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
tion of autologous cytolytic T cells in vitro without
deleterious effects on major histocompatibility
complex (MHC)-I expression 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
the in vitro ability to bind to cognate antigenic
targets and to deliver a local costimulatory signal
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 antibodyfusion
protein administration is being evaluated
further.
A novel antibody-fusion that targets delivery
of endostatin to the site of her2/neu expressing
tumors also has 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
fusion protein targeting to xenogeneic (e.g., CEA,
her2/neu) antigens, while preserving T-cell immune
effector functions. The B cell-deficient model
also has demonstrated that T-cell responses to
tumor may be better than those seen in the immunocompetent
mouse. The laboratory currently
is investigating the reasons for altered responses
in the absence of B cells and the possibility of
applying this approach to the human setting using
antibody depletion of B cells with rituximab.
Dr. Rosenblatt and his colleagues also have
collaborated with the laboratory of Vicente
122
Planelles, Ph.D., at the University of Utah, on
the development of several new approaches to
HIV-1 gene therapy. These include the use of
mutated tRNA LYS3 primers, which can anneal to
the sequences other than primer–binding sequences
on the HIV-1 genome, or tRNA LYS3 mutated
in adenosine residue A58, which prevents
normal methylation of the adenosine residue and
disrupts proper termination of the nascent reverse
transcript, thereby inhibiting completion of HIV-
1 reverse transcription in model systems. Other
investigations have centered on the effects of defective
HIV-1 derived vectors on HIV-1 spread in
culture. Recent experiments have demonstrated
that efficient trafficking of defective HIV-1 vectors
is observed in vitro and the following superinfection
with wild type HIV-1 and that such
trafficking results in a marked inhibition of wild
type viral spread.
SELECTED PUBLICATIONS
2002
Lancet, JE, Rosenblatt, JD , and Karp, JE.
Farnesyltransferase inhibitors and myeloid malignancies:
phase I evidence of Zarnestra activity in
high-risk leukemias. Seminars in Hematology
39:31-35, 2002.
Tolba, KA, Bowers, WJ, Muller, J, Housekneckt,
V, Giuliano, RE, Federoff, HJ, and Rosenblatt,
JD. Herpes simplex virus (HSV) amplicon-mediated
codelivery of secondary lymphoid tissue
chemokine and CD40L results in augmented antitumor
activity. Cancer Research 62:6545-51,
2002.
Rosenblatt, JD , Shin, SU, Nechustan, H, Yi,
KH, and Tolba, K. Potential role of chemokines
in immune therapy of cancer. Israel Medical Association
Journal 4:1054-59, 2002.
Tolba, KA, Bowers, WJ, Eling, DJ, Casey, AE,
Kipps, TJ, Federoff, HJ, and Rosenblatt, JD .
HSV amplicon mediated-delivery of LIGHT enhances
the antigen-presenting capacity of chronic
lymphocytic leukemia. Molecular Therapy 6:455-
63, 2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004