SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M
HIGHLIGHTS/DISCOVERIES
Novel treatments with the following agents were
designed and tested clinically by Dr. Rocha Lima:
• IrinoGem (gemcitabine and irinotecan in combination)
for pancreatic cancer and lung cancer
(both small and non-small cell lung cancer).
• DocGem in lung cancer.
• ETopoTax in small cell lung cancer.
His clinical efforts with the agent IrinoGem
resulted in establishing it as a new clinical treatment
option for pancreatic cancer.
JOSEPH D. ROSENBLATT, M.D.
Professor of Medicine and
Division Chief of Hematology-Oncology
DESCRIPTION OF RESEARCH
Dr. Rosenblatt’s research focuses on the development
of novel immune therapy and gene
therapy strategies for cancer. Current research has
focused on the potential role of recruitment of
immune effector cells, using the local elaboration
of both constitutive and inflammatory chemokines,
such as secondary lymphoid chemokine (SLC),
DC-CK1 and/or RANTES respectively, on the
development of an anti-tumor response. Chemokine
delivery has been investigated alone, or in combination
with, expression of the costimulatory ligands
CD80 (B7.1) or CD40L. Several delivery strategies
have been investigated including the use of retroviral
vectors, and/or the use of herpes simplex virus (HSV)
amplicon vectors in several murine tumor models.
Preliminary results suggest that the recruitment
of naïve T cells using SLC is a particularly effective
means of enhancing the anti-tumor immune
response, particularly when combined with CD40Linduced
co-stimulation. This strategy is being
formally investigated using the OT-1 transgenic
mouse model, which has a constitutively expressed
T-cell receptor with defined anti-ovalbumin specificity
and the murine tumors expressing the target
ovalbumin antigen, for effects on tumor-induced
tolerance and the development of systemic immunity.
In a separate effort, the utility of HSV-derived
helper virus-free amplicons is being tested
for efficacy in augmenting the immunogenicity
and antigen-presenting capability of fresh chronic
lymphocytic leukemia cells (CLL). Both CD40L
and CD80, and/or the tumor necrosis factor (TNF)
ligand family member LIGHT have been targeted
to fresh CLL cells using the helper free HSV
amplicons. Results suggest the augmented ability
of such CLL cells to present antigen in an allogeneic
mixed-lymphocyte-tumor cell reaction, and/
or to serve as stimulatory cells for the derivation
of autologous cytolytic T cells in vitro without
deleterious effects on MHC-I expression is seen
with HSV helper virus-containing preparations.
A novel means of immune effector molecule
delivery, which combines the antigen binding
capabilities and localization characteristics of antibodies
with the local delivery of a co-stimulatory
molecule, anti-angiogenic peptide, or a chemokine,
also is under investigation. Antibody fusion
proteins targeting the human breast and ovarian
cancer her2/neu antigen, linked to the extracellular
domains of the B7.1 and/or 41BB-L
costimulatory ligands, have been synthesized and
their in vitro ability to bind to cognate antigenic
targets and to deliver a local co-stimulatory signal
has been documented. Additional fusions currently
being developed in the laboratory include
fusion of the anti-angiogenic peptide endostatin
to anti-her2/neu antibody sequences, as well as
fusion of the inflammatory chemokine RANTES.
Selective targeting of immune effector cells using
both local chemokine vector administration or
antibody-fusion protein administration is being
evaluated further.
A novel antibody-fusion that targets delivery
of endostatin to the site of her2/neu-expressing
tumors has also been synthesized in collaboration
with Seung-Uon Shin, M.D., and shows excellent
efficacy in preclinical models. This fusion appears
to substantially improve the results obtained with
either antibody or endostatin alone.
Currently, Dr. Rosenblatt’s laboratory is
studying efficacy using a novel B-cell deficient
mouse model, which allows testing of antibody
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UM/Sylvester Comprehensive Cancer Center Scientific Report 2004