The Lucky Years: How to Thrive in the Brave New World of Health (6 page)

The drugs getting the most attention are called checkpoint inhibitors. These release the natural brakes on the immune system so it can then launch an assault on the cancer. The treatment itself is called checkpoint blockage therapy. Two “switches” in the body, for example,
that prevent tumor cells from attack by the immune system are labeled CTLA-4 and PD-L1. When these buttons are “on,” the immune system is turned down so it can’t recognize and kill cancerous cells. But when we disrupt these switches and block their functionality, this essentially enables the immune system’s sentry—those T cells—to find and pummel the cancerous cells. It’s important to note that cancer isn’t a foreign mass of cells. It’s our own cells run amok, hence it’s difficult for the immune system to “see” them.

In one of the more extraordinary clinical trials taking place today, researchers at Duke University are using a different immune strategy by reengineering the polio virus. The idea of using viruses to attack cancer has been around for more than a hundred years, but we didn’t have the technology or know-how to conduct these experiments until recently. The last case of naturally occurring polio infection occurred in the United States in 1979. These Duke researchers noticed something interesting about the virus: it kills cells by entering them through a “door” called a receptor. The special receptor for the polio virus turns out to be present on most solid tumor cells—lung, breast, brain, prostate—but not on most normal cells. The problem is that it can also attach to nervous system cells called neurons. When it kills them, the result is the muscular paralysis of polio. By extracting the disease-causing part of the virus that infects normal neurons, replacing it with the benign cold virus, and keeping only the part that attaches to and kills cancer cells, we can create a safe virus. Once injected directly into the tumor, it infects a few of the cancer cells and kills them while at the same time nudging the immune system. The immune system wakes up and thinks,
This is polio!
and kills the “bystander” tumor cells as well. The virus essentially tags the tumor as a “foreign” object and arouses the body’s immune system to attack.

The studies using the polio virus have thus far been done mostly on patients battling advanced glioblastoma, one of the deadliest and most aggressive types of brain cancer, which often leads to death within weeks after standard treatments have failed. Researchers have managed to prolong the lives of some people by months, even years.
⁹

Brain scans of a twenty-year-old college student treated with the engineered polio virus (PVS-RIPO) by an infusion through a catheter directly placed into the tumor. The first panel shows the tumor (shaded area in upper left of the brain); the second panel shows the tumor after two months of treatment (where the tumor actually appears larger in size due to the inflammation of the antitumor response); and the third panel shows the tumor shrinking at nine months of treatment.

The idea that we can leverage our own immune systems to cure cancer is a romantic one, but it’s not without its dangers. Our immune system, after all, is powerful on its own when allowed to operate at full speed. It can be risky to release its brakes, even in the hopes that it can clobber those devilish cells gone mad. Some patients who have tried immunotherapy died after developing devastating complications caused by an unrestrained immune system that indiscriminately attacks not only the cancer but also healthy and essential tissues and organs. Through ongoing clinical trials, researchers hope to overcome this challenge in the future. Immunotherapy is and will continue to be an important weapon against cancer, but it’s currently limited in the cancers it targets and the patients it benefits. The challenge is to figure out in advance who will benefit. We also need to improve our understanding of which combination of checkpoint inhibitors or other immune-altering intervention best equips the body’s immune system with anticancer ammunition.

As it happens, the more mutations a cancer has, the easier it often is to target with some immunotherapies because its cells become more “foreign looking” to the body’s own immune system. Put another way, the more abnormal a tumor becomes, the harder evading detection by
the immune system becomes, especially after some drug therapy puts that immune system on high alert and fits it with special “night-vision” goggles. This phenomenon was recently revealed in a standout paper for the
New England Journal of Medicine
by a team from Johns Hopkins Sidney Kimmel Comprehensive Cancer Center.
¹⁰

DNA is constantly being repaired in the body, and the tools to do so are called “DNA mismatch repair.” The Hopkins group looked at the presence or absence of DNA mismatch repair genes, which code for the system the body uses to recognize and fix bad DNA. They noted that regardless of the type of cancer, tumors that didn’t have this repair system working properly were more likely to respond to the immune-brake system-altering, anti-PD-1 drug than those with tumors that had an intact mismatch repair. In other words, the worse the tumor cells were at repairing DNA, the better the patients responded to treatment. Immunotherapy likely won’t stand on its own; it will be used in combination with other therapies, including chemo, radiation, and molecularly targeted drugs. But it will nonetheless become an indispensable tool made all the more powerful with adjunct weapons.

One of the surprising findings about immunotherapy is that many people who have tried it often report feeling better though their cancer is still there and may have even grown. But that’s the problem with my specialty. Our only metric for success is shrinking a tumor. Slowing its growth, making somebody feel better, or watching a person continue to live longer than expected isn’t classically accepted as “success” in cancer treatment.

If you come to see me in the office with a cancer that measures 5 centimeters, and if I give you a treatment, and when we remeasure the cancer in several months, it is 7 centimeters, did the treatment work? Would your cancer have been 15 centimeters without treatment? Most of the time with new drugs that stop or slow cancer, doctors and their patients are flying blind. In any randomized clinical trial, the drug might help a group of patients live longer, but it’s very difficult to know what it’s doing in the individual patient. Also, success will mean something different to each patient. If you can live another two good years, for
example, on drug
X
, do you care how big your tumor is so long as you can tolerate the side effects and gain those extra quality years? I’ve never had a patient tell me, “I wish I had died last year.” Even my sickest patients don’t regret living longer than expected. They will do pretty much anything to live one more day, and they are often willing to try new strategies no matter how absurd they sound. They will, put simply, take risks with me in our fearless flight.

Let’s go back in time again. At roughly the same time Coley was experimenting with his toxins and trying to keep his critics from silencing his message, the Russian scientist Élie Metchnikoff was revealing how
Lactobacillus
bacteria could be related to health.

A photo of Élie Metchnikoff, father of natural immunity and 1908 Nobel Prize laureate in Physiology or Medicine, in his Ukraine laboratory.

Metchnikoff is considered the father of natural immunity. His work set the stage for the current popularity of consuming beneficial bacteria
to nourish the gut’s microbiome—the tribes of microbes in the intestinal tract that collaborate with your entire physiology. Metchnikoff predicted many aspects of current immune biology and was the first to suggest that we can benefit from lactic acid bacteria (or
Lactobacillus
). According to his theory, illnesses and aging are accelerated by the release of toxic substances in the gut by certain bacterial organisms, and lactic acid could prolong life by replacing the harmful microbes with useful ones. His ideas came from noticing the longevity of Bulgarian peasants and hypothesizing that it might be the result of their eating fermented milk products (principally yogurt). Metchnikoff himself drank sour milk every day based on his theory. More than a century ago, he said that “oral administration of cultures of fermentative bacteria would implant the beneficial bacteria in the intestinal tract.” Yet only in the past decade has science validated and begun to understand Metchnikoff’s bold assertions. In 2015, more studies emerged showing the power of the microbiome, some of which showed how certain foods you eat can change the composition of the bacteria colonies in your gut to either lead your body down the path to metabolic syndrome and obesity, or keep you slender and humming to the right metabolic tune.
¹¹
We’ll be exploring more about these findings and the microbiome in chapter 4. In the future, leveraging your microbiome for the better will likely be part of your health equation.

In 2008, the
European Journal of Immunology
paid tribute to Metchnikoff on the hundredth anniversary of his Nobel Prize in a beautifully written article chronicling his life and his contributions to society.
¹²
He was the first scientist to understand natural immunity to infection, the significance of inflammation, the role of digestion in immunity, the importance of gut flora, the implications of “self” versus “nonself” within the context of immunity so the body knows the difference between its own cells and foreign invaders. He even led the way in shaping the essence of the scientific study, for Metchnikoff taught how to go from observations to hypothesis for experimental testing. By the end of his life, he believed strongly in the power of ingesting good bacteria, principally
lactobacilli
, and he urged others to do so as well but was often
ridiculed. Cartoons depicted him administering probiotics to people who wanted to live to one hundred.

Metchnikoff believed his sour-milk (fermented) therapies could also help stop the aging process. When his work in the area was described publicly, a French cartoon (shown here), titled “Manufacture de Centenaires,” spoofed Metchnikoff’s enthusiasm for probiotics as a panacea, portraying him as one who would manufacture centenarians.

If only he could see the world today! The scientific community is finally catching up with Metchnikoff’s ideas. May other “old bottles of wine” from the past be uncorked to spill their wisdom in the Lucky Years.

Today, you might not know whether or not a glass of red wine at
night is helping you, if a daily baby aspirin is a good or bad idea, or which probiotic could help your digestion. But sometime soon, a blood test will be all you need to find out what’s best for you. Even without that definitive knowledge today, you can take action. While we await definitive studies demonstrating the impact of every aspect of your unique lifestyle and environment, we do have an enormous amount of evidence from other areas of medicine to help you make the best choices.