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Vaccines for all
April 2006
by John Rothman  |  Email the author
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Autologous vaccines are formulated around two core concepts: that each patient's immune system and immune response to cancer is unique; and that, to stimulate the immune system to effectively cure cancer, it is necessary to collect cells to bioengineer vaccines targeting immune recognition sites based upon the patient's individual genetics. This line of research has advanced our understanding of cancer and the immune system, and resulted in some success in the development of novel therapeutic agents and methods.
 
Unfortunately, the same research has not led to widespread cancer cures. Custom-made, patient-specific agents are expensive (some therapies are quoting costs of more than $50,000 per dose), and their potential approval creates unusual and yet unresolved regulatory considerations.
 
Recent understanding, based in part on the responses to autologous vaccines, has resulted in new methods and therapeutic agents that promise higher cancer response rates than previously possible, without the cost and difficulties associated with patient-specific vaccines. One such approach is based on the long-held understanding that the manner in which antigens are presented to the immune system may be as important as the antigens themselves. Thus, an antigen commonly expressed in a cancer could be used to mount a therapeutically effective immune response if properly presented.
 
A recent application of this understanding recognizes that the immune system has evolved to deal with infections, as opposed to peptides, pieces of DNA, antibodies, or even cells that are removed from patients, activated, and returned. This has led to the exploration of bioengineering relatively harmless microbes to express cancer antigens. In this way, it might be possible to administer a modified microbe to a cancer patient to invoke an infection that generates a strong immune response, not only curing the cancer but also generating a long-lived immunity that prevents cancer reoccurrence once the infection passes. These agents are called live vaccines.
 
At Advaxis, we are engaged in such research using the microbe Listeria monocytogenes (Lm), a common pathogen that humans routinely ingest without consequence, typically in dairy products. It occasionally cause disease (usually food poisoning) when ingested in large amounts in spoiled food or by immuno-compromised people. Since Listeria is a bacterium, it strongly stimulates "innate" (non-specific) immunity: a powerful stimulator of adaptive immune responses directed against specific targets.
 
Because Lm preferentially infects antigen processing cells (APC), which create the recognition molecules that stimulate the immune system to identify and kill specific invaders, it is possible to secrete cancer antigens directly within these cells. And because we have engineered specific types of fusion proteins that target cancer antigen delivery to the part of the APC that recognizes these molecules, it is possible to more dramatically increase the cellular response to these antigens than with antigen alone. This results in the activation of an unusually high level of cytotoxic lymphocytes to kill the specific tumor that displays the engineered antigen and does not require the difficult and expensive processes needed for autologous vaccines.
 
Our first agent to reach the clinic targets an antigen displayed in approximately 50 percent of cervical cancers. If this treatment is effective, the same agent could be used in all women infected with cancer that expresses the target antigen. In hundreds of experiments with animals, our response rate has been 100 percent, with complete responses varying from 50 to 100 percent. The confirmation of these findings in human subjects would validate this method of antigen delivery and the belief that non-patient-specific therapy yields significant therapeutic responses perhaps exceeding those produced using autologous methods.
 
 
Dr. John Rothman is vice president of clinical development at Princeton, N.J.-based Advaxis Inc. He studied at the Department of Pharmacology at the Tulane University School of Medicine with Dr. Louis Ignarro and completed his dissertation research at the New Orleans Veterans Affairs Hospital with Dr. Andrew Schally, both laureates of the Nobel Prize in Medicine.

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