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 monoclonal antibodies.
"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 intravenously.
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 effective.