A Clever Vaccine Is Enlisted in the War Against MS

A California biotech company hopes to boost the immune system without side-effects.

by Rob Ingraham

Descriptions of the body’s built-in defenses against disease—our immune system—abound in military terms. For example, a recent article in Scientific American entitled “Peacekeepers of the Immune System” described multiple sclerosis (MS), insulin- dependent diabetes, and rheumatoid arthritis as the work of “renegade” white blood cells known as T- cells. “Normal versions of these cells serve as officers in the immune system’s armed forces, responsible for unleashing the system’s combat troops against disease-causing microorganisms.” (Fehervari & Sakaguchi, October 2006).

Targeting these renegade T-cells in the war against relapsing-remitting multiple sclerosis, the most common form of MS, is the goal of a Carlsbad, California, biotech firm, Immune Response Corp. (www.imnr.com), and the firm is about to enter Phase II trials of a new vaccine called NeuroVaxâ„¢.

Self vs. Non-self

To function properly, the immune system must discriminate between “self” and “non-self”—that is, it must determine what is natural tissue and what is foreign and should be destroyed or rejected. When self/non-self discrimination fails, the immune system mistakenly destroys the natural cells and healthy tissues of the body and causes “autoimmune” diseases such as MS and numerous other serious, and frequently fatal, conditions.

Determining what is self and what is non-self falls primarily to T-cells. The ‘T’ stands for the thymus gland where these cells are produced. In addition to producing T-cells, the thymus—through a process scientists describe as “educating” immature T-cells—also produces a variation known as a “regulatory T-cell,” or T-reg. T-regs serve the opposite function of T-cells: they suppress the immune system instead of unleashing it. The main job of T-regs is preventing autoimmune disease and scientists have found that people with MS—and, presumably, other autoimmune diseases- have a lower than normal level of these T-regs.

T-reg cells differ from other T-cells by the presence of a large number of intracellular molecules identified in biological shorthand as, Foxp3, which function as the master regulator in the development and function of all regulatory T-cells. The existence of such “suppressor” T- cells was controversial among immunologists for many years, but recent advances in understanding the molecular structure of these cells have firmly established their existence and their critical role in the immune system. Interest in regulatory T-cells has been booming in the wake of recent experimental evidence demonstrating that the suppressive features of these cells might be harnessed to treat autoimmune diseases. T-regs may also prove critical in preventing the body from rejecting transplanted organs and helping transplant patients finally discontinue the lifetime regimen of harsh immunosuppresive drugs.

While the thymus is an efficient producer of both T-cells and T-regs, on occasion a defective T-cell slips past the thymus’s security system and escapes into the general population of blood cells. In MS, these defective—or pathogenic—T-cells misread the myelin sheath that surrounds and protects nerve fibers (i.e., they interpret the myelin as “non-self”) and attack it, eventually interrupting the normal transmission of nerve impulses, resulting in movement and balance disabilities, vision impairment and, ultimately, death. A healthy person usually has enough T-reg cells to fight and defeat defective T-cells, but a person with a lower than normal number of T-reg cells cannot overcome the renegades attacking the myelin sheath and MS—an autoimmune disease—is the result.

Targeting Renegade T-cells

Boosting the number of T-regs to combat defective T-cells is the approach of IRC. President and CEO Dr. Joseph O’Neill explained that IRC researchers created a vaccine—NeuroVax—injected once a month, intramuscularly, that has shown promise in Phase I trials.

“Renegade T-cells have certain proteins on their surface that distinguish them from normal T-cells,” O’Neill noted. IRC scientists made copies of three of these proteins and, through a vaccine injection, “flood” the patient’s system with these protein copies. The vaccine essentially “tricks” the T-regs into behaving as if there were many more defective T-cells in the system and, as cells reproduce by subdividing, the T-regs “kick up” production of more T-regs at the command of their “master regulator,” the Foxp3 molecules. With the number of T-regs back to normal, it is theorized that there will be enough to effectively fight, and suppress, the renegades.

In the less dramatic language of the company’s announcement, “NeuroVax is thought to stimulate the proliferation of Foxp3 regulatory T-cells, which may, in turn, down-regulate the activity of pathogenic T-cells that destroy myelin in MS patients.”

O’Neill is cautious about assessing Phase I results: “Trials so far have been with very small numbers of patients, less than 40, and with only 16 or so getting the actual vaccine and the rest being a control group.” But results have been compelling. “The vaccine has shown an immunological effect in every one we’ve tried it on. It’s been a small number of patients, but the [number of] T-regs have gone up in everyone.”

Toleration Factor

Another reason for optimism, according to O’Neill, is an apparent lack of side effects. “One of the main attractions of NeuroVax—and one of the reasons we’re so excited by our Phase I results—is that there are no side effects. It’s very well-tolerated by patients. Basically it’s a non-toxic approach to treating MS.”

“A lot of MS patients are very reluctant, or don’t even want treatment, because of the side effects. The typical MS patient is a young woman in the prime of her life and she just doesn’t want to go around feeling like she’s got the flu all the time. If we can give a once-a-month injection, without disrupting the patient’s quality of life, I think that’s very exciting.”

In addition to being non-toxic in Phase I, NeuroVax patients that had magnetic resonance imaging (MRI) tests after six months of injections showed reductions in new “gandolinium enhancing lesions”-a key marker of MS disease activity. “We’ve seen a reduction in lesions with MRI,” O’Neill said. “It’s encouraging.”

O’Neill said Phase II—which will be a multicenter study over a period of 12 months and involving about 200 MS patients in Europe—is “a proof of concept trial.” That is, “does [Phase I] hold together with a larger number of patients?”

Another significant element about the NeuroVax approach, according to O’Neill, is how it relates to the current body of scientific knowledge about MS. “Our approach fits nicely with what we understand about the mechanism of MS. It makes sense scientifically, and it’s very elegant, intellectually.”

If Phase II is successful, Phase III will involve a much larger number of patients and will likely be conducted in the US, O’Neill said. If all goes well, NeuroVax may be 2 to 3 years away from approval by the federal Food and Drug Administration (FDA). “We’ve been working with the FDA all along, showing them what we’re doing, how we’re structuring the trials, and making sure that they accept our approach as valid,” O’Neill said.

“But the bottom line, of course, is a demonstrable improvement in patient health. That’s what we’ve really got to demonstrate. So we’re cautious, but we’re also very encouraged.”

Finally, in the oddly Zen-like phrasing of Drs. Fehervari and Sakaguchi in their Scientific American article: “In permitting the destruction of non-self while preventing the destruction of self, T-regs may prove to be the ultimate immunological peacekeepers.”

Reference

Fehervari, Z., & Sakaguchi, S. (October, 2006). Peacekeepers of the immune system. Scientific American, 57-63.

Rob Ingraham is senior editor.