-C expression using small interfering RNA vectors in mammary tumors inhibits tumor lymphangiogenesis and spontaneous metastasis and enhances survival. Cancer Research. 65(19): 9004-11

Robinson SN, Chavez JM, Blonder JM, Pisarev VM, Mosley RL, Sang H, Rosenthal GJ, Talmadge JE. 2005. Hematopoietic Progenitor Cell Mobilization in Mice by Sustained Delivery of Granulocyte Colony-Stimulating Factor. 2005. Journal of Interferon and Cancer Research. 25(8):490-500.

Talmadge JE. 2006. Immunostimulants in Cancer Therapy. In: Textbook Principles of Immunopharmacology. Second Edition. Editors: RP Nijkamp and M Parnham. Birkhauser Publishing.

Futakuchi M, Talmadge JE, Singh RK.  Synergy between tumor immunotherapy and anti-angiogenic therapy.  (Review).  Archivum Immunologiae et Therapiae Experimentalis, 2006. In press.

Talmadge JE, Singh RK, Solheim J.  Activity of Cytokine Mediators of Dendritic Cell Chemotaxis and Expansion.  Recent Research Developments in Cancer, Transworld Research Network, 2006. In press.

Talmadge JE, Hugli TE, Fuminori A. Editorial. International Immunopharmacology. 2006. In press.

Solheim JC, Reber AJ, Ashour AE, Robinson S, Futakuchi M, Kurz SG, Hood K, Fields RR, Shafer LR, Cornell D, Sutjipto S, Zurawski S, LaFace DM, Singh RK, Talmadge JE.  Spleen but not tumors infiltration by dendritic and T cells is increased by intravenous adenovirus-Flt3 ligand injection. Cancer Gene Therapy. 2006 In press.

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Fuminori Abe, Ph.D. (Nippon Kayaku Co., Ltd., Japan)
Ana Ageitos, M.D. (Fundacion Jimenez Diaz Servicio de Oncologia, Spain)
Abdullah Ayadin, M.D. (Turkey)
John Bishay, Ph.D. (University of Nebraska Medical Center, U.S.A.)
Peter Berglund, Ph.D. (Sweden)
Paul Black, Ph.D. (DAIDS/NIAID/NIH, U.S.A.)
Suleyman Buyukberber, M.D. (Gaziantep University, Turkey)
Paula Castelli, Ph.D. (University of Cagliari, Italy)
Ugur Coskun, M.D. (Turkey)
Bhavana Dave, Ph.D. (University of Nebraska Medical Center, U.S.A.)
Moses Dunkor, M.S. (University of Nebraska Omaha, U.S.A.)
Stefan Egger, M.D., Ph.D. (Austria)
Dumrul Gulen, Ph.D. (University of Nebraska Omaha, U.S.A.)
Diethelm Harman, Ph.D. (Switzerland)
Kazuhiko Ino, M.D., Ph.D. (Nagoya University School of Medicine, Japan)
Xeude Lin, M.S. (University of Nebraska Medical Center, U.S.A.)
Kevin Mills, Ph.D. (Miltenyi Biotec Inc., U.S.A.)
Elif Ozerol, Ph.D. (Inonu Universitesi, Turkey)
Ibrahim Ozerol, M.D. (Inonu Universitesi, Turkey)
Rakesh Singh, Ph.D. (University of Nebraska Medical Center, U.S.A.)
Tsutomu Watanabe, M.D., Ph.D. (Tokushima University Hospital, Japan)
Yoshinori Yasui, M.D. (Osaka City General Hospital, Japan)
Manabu Hirai, M.D. (Osaka City General Hospital, Japan)
Vladimir Pisarev, M.D., Ph.D., D.Sc. (University of Nebraska Medical Center, U.S.A.)
Prahlad Parajuli, Ph.D., (Wayne State University School of Medicine, U.S.A.)
Simon Robinson, Ph.D., (University of Nebraska Medical Center, U.S.A.)
Shilin Yang, M.D., Ph.D. (University of Nebraska Medical Center, U.S.A.)
Hongxun Sang, M.D., Ph.D. (University of Nebraska Medical Center, U.S.A.)

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• CURRENT RESEARCH PROJECTS:

The primary translational research emphasis is on gene therapeutic vaccines for breast cancer.  In a phase II clinical study with Drs Cowan and Reed at UNMC and Dr. Gabrilovich at Moffitt Cancer Center we have initiated the first gene therapy study in Nebraska and the only p53 vaccine for breast cancer.  The goal is a comparison of the T cell response to Adv-p53 transfected DC vaccine when administered during or following dose dense chemotherapy.

We are also studying the mechanism of immunologic reconstitution following non-myeloablative allogeneic stem cell transplantation.  In order to reduce the GVHD we are initiating a clinical study to examine the effect of the T cell depletion of stem cell products on immune recovery to be followed with a clinical protocol examining the effect of a dose escalation add-back of dendritic cells to the T cell depleted stem cell product. 

Basic/translational research studies are focused on host-tumor interactions during tumor progression, metastasis and cytoreductive therapy.  We have established a program in Molecular Therapeutics that is focused on COX-2 inhibitors, all-trans-retinoic acid (ATRA) and VEGF inhibition and their regulation of immune intervention.  Our goal is to overcome tumor and iatrogenic suppression of DC function and T cell responses to vaccines and DC manipulation with gene therapy using adenovirus vectors with the Flt3L transgene.  These collaborative studies include Drs. Joyce Solheim (Eppley Cancer Institute), Rakesh Singh (Pathology & Microbiology) and various scientists at Canji and Introgen. 

We have identified a critical regulatory role for a unique cellular phenotype strongly associated with tumor-associated immunosuppression that when removed slows tumor growth and prolongs survival.  Studies into the mechanism of immunosuppression suggest a critical role for inducible nitric oxide synthase as a local/regional mediator of T cell suppression.  These studies are on-going in both rodent and human studies,

We are working with Alnis on the targeting of nanoparticles with a chemotherapeutic payload for the treatment of cancer.  Primary studies include biodistribution, toxicology pharmacokinetics and efficacy. 

Significant effort is directed towards forming a good manufacturing practice/good tissue practice manufacturing of clinical therapeutics.  Currently these include gene and cellular therapeutics. 

Immunotherapy and the combination of immune therapy with traditional therapeutics including surgery and chemotherapy form the primary emphasis in the laboratory of transplantation immunology.  Currently we are focused on dendritic cell injection, vaccines and regulation of dendritic cells using gene therapy, cytokines (Flt3L and GM-CSF) and molecular therapeutics.

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• SPECIALIZED LABORATORY/CLINICAL RESEARCH RESOURCES:

Storm, KS ELISPOT, gamma counter, beta counters, blood analyzers, Zeiss flourscent microscopes, Kodak 2000 MM Imager, Cryostat.

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