In 1891, a man could plunge a syringe loaded with toxic bacteria into the neck of another man — simply on a hunch.

In May of that year, William B. Coley was the man holding that dubious syringe in the apartment of a 35-year-old Italian immigrant and drug addict named Zola. Poor Zola was told he might have only weeks to live due to an egg-size, inoperable tumor obstructing his pharynx, making it impossible for him to swallow food. Zola’s last shot at survival was in the hands of Coley, a 29-year-old bone surgeon who had just completed his training at New York Memorial Hospital. The young surgeon believed he was holding a cure for cancer in that syringe.

Coley was fascinated by a smattering of curious cancer stories referenced in the medical literature of the era: Patients riddled with inoperable tumors suddenly found themselves cancer-free after contracting erysipelas, another potentially fatal ailment at the time, caused by Streptococcus bacteria and marked by fever and hardened, painful rashes. Coley unearthed 47 similar cases and grew so intrigued by the apparent link that he scoured the ghettos of New York’s Lower East Side to find a German immigrant whose cancer had disappeared, according to medical records, after contracting erysipelas following several failed attempts to remove his tumor. Coley eventually found his man, scars and all, who was free of disease and in good health — seven years after doctors considered his case hopeless.

That was all Coley needed to proceed directly to human trials, and Zola would become his first test subject. Coley filled a syringe with living Streptococcus pyogenes, known to induce erysipelas attacks, and injected the solution directly into Zola’s tumor. It took awhile — in fact, it took repeated injections over five months — but finally, an hour after one particular injection in October, Zola broke out into sweaty chills, and his body temperature soared to 105 degrees.

For Zola (left), Coley's toxin-triggered infection liquefied the tumor in days. But toxin-induced infections were unpredictable; the patient at right had 63 injections before his tumor shrank. Some patients died. Cancer Research Institute/Proceedings of the Royal Society of Medicine 01/1910/3 (Surg Sect): 1-48

Just two days into the throes of erysipelas, the man’s tumor began to liquefy and shrink; within two weeks, it completely disappeared. Zola’s immune system had turned its weaponry against the tumor after a call to action from a feverish infection. According to follow-up reports, Zola remained well for eight more years before dying from a recurrence of the tumor in his native Italy.

Coley wasn’t the first to observe this compelling quirk of the immune system that gave Zola and others extra years on their lives, if not complete remission. The earliest mention of cancer-fighting infections dates to a citation from 1550 B.C. and is attributed to Egyptian physician Imhotep, who called for treating the wound with cloth coated in a poultice that would almost certainly lead to infection, and then cutting into the tumor. Coley, however, was the first to study and test the efficacy of what would come to be known as immunotherapy, coaxing the human immune system to fight cancer.

After his success with Zola in that New York apartment, Coley dedicated the next 40 years of his life to perfecting his unorthodox cancer treatment. In the process, he would become both a nationally revered cancer surgeon and an embattled figure who stubbornly defended both his treatment and his reputation until his death in 1936. Now, more than 100 years after his first fateful success, cancer researchers are still traveling the path Coley blazed long ago.

Rise and Fall In the two years following Zola’s treatment, Coley treated 10 more patients with live bacteria, but his approach proved to be highly unpredictable. Sometimes he couldn’t induce an infection; other times, patients had strong reactions but saw no cancer-fighting effect. On two consecutive occasions, the erysipelas infection killed the patients. So Coley changed course and crafted a vaccine with two dead bacteria, S. pyogenes and Serratia marcescens. Research at the time indicated the latter increased the virulence of the former when combined with each other, allowing the injections to induce the feverish effects while drastically reducing the risk of death. This reimagined mixture became known as Coley’s Toxin.

The pharmaceutical firm Parke-Davis & Co. made various formulations of Coley’s Toxin available to all physicians from 1899 to 1951, and at least 42 physicians from Europe and North America reported success stories in patients treated with the toxin, specifically for bone and soft-tissue sarcomas. In a 1945 study of the toxins’ efficacy, among 312 inoperable cases of cancer, 190 were considered regressions after treatment — a cure rate of about 60 percent. Coley went on to treat nearly 1,000 patients with his toxin and published more than 150 papers on the subject.

