David T. Curiel, M.D., Ph.D. heads the Gene Therapy Center (GTC) of the University of Alabama at Birmingham. Dr. Curiel graduated medical school at Emory University in 1982 where he also completed his internship and residency in Internal Medicine. Dr. Curiel’s scientific training includes tenureship at the National Institutes of Health in Bethesda, Maryland, at the Pulmonary Branch of the Heart and Lung, and Blood Institute (NHLBI) from 1985-1989, a fellowship in Biotechnology at the National Cancer Institute, Navy Medical Oncology Branch from 1989-1990.

Dr. Curiel has been at the University of Alabama at Birmingham since 1993. He received his Ph.D. in 2002 from the University of Groningen, in the Netherlands. In addition to his role as Director of the Gene Therapy Center, he is Director of the Division of Human Gene Therapy which is affiliated with the Departments of Medicine, Pathology and Surgery at the University of Alabama at Birmingham, the holder of the Jeanne and Anne Griffin Chair for Women’s Cancer Research, and a Professor of experimental gene therapy at the Free University of Amsterdam, in The Netherlands.

About the lecture

Strategies to Adapt Adenovirus for Immunotherapy Applications

The central role of dendritic cells (DC) in the generation of an active immune response has led to the development of vaccine strategies which seek to directly exploit this key cell mediator. This has been especially relevant in the context of tumor immunotherapy whereby approaches have been advanced to achieve active immunization via DC loading to prime effective presentation of tumor-associated antigens (TAA). Methods to accomplish this goal have included the generation of tumor cell-DC fusions as well as direct DC loading with TAA genes and/or gene products. This latter approach has predicated the search for effective vectors to achieve DC transduction in a manner which is non-deleterious to their immunostimulatory functions.

To address this goal we have developed a highly novel approach to accomplish tropism modification of adenoviral vectors (Ad) for DC-selective transduction. Specifically, we have routed Ad via the DC cell surface marker CD40. This maneuver has allowed efficient DC transduction with the accrued advantage of profound DC activiation. Of note, the CD40-targeted Ad approach also achieved an enhanced vaccine effect in a murine model of tumor immunotherapy targeting the E7 protein of human papilloma virus.

We have sought to advance human clinical translation of this approach by genetically modifying the Ad capsid to target CD40. Specifically, we have accomplished viral capsid incorporation of human CD40L, the natural ligand for CD40. Studies in in vitro systems have validated that our novel vector approach achieves not only effective antigen loading of DCs in situ but also directly activates DC to enhance their immunostimulatory function. Of note, these critical properties have been demonstrated in a stringent human skin plug substrate system directly relevant to human vaccine application.

Immunotherapy offers a promising interventional strategy for disseminated carcinoma. It is evident that the Ad tropism modification technology we have defined may allow optimized in situ antigen loading of DCs for immunotherapy purposes. The studies we propose herein will allow us to test our overall oncept of targeted Ad-based DC vaccinology in a highly stringent murine model of tumor immunotherapy. Following this line of investigation we envision the realization of a human clinical immunotherapy trial for cancer based upon our optimized DC-selective Ad vector.

Quoted from the 2004-2005 College of Pharmacy Loyd E. Harris Distinguished Lecture Series Lecture Announcement Brochure.