SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

T U M O R I M M U N O L O G Y P R O G R A M
CD80-mediated T-cell dependent anti-tumor
immunity and the generation of protective immunity
in animals are resistant to rechallenge. In
addition, they found that constitutive expression
of one or more of the cytokines IL-1α, IL-6, and
GM-CSF is associated with down-modulation of
CD80 co-stimulatory molecule expression in oral
HNSCC cells. The HNSCC cell lines that exhibit
a combination of constitutive cytokine expression
and low CD80 expression also exhibit
increased tumorigenic potential in immune-competent
mice, as previously reported. Reduction of
CD80 co-stimulatory molecule expression by
pro-inflammatory cytokines IL-1α, IL-6, and
GM-CSF has not been previously described. This
decrease in CD80 expression during malignant
progression of HNSCC may result in dysfunctional
anti-tumor immunity, thereby promoting
malignant growth.
Studies are under way to determine the regulatory
mechanisms of cytokine-induced downregulation
of CD80 expression and to determine
the prognostic significance of its expression on
tumor specimens from patients with HNSCC.
Once the role and regulation of CD80 in
HNSCC are understood, CD80 expression can
be up-regulated pharmacologically in new and
innovative approaches to increase anti-tumor immune
responses for the prevention and treatment
of HNSCC.
SELECTED PUBLICATIONS
2002
Thomas, GR, Regalado, JJ, and McClinton, M.
A rare case of mucoepidermoid carcinoma of the
nasal cavity. Ear, Nose, and Throat Journal
81:519-22, 2002.
2003
Pandey, M, Chandramohan, K, Thomas, G,
Mathew, A, Sebastian, P, Somanathan, T,
Abraham, EK, Rajan, B, and Krishnan Nair, M.
Soft tissue sarcoma of the head and neck region
in adults. International Journal of Oral and Maxillofacial
Surgery 32:43-48, 2003.
124
KHALED TOLBA, M.D.
Assistant Professor of Medicine
DESCRIPTION OF RESEARCH
During the past five years, Dr. Tolba has been
developing immunotherapeutic strategies for
B-cell hematologic malignancies, with particular
interest in chronic lymphocytic leukemia (CLL).
CLL is the most common leukemia in the Western
hemisphere. As a relatively slow-progressing
tumor with readily accessible tumor cells, it offers
an opportunity to develop and test immunotherapeutic
interventions. A number of profound
immunologic deficiencies affecting both the B-
and T-cell responses, however, have posed a challenge
to immune therapy of CLL.
The laboratory has co-developed and
adapted the use of herpes simplex virus (HSV)
amplicons for gene transduction of CLL cells.
Using CD40L as an effector molecule, they have
shown robust induction of co-stimulatory molecules
on transduced and bystander cells
and in roughly one-third of tested patients
demonstrated the capacity to generate cytotoxic
T lymphocyte (CTL) activity. This capacity to
elicit autologous CTL response, however, was not
universal as more than half the patients tested
failed to mount such a response in spite of adequate
up-regulation of co-stimulatory signal on
both transduced and bystander CLL cells. In addition
to being a highly efficient gene transfer vector,
herpes simplex virus (HSV)-based amplicons
possess the capacity to engage and activate different
elements of the innate immune system. Currently,
the laboratory is studying various aspects of HSV
amplicon/innate immune interaction and their
influence on the outcome of an adaptive antitumor
immune response.
Immune therapeutic strategies targeting the
innate immune system might offer an alternative
pathway to bypass inherent CD8 + T-cell defects
and effectively mount a systemic anti-tumor immune
response. Dr. Tolba and his colleagues are
exploring how HSV amplicon interacts with the
family of toll-like (TL) receptors and up-regulates
NKG2D ligands on target cells.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004