The widespread use of his treatment and his prolific publishing record made Coley a leading cancer expert in the eyes of the public. And Coley was justly regarded for his success as a cancer surgeon — he retired from New York Memorial Hospital in 1933 as chief of the bone tumor service. (His son Bradley was appointed his successor.) In 1935 Coley was inducted as an honorary fellow into the Royal College of Surgeons of England, becoming just the fifth American to receive that honor. But where his toxin was concerned, Coley was a target for criticism in the medical community, and with good reason: His breakthrough was built upon a shaky foundation.

Coley’s research had one major, damning flaw: He couldn’t explain why his toxins worked

Coley may have been an audacious clinician whose work helped hundreds of patients, but a scientist, he was not. He knew how to treat his patients, but he was never trained in laboratory work, and his toxin research didn’t meet the increasingly stringent scientific standards of the era. Physicians chided Coley for poorly controlled and documented experiments. For example, he injected the toxin into multiple locations in test patients without properly noting the location of each injection.

Despite his best efforts, the toxin was still inconsistent at best: Thirteen different formulations of his toxin were produced at one point, with some mixtures more effective than others. Furthermore, each patient reacted unpredictably to the toxins, and the toxins still were sometimes fatal.

But even if Coley had been more meticulous, he was still battling a medical establishment that firmly believed any cancer cure that didn’t require surgery meant the “disease” was misdiagnosed as cancer. Plus, many doctors had a justifiably hard time reconciling the Hippocratic oath with the idea of inducing a potentially fatal infection in already-suffering patients.

Early in the 20th century, radiation therapy was also an emerging cancer treatment, and the nation’s preeminent cancer pathologist, James Ewing, staunchly favored treating patients with this promising new method. Ewing also happened to be Coley’s boss and biggest opponent — never a good combination. Ewing forbade Coley from using his toxin inside Memorial Hospital.

Coley’s research had one major, damning flaw: He couldn’t explain why his toxins worked. They just did (sometimes). Until the day he died, Coley tenaciously held to the belief that microorganisms caused cancer — a theory long dismissed by the medical establishment — and that his toxin somehow killed those cancer-causing organisms in the body.

He must not have been alone in this conviction. More than 15 years after Coley’s death — not of cancer, incidentally, or an ironic erysipelas infection, but of chronic diverticulitis — Parke-Davis continued to make Coley’s Toxin, even as chemotherapy and radiation rose to the forefront of cancer treatment. By 1962, however, the U.S. Food and Drug Administration refused to acknowledge the toxin as a proven drug and made it illegal to use to treat cancer. Still, the legacy of Coley’s Toxin would not be forgotten.

Coley Vindicated Over the next several decades, researchers stuck their toes into the murky and temperamental waters of immunotherapy. Since the 1960s, the medical community has gone back and forth as to whether the immune system could be made to launch an anti-tumor offensive. It’s only relatively recently that researchers have finally confirmed that, yes, our immune system is indeed programmed to fight cancer.

William Coley's daughter, Helen Coley Nauts kept up the fight. Cancer Research Institute

Coley’s daughter, Helen Coley Nauts, deserves a lot of credit for keeping her father’s legacy relevant. After her father died, she dedicated her life to studying his toxins and reviewing his work. Although Nauts herself had no formal medical training, she published more than 18 monographs and identified more than 500 patients who were successfully treated with her father’s toxin. In 1953, she founded the Cancer Research Institute, which still exists today, to honor her father and advance the field of immunotherapy research. Up to the end of her life in 2001, Nauts was tireless — some might even say obsessed — in her efforts to have her father’s work reappraised by mainstream cancer researchers. She largely succeeded. Today, immunotherapy is a rapidly ascending field of cancer research because scientists are finally figuring out the immune system’s quirks, and the pharmaceutical industry is getting into the game. “Immunotherapy is probably the hottest area of cancer research right now,” says Jill O’Donnell-Tormey, CEO and director of scientific affairs at the Cancer Research Institute. She notes that biotech firms are investing heavily in immunotherapy research, and about 40 percent of the roughly 6,000 cancer clinical trials taking place