Andrea
Gambotto M.D.
Contact information:
208 Biotech Center
University of Pittsburgh
300 Technology Drive
Pittsburgh, PA 15219
Phone: 412-383-9759
Fax: 412-383-9760
e-mail: gambottoa@msx.upmc.edu
Research Interests:
I'm trained in medicine, molecular genetics,
and immunology. I'm currently an Assistant Professor of Surgery
and Co-Director of the Vector Core Facility, at the University
of Pittsburgh, Biotechnology Center. Since arriving in Pittsburgh
in 1994 I directed a number of studies in the areas of gene
therapy and immunotherapy. I have an extensive experience in
the construction of recombinant viral vectors, with almost 100
recombinant viruses constructed and characterized, molecular
biology and recombinant proteins.
My research has focused on several areas of
gene therapy related to cancer immunology, infectious diseases
and transplantation. Specifically, I have developed cytokine
mediated cancer gene therapy, in the context of adenoviral mediated
IL-12 gene delivery; genetic modification of dendritic cells
for use in the modulation of immune responses for infectious
diseases, transplantation and cancer. I also improved adenoviral
constructs and have optimized adenoviral infection in vitro
and in vivo. Given this broad interests I have several areas
of research focus.
I. Cancer Immunology:
a) Cytokine mediated
immunotherapy for cancer. Focus of this research area is the
investigation and comparison of the effects of different cytokines,
such as IL-10, IL-12, IL-15, IL-18, the trimeric forms of TNF
ligand superfamily, such as CD154, TRANCE, 4-1BBL, OX40L, TRAIL
and their cognate soluble receptors on the modulation of immunoresponses.
b) Vaccine strategies
development. Our group has pioneered studies on tumor associate
antigen dendritic cells engineering. We have adopted several
approaches employing different viral and non-viral delivery
systems (figure 1). More recently, I also have focused also
on the development of modified recombinant proteins capable
of inducing both class I and class II MHC-restricted T-cell
responses.
II Infectious Disease:
a) My laboratory is involved in the testing of the immunogenicity
of various experimental HIV/SIV vaccine candidates given to
rhesus monkeys. Two aspects of evaluation are of paramount importance:
the ability of a given vaccine treatment to prime an immune
response that could protect against HIV/SIV challenge, and the
therapeutic effects of the induction of a T-cells mediated responses
in an established HIV/SIV infection. In vivo and ex vivo adenoviral
mediated HIV/SIV antigen delivery strategies are currently under
investigation.
b) One potential strategy
for vaccinating or stimulating the immune response against Epstein
Barr Virus (EBV) for treatment of lymphoproliferative disorders
is to use DCs genetically modified to express defined EBV antigenic
proteins. Dendritic cells are antigen-presenting cells that
are potent stimulators of primary T cell responses. We have
demonstrated that DCs genetically engineered to express the
EBV antigens gene are able to correctly process and present
the HLA-restricted immunodominant peptides and serve as potent
stimulators of EBV specific CTL in vitro. To genetically modify
DCs, replication-defective E1-E3 deleted adenoviruses have been
used to construct vectors that expressed full length EBV-antigens
cDNAs. Our preliminary studies support the use of EBV antigen-engineered
DC in vaccine and immunotherapeutic trials and lead to approaches
for treating or preventing lymphoproliferative disorders associated
with EBV infection.
III. Transplantation:
My laboratory is also working on the development of methods
for engineering dendritic cells to downregulate their immunostimulatory
capabilities for use as tolerogenic effectors. For this purpose
a genetic engineered approach has been adopted as well as alternative
strategies. Inactivation of key genes such B7.1/2 or CD40 etc.
on APC's is the final goal of this research. Animal models in
which the downregulation of a predicted immunoresponse could
be monitored, are currently used.
Publications:
1. Gambotto A., Tuting T., McVey DL., Kovesdi I.,Tahara H.,
Lotze MT. and Robbins PD. "Induction of antitumor immunity by
direct Intratumoral injection of recombinant adenovirus vector
expressing Interleukin-12" Cancer Gene Therapy. 1999 Jan-Feb;6(1):45-53
2. Lu L., Lee L., Gambotto A., Zhong C., Robbins
PD., Qian S., and Thomson AW., "Adenoviral delivery of CTLA4Ig
into myeloid dendritic cells promotes their in vitro tolerogenicity
and survival in allogenic recipient" Gene Therapy. Therapy (1999)
6, 554-563
3. Tüting T., Steitz J., Brück J., Steinbrink
K., Gambotto A., DeLeo AB., Robbins PD., Wagner SN., Knop J.
and Enk AH. "Dendritic cell-based genetic immunization in mice
with a recombinant adenovirus encoding murine TRP2 induces effective
anti-melanoma immunity" Journal of Gene Medicine. 1999 Nov-Dec
6, 400-406
4. Ranieri E, Herr W., Gambotto A., Olson
W., Rowe D., Robbins PD., Gesualdo L., Storkus WJ. "Transduced
dendritic cells with an adenoviral vector encoding for Epstein-Barr
virus Latent Membrane Protein 2 : a new modality for vaccination"
J Virol. 1999 Dec;73(12):10416-25.
5. Gambotto A., Kim S.H.., Kim S. and Robbins
P.D. "Methods for Constructing and Producing Retroviral Vectors"
In Developmental Biology Protocols, R. S. Tuan and C. W. Lo,
eds. Human Press, Inc., Totowa, N. J.,
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