feature1
Scanning electron micrograph (SEM) of T lymphocytes (green) bound to antigens on a cancer cell.
© STEVE GSCHMEISSNER/SCIENCE SOURCE

More than a century ago, American bone surgeon William Coley came across the case of Fred Stein, whose aggressive cheek sarcoma had disappeared after he suffered a Streptococcus pyogenes infection following surgery to remove part of the large tumor. Seven years later, Coley tracked Stein down and found him alive, with no evidence of cancer. Amazed, Coley speculated that the immune response to the bacterial infection had played an integral role in fighting the disease, and the doctor went on to inoculate more than 10 other patients suffering from inoperable tumors with Streptococcus bacteria. Sure enough, several of those who survived the infection—and one who did not—experienced tumor reduction. Coley subsequently developed and tested the effect of injecting dead bacteria into tumors, hoping to stimulate an immune response without risking fatal infection, and found that he was able to cause complete regression of cancer in some patients with sarcoma, a type of malignant tumor often arising from bone, muscle, or fat. Unfortunately, with the increasing use of radiation treatments and the advent of systemic chemotherapy, much of Coley’s work was abandoned by the time he died in 1936.

Today, however, the use of immune modulation to treat cancer is finally receiving its due. Unlike chemotherapy and radiation treatments, which directly attack cancer cells, immunotherapy agents augment the body’s normal immune machinery, increasing its ability to fight tumors. This strategy involves either introducing compounds that directly stimulate the immune cells to work harder, or introducing synthetic proteins that mimic the components of the normal immune response, thereby increasing the body’s entire immune reaction. Last year, cancer immunotherapy was named “Breakthrough of the Year” by the journal Science, placing it in the company of the first cloned mammal and the complete sequencing of the human genome. With a handful of therapies already on the market, and dozens more showing promise in all stages of clinical development, these treatments are poised to forever change the way that we approach cancer management.

The power of the immune response

The human immune system orchestrates processes that continuously survey the host environment and protect it from infection. The two main components of the human immune system, the innate and adaptive arms, work together to fight infection and, importantly, to remember which pathogens the host has encountered in the past. Alerted by danger signals in the form of common microbial peptides, surface molecules, or gene sequences, innate immune cells such as macrophages and neutrophils invoke broad mechanisms to quickly fight foreign invaders. At the same time, B cells of the adaptive immune system generate a highly specific response, creating antibodies that can recognize and clear the pathogens. Antigen-specific T cells, activated by innate immune cells that have ingested the pathogen, further boost the body’s response. These B and T cells have lasting memory, allowing them to generate faster and stronger responses on subsequent exposures.

In the 1960s and ’70s, Lloyd Old of the Ludwig Institute for Cancer Research at Memorial Sloan Kettering Cancer Center (MSKCC) helped rekindle interest in cancer immunotherapy research, finding, among other things, that tumor cells display different surface antigens than healthy cells. These so-called tumor-associated antigens serve as the basis for developing cancer treatment vaccines, which attempt to stimulate a tumor-specific immune response. Old’s discoveries were followed in the 1980s by the work of Steven Rosenberg at the National Institutes of Health. Rosenberg studied the use of cytokines, which normally act to stimulate the immune system, to treat cancer.

More recently, the advent of immune checkpoint blockade approaches pioneered by James Allison, formerly of MSKCC and current chair of the University of Texas MD Anderson Cancer Center Department of Immunology, has written immunotherapy into the oncologist’s playbook. To ensure that the immune system does not become overactive, causing tissue damage or attacking the body, regulatory T cells (or Tregs) and myeloid-derived suppressor cells secrete anti-inflammatory proteins or directly inhibit pro-inflammatory immune cells. Additionally, immune checkpoint proteins expressed on the surface of activated immune cells serve to neutralize the immune response. Tumors may in fact exploit these very anti-inflammatory pathways, perhaps by stimulating an increase in Tregs or increased immune-checkpoint protein expression, to evade recognition by the immune system. Allison is now pioneering techniques to block these checkpoints, allowing the immune response to continue to fight the tumor unhindered.

These exciting new therapies are able to prolong life in patients whose cancers were previously deemed fatal, with kidney cancer and malignant melanoma leading the pack.

Vaccinating to treat cancer

cancer-vaccines

VACCINATING CANCER: Most cancer vaccines in development involve an injection containing a component of a tumor-specific antigen, with the goal of increasing the immune system’s tumor-specific activity. Others, such as Sipuleucel-T, involve the extraction of a patient’s antigen-presenting cells (APCs), which are cultured with antigens from the patient’s tumor along with immune-stimulating factors