On a hot Phoenix afternoon, an elderly couple watches as their young grandchildren splash around in a swimming pool. On the surface, the scene seems quiet, picturesque, and relaxing. But Joseph Lustgarten, Ph.D., sees an immediate correlation to cancer research and immunology and feels a looming sense of urgency. What's the connection?

To Dr. Lustgarten, the elderly couple represents a growing segment of the American population--that most at risk of developing certain forms of cancer, including breast, prostate, and colorectal cancers. The Baby Boom generation is fast approaching retirement age, and "in the next 20 years, the majority of the population will be elderly," Dr. Lustgarten says. Today, nearly half of newly diagnosed cancers are found in people that are age 65 or older--and Dr. Lustgarten predicts that as the elderly population increases, that number may rise to 75 percent or higher.

Why the impending rise in cancer occurrence among the elderly? Put bluntly, existing cancer therapies for the elderly don't work as well as they should. And Dr. Lustgarten has proof of a correlation between cancer development and a decline in immune system function in the elderly.

Knowing Your Audience

Most work in cancer immunology uses young animal models with robust immune systems--which is alarming given that cancer statistics show a disproportionately higher occurrence of tumors in the elderly.

"Over the past 20 years many groups have used young mouse models, with very little consideration given to the effect that aging has on the immune system," says Dr. Lustgarten. Why is that the case?

Frankly, it's time consuming and expensive for researchers to spend two or more years aging an animal population for study. Yet Dr. Lustgarten and his team have learned that doing so is absolutely necessary.

In a recently published paper (J Immunol. 2006 177, 8348-55.) Dr. Lustgarten and fellow researcher Ana Lucia Dominguez describe, for the first time, an animal tumor model where self tolerance (bodily problems that fail to provoke an immune response) and aging are present at the same time. These transgenic mice develop spontaneous tumors when they are more than 22 months old - senior citizen status in mouse years. "This model demonstrates that many therapies that do work in the young have minimal or even no effect in the elderly," Dr. Lustgarten says. "An older person just doesn't have the same vigorous immune response as a youngster."

As we age, the efficiency of our immune system declines, especially after about age 65--reducing the effectiveness of therapies that rely on provoking immune system responses. To illustrate, many people are vaccinated against the flu virus every year. Flu is extremely immunogenic and the body mounts strong responses against it. "But when you compare the vaccination success rates, 90 percent of the young population gets protected," says Dr. Lustgarten, "while only 30 percent of the aged population is protected." The reason for the difference lies in the immune system response. "The difference is not the vaccine's fault," Dr. Lustgarten emphasizes, noting that the same vaccines are used in young and old alike.

Now contrast the flu--which provokes a strong immune system response--to tumor cells, which are inherently self-tolerant, meaning that they will not provoke an immune system response. The immune system essentially recognizes tumor cells as belonging to the body--"a sort of new organ," Dr. Lustgarten says--and doesn't reject them. How can aged immune systems be expected to defend against internal malignancies when they often can't even take on the flu? "The way we're vaccinating the young is fine," Dr. Lustgarten concludes, "but new strategies need to be developed in order to effectively stimulate anti-tumor immune responses in both the young and the old."

While researchers are still learning exactly how the immune system declines, they have noted that lymphocytes--the umbrella term for the B and T cells that patrol our bodies looking for invaders such as infections and cancerous tumors--are less vigorous in responding to system threats in the aged. Put simply, aging compromises the body's ability to promote T cell responses--making it more difficult to launch an immune response against self-tumor antigens in old tolerant hosts.

Dr. Lustgarten's team also demonstrated that T regulatory cells (T-regs) accumulate in the aging immune system and that there is a direct correlation between T-reg accumulation and immune system decline. Furthermore, new emerging data from his laboratory indicate that other molecules important to immune system regulation are disregulated in the old.

What's the solution? Reducing T-reg expansion and other immune-suppression mechanism could be critical for restoring immune system responses. "Giving a boost to the aging immune system will help it to suppress tumors," Dr. Lustgarten hypothesizes. But is that easier said than done?

Keeping the Balance

The next phase of Dr. Lustgarten's work involves a genomic and proteomic analysis of immune system responses. "We're taking T cells and antigen presenting cells and evaluating the fundamental biological differences between the young and old immune cells," he explains. These type of experiments will help to identify deficiencies that could be harnessed to develop new therapies to improve the immune system of aged patients.

Work from Dr. Lustgarten's laboratory indicates that some adjuvants--agents that have potential to stimulate the immune system and provoke a response--are effective in the young but are not necessarily effective in the old. Therefore, "we need to be careful when therapies are selected to induce immune responses in the old," Dr. Lustgarten says.

The goal is to add the right agents to achieve a correct immune system balance, much the way that adding chlorine to a swimming pool maintains a delicate environmental balance. Too little chlorine and algae quickly blooms, progressing quickly from a single cluster into a festering green mess. In the same way that adding a little extra chlorine to restore pool balance may remove algae when it's in an early bloom stage--before it has completely taken over--using adjuvants to stimulate and maintain the T-reg balance can help to prevent or eliminate tumor cells in early-stage disease.

Do these ongoing discoveries mean that one day a person with a severe cancer diagnosis will be able to receive a series of vaccinations and come away cured? Not exactly. Surgery will remain the best treatment for large mass cancer, Dr. Lustgarten says, much in the way that a pool in full algae bloom must be drained, scrubbed clean, and refilled. There is simply no way to add enough chlorine to overcome the large bloom while maintaining a healthy environmental balance. The problem itself must be removed and the system cleared before balance can be restored.

However, the work being done by Dr. Lustgarten and his team does hold promise for developing effective anti-tumor vaccinations for the elderly--and the potential development of cost-effective treatment strategies that effectively stimulate anti-tumor responses in young and old alike.

- Michael Terrill, March 2008