SAN FRANCISCOAdvances in gene therapy, cancer vaccines,
and a variety of new antibody therapies for hematologic malignancies were the
focus of a satellite symposium to the 42nd Annual Meeting of the American
Society of Hematology titled Scientific and Technical Innovations in Biology:
Initiating Advances in Therapeutic Approaches to Hematological Malignancies.
The program was sponsored by Fox Chase Cancer Center through an unrestricted
educational grant from Genentech BioOncology and IDEC Pharmaceuticals.
Gene Technology and its Application in Therapy
It may now be possible to correct the gene defects of
neoplastic cells, suggested Thomas J. Kipps, MD, PhD, professor and head of the
Division of Hematology/Oncology, University of California, San Diego. Dr. Kipps
said that cancer is a genetic disease and that gene transfer may correct the
underlying defects, either by replacing genes missing in tumor cells or by
silencing defective genes whose expression leads to cancer.
"Gene transfer also might be used to selectively kill
tumor cells or to induce host antitumor immunity," Dr. Kipps said. His
focus was on the use of gene therapy for active induction of host immunity
against tumor cells, in contrast to passive immune therapy using therapeutic
"The problem in active immunotherapy is the inability of
the host to recognize tumor cells. This might be due to a loss of T cells that
recognize tumor, or to the silencing of those T cells that potentially can
recognize and reject the tumor. Recent studies suggest that it may be possible
to overcome immune tolerance to induce active immune activity against the
tumor," Dr. Kipps said.
The most common vectors being studied in an attempt to achieve
this goal are plasmids that carry DNA into the cell or viruses that transfer
genes into the cell (such as adenovirus and herpes simplex virus). Dr. Kipps
said that considerable interest is currently centered on the CD154 protein,
which is expressed on T cells soon after T-cell activation and that interacts
with CD40. This leads to activation of antigen-presenting cells that can induce
T-cell proliferation and cytokine production. (See Figure 1.) Researchers are
using infection with an adenovirus-CD154 construct to convert
"stealth" leukemia cells into "alarm" antigen-presenting
cells (APC) that can activate the immune system against leukemia cells.
"Infection with Ad-CD154 results in stable, high-level
surface expression of CD154 on chronic lymphocytic leukemia (CLL) cells. This
induces these cells to express high levels of immunostimulatory
molecules," Dr. Kipps said. "In addition, Ad-CD154-infected CLL cells
induce bystander CLL cells to express immunostimulatory molecules that also can
activate T cells, to produce other T cells that are cytotoxic against leukemia
cells." Pilot studies of this approach in CLL patients showed a decrease
in leukemic cell count and some stabilization of disease in treated patients.
"The phase-I Ad-CD154 CLL clinical trial showed an
increase in immune cytokines (IL-12 and IFN-gamma), phenotypic changes in
transduced and bystander CLL B cells, an increase in blood absolute T-cell
counts, an increase in leukemia-specific T cells, a decrease in absolute
lymphocyte counts, and a decrease in lymph node size," Dr. Kipps reported.
Ad-CD154 is now being studied in a phase-II trial of CLL
patients who were refractory to standard therapy or who had advanced disease
and elected to have Ad-CD154 as front-line therapy. Patients are being given 5-10
biweekly doses of 3-5 × 108 transduced Ad-CD154 CLL cells administered
Advances in Immunology Extend into Clinical Practice
Louis M. Weiner, MD, chairman and senior member, Department of
Medical Oncology, Fox Chase Cancer Center, Philadelphia, described monoclonal
antibodies as, "the first successful attempt in the history of oncology to
develop targeted cancer treatment."
"The common theme of targeted therapy is target
acquisition leading to manipulation of cellular function. Targets can be
located on tumor cells, in the tumor microenvironment, or in host response
elements," Dr. Weiner said.
Determinants of tumor targeting by antibodies include antigen
specificity, tumor physiology, antibody size, systemic clearance and
metabolism, antibody valence effects on antibody retention in the tumor, and
antibody affinity. Limitations include high intratumoral pressure leading to
convection pressure and impeding the move of antibodies to the center of the
tumor. Dr. Weiner said that in solid tumors, IgG molecules might require a
month to pass from blood vessel to tumor interior.
Therapeutic applications of antibodies include perturbation of
signal transduction, immunoconjugates, and antibody-dependent cellular
cytotoxicity (ADCC). Obstacles to ADCC include getting the antibody to the
tumor site, restricted leukocyte traffic to the tumor, inadequate in situ
effector cell expansion and activation, and tumor-mediated immune inhibition,
which may contribute to failure to expand in situ effector cells.
Signal transduction perturbation is accomplishing by using the
Fc domain of the antibody to engage cell surface targets. Immunoconjugates are
antibodies bound to isotopes, toxins, cytotoxic agents, or cytokines. ADCC
targets the T cell. The antibody Fc domain interacts with natural killer cells
or macrophages and causes phagocytosis or cytotoxicity via perforin molecules.
Antibody-dependent enzyme prodrug therapy (ADEPT) delivers an
antibody-enzyme conjugate to the tumor, and the enzyme at the tumor site
essentially converts a prodrug the patient has taken to active drug.
Another approach is pretargeted radioimmunotherapy.
Antibody-streptavidin conjugate is delivered to the tumor; unbound
immunoconjugate is cleared; and biotinylated radionuclide is then given, which
sticks to the immunoconjugate and irradiates the tumor cell.
Dr. Weiner said that use of anti-idiotype vaccines represents
another promising approach and that some vaccines effective against tumor
antigens can be prepared without the use of a tumor antigen. Antibody Ab1 is
produced to the tumor antigen, and Ab2 is produced against Ab1. "Ab2
immunization stimulates production of Ab3, leading to a specific antitumor
antigen response," Dr. Weiner said.
Functional targets for antibodies currently under study include
HER2/neu, epidermal growth factor receptor (EGFR), CD20, B-cell idiotype,
vascular endothelial growth factor receptors, and Apo-2/TRAIL ligand.
"There has been a sea change in how we look at these molecules," Dr.
Weiner said. "Previously we looked for high tumor specificity. Signal
transduction is also affected in normal cells, but tumor cells may be more
dependent on the function of selective signaling pathways, so that such
pathways can be the Achilles heel of the tumor." He also noted that most
antibodies that do not perturb signal transduction are not therapeutically