Cancer immunotherapy: how to shoot a target moving faster than a bullet?

By Jun Tang

One out of every two men and one in three women will be affected by cancer in their lifetimes. Cancer devastates the people it afflicts, traumatizes their family and friends, and puzzles scientists and physicians who dedicate their lives to understanding and fighting the disease. When President Richard Nixon signed the National Cancer Act of 1971 and declared an all-out “War on Cancer,” many naively believed that cancer would soon be defeated, just as we celebrated our victories against smallpox and tuberculosis. Half a century later, we are still far from winning the war. As the Pulitzer-winning author Siddhartha Mukherjee dubbed it, and as we have gradually learned from endless battles with the disease, cancer is The Emperor of All Maladies.

Recent news from the front lines of cancer research suggests that we are gaining ground in the war on cancer. The FDA approved the first antibody immunotherapy targeting CTLA-4 (marketed as Yervoy by Bristol-Myers Squibb) in 2011 and the second, more effective antibody neutralizing PD-1 (marketed as Keytruda by Merck) in 2014, both for late-stage melanoma. In 2013, the journal Science named cancer immunotherapy “Breakthrough of the year.” Since then, cancer immunotherapy has dominated the discussion in the field of oncology and is gradually catching public attention. So what is cancer immunotherapy, and why is it inspiring so much optimism? Simply put, cancer immunotherapy aims to use our own immune system to fight cancer. Before expanding on cancer immunotherapy and its distinction from previous cancer therapies, let’s first understand how cancer acts.

Imagine our bodies as a city, where cell types with specialized functions—melanocytes, neurons, epithelial cells, and many others—work seamlessly together to keep the city functional and thriving. One day, a regular cell decided to join a cult called “cancer,” which mandates its members to trespass every law, regulation, and social order to achieve one single mission—conquer the entire city. Gradually, the cancer cells occupy a block, then a borough, and finally invade all parts of the city. When cancer cells enter a new place, they evict existing cells from their buildings, steal their food, tear down their homes, and decimate their communities. Gradually, cancer cells hijack all major resources while contributing nothing to the city. Starved and dismantled, the city has no defense to keep normal cells safe, no nutrients to feed the hungry, no caretakers to nurture the young, and no energy to keep everyone warm. The city is dying.

To save the city, and indeed the body, we need to fight the cancer cells. Typically, we first identify the weaknesses of cancer cells and use the most effective weapons to attack them. If cancer cells have a base camp in a block, we demolish every building in the neighborhood or even throw in a small-scale nuclear bomb (similar to surgery and radiotherapy for treating local tumors). If cancer cells have spread across the city, we target the cancer cells’ weak spots, killing most cancer cells while inevitably paralyzing many normal ones (similar to chemotherapy for treating metastatic cancer). We might poison or deplete cancer cells’ unique source of nutrients or sabotage their distinct mechanism of growing, eradicating cancer cells at a minimal casualty on normal cells (similar to targeted therapies such as Gleevec that are very effective with negligible side effects). In most cases, these coarse offenses work well initially but slowly become ineffective as cancer cells mutate to fix their weakness and learn to look like normal cells, making them “invisible” in our body. At this point, any weapons would do as much harm to normal cells as to cancer cells, and we are doomed to defeat.

Cancer is a persistent and elusive foe. Its unprecedented survival capability originates from the fruit of billions of years’ evolution—genetic mutations. Cancer mutates at a frenetic speed in response to our anti-cancer offenses, creating tremendous opportunities to outmaneuver. This is a small-scale, accelerated “natural selection” at work inside the body, where cancer cells are driven to become “the fittest” under the selection imposed by traditional cancer treatments like radiotherapy, chemotherapy, and even some targeted-therapy. Eventually, cancer cells develop many effective but distinct tactics to dodge cancer treatments, which means not one but many different cancers are attacking the body at the same time. At this stage, any single treatment that may kill some cancer cells would spare or even help other cancer cells with different mutations.

Can we also tap into the power of genetic mutations to create counter-strikes to fight ever-changing cancer cells? After all, cancer does not monopolize genetic mutations. In fact, our own immune system has also evolved to harness the power of genetic mutations to fight constant invasion of unknown foreign pathogens. In the immune system, B cells tirelessly generate antibodies (small proteins that specifically bind to invading antigens), which can call in macrophages—the defensive agents of our body—to terminate the antibody-bound invaders; dendritic cells can spot the plain-clothed, radicalized cells that are plotting a massacre in the body; cytotoxic T cells can hunt down viruses hidden in cells that reside in the most inaccessible alcove in the body. Through well-controlled genetic mutations, B cells can generate a reservoir of antibodies that target almost any invaders, and cytotoxic T cells can distinguish the hair-width difference between virus-infected cells and normal ones, marking the former for the kill. However, against cancer cells that look almost identical to normal cells, these immune cells are hesitant to train their weapons on seemingly innocent, healthy cells. By taking advantage of immune cells’ conservation, cancer cells continue their rampant sabotage of the body.

The main strategy of cancer immunotherapy is to educate the defense and investigative agents in our immune system to specifically attack cancer cells. The first attempt dates back to 1891, when William B. Coley injected bacterial toxins—Coley’s toxin—into patients with bone cancer. After a century of trial and error, we have finally learned a few tricks that can persuade immune cells to battle with cancer cells. We now can develop antibodies that specifically bind to cancer cells, which then can be “seen” and executed by immune cells such as macrophages. We can feed intelligence about cancer cells to dendritic cells that will subsequently urge all immune cells to watch out for cancer cells. Armed with the intelligence from dendritic cells, cytotoxic T cells can direct their unparalleled weapons to terminate cancer cells. Once immune cells see cancer cells as invaders in the body, they will comb all corners and terminate any confirmed cancer cells. This extensive and thorough strategy is a much more effective counter-strike to the guerilla tactics of cancer.

Although today’s cancer immunotherapies only unleash a small fraction of power residing in our immune system, they have already transformed the landscape of a few cancers. Melanoma, the deadliest skin cancer, has been successfully treated by immunotherapies in a number of patients by anti-PD1 antibody immunotherapy. In the case of acute lymphoblastic leukemia (ALL), T cells from an ALL patient can be extracted and engineered in a petri dish to recognize unique antigens on the surface of leukemia cells. Once the “educated” T cells are infused back to the patient, they can kill the cancer cells bearing the antigens, no matter where they reside, leading to long-term remission lasting for years in the patient.

Immunotherapies have produced several medical advances in the past few years and many more seem to be on their way. But none of these achievements would have been possible without decades of basic research by dedicated scientists. It was three decades of painstaking research on CTLA-4 and PD-1 (two molecules that prevent T cells from attacking cancer cells) that built the basis for Yervoy and Keytruda, the two drugs that cure melanoma in some patients. It was the discovery of dendritic cells led by Ralph Steinman, the 2011 Nobel Laureate from Rockefeller University, in the 1970s and the invention of chimeric antigen receptors (CARs) in T cells pioneered by Zelig Eshhar that opened the door to dendritic cell-based cancer vaccines and cancer-killing T cells that have saved many lives from hopeless late stage cancers.

“If you know both yourself and your enemy, you can win numerous battles without jeopardy,” said the legendary Chinese general Sun Tzu more than 2,500 years ago. In our fight against “The Emperor of All Maladies,” we need to better understand our foe to predict its next tactic of attack, and we need to comprehend basic biology of our own immune system to respond with an effective counter-strike. The key battles are likely to be fought not just by the bedside, but also in a petri dish, because that is the place where we observe, most clearly, both our enemy and ourselves. ◉

 

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