WASHINGTON -- Since antigens of cancers stimulate a ratherweak attack by the immune system at best, the goal of cancervaccines is to help the immune system target and slay thetumor. This can be done by augmenting the attraction betweenantibody and antigen by increasing either the antigenicity oftumor or the power of the immune system to find and killtumor cells.
Some of the world's best cancer researchers described theresults of their approaches and discussed their theories at theInternational Conference on Gene Therapy & Vaccines forCancer here on Wednesday. The conference was part of BioEast,which is being sponsored by the International Federation forthe Advancement of Genetic Engineering and GeneticEngineering News.
Tagging Tumors with Ganciclovir-Sensitivity Genes
Gene therapy pioneer Ken Culver's approach to killing cancerhas been to clone the herpes simplex-thymidine kinase (HS-tk)gene onto a tumor-seeking vector to selectively transducecancer cells. The HS-tk gene renders the tumor vulnerable toganciclovir, the anti-herpes drug.
Culver, founder and executive director of the Human GeneTherapy Research Institute in Des Moines, Iowa, injects vector-producer cells directly into the tumor. For several weeks thesecells crank out vector with gene, augmenting transduction eveninto metastatic cells, Culver believes. If only 10 percent of thecancer cells are transfected, the entire cancer can be killed, hesaid. In long-term survival experiments in rats, 50-60 percentwere cured.
The technique could be used to treat a variety of tumors,including meningeal, lung, breast and colorectal. Culver saidresearchers in India are particularly interested in his techniquebecause the national habit of chewing tobacco causes copioushead and neck cancers.
Discovering Powerful Peptide Antigens
Robert Chestnut's approach has been to develop a way ofdiscovering the most powerful antigenic peptides. Antigenicpeptides are expressed on the surface of many cells andtumors, where they draw cytotoxic T lymphocytes.
The beauty of this approach is that there are probablypowerful antigenic peptides to most forms of cancer, saidChestnut, who is director of immunology at Cytel Corp. of SanDiego.
If they can be isolated from among the thousands of peptidesthat can be generated from cancerous material, the antigenicpeptides can be synthesized and used as cancer vaccines.
It's a three-step process. First is the identification of the motifson major histocompatibility complex (MHC) molecules thatwould bind these peptides. This is a matter of findinghomologies on MHC-binding peptides as well as studying thepropensity for binding at non-homologous positions.
After this information is incorporated into a computer, antigensthe computer selects as most promising are tested in vitro andin animal systems for their ability to bind cytotoxic Tlymphocytes.
"We have tested the random library of human papilloma virus,"said Chestnut. "We have shown that these algorithms are 100percent effective in predicting those (peptides) that bind withhigh efficiency."
A next step would be to develop ways to link various CTLantigenic peptides to delivery molecules and to inject thematerial in vivo.
"I think they will be useful in combination to deliver to peoplewith a high tumor burden and to prevent metastases followingdebulking," said Chestnut.
Ronald Levy, professor of medicine and chief of the Division ofOncology in the Department of Medicine at Stanford University,has cloned together the immunogenically weak but tumor-specific variable regions of immunoglobulin molecules,expressed on malignant B cells and GM-CSF. Theimmunoglobulin-derived portion of the construct comes fromthe patient.
By alternating chemotherapy with attack by his immunologicassemblage, Levy was able to prevent regrowth of tumor inabout half of his murine research subjects.
To gain admission to human trials, lymphoma patients had tobe in complete remission or have minimal cancer, and to havecompleted no more than one round of chemotherapy. "We wantpatients' immune systems to be intact," Levy said.
As of last September -- when the patients had been followedfor 2.5 years -- all eleven lymphoma patients in remissionwhose immune systems had responded against their ideotypicproteins remained tumor-free. But among responders not inremission, only two out of eight were successfully fighting thecancer. And all seven non-responders had lost ground againstthe disease.
"The data is encouraging but does not prove efficacy," saidLevy, noting that a randomized, controlled trial is needed.
Levy said the technique could be used against other cancers."One can substitute for variable sequences that containmutated RAS and test this principle in systems of other tumorantigens that would be more global, generic."
-- David Holzman Washington Editor
(c) 1997 American Health Consultants. All rights reserved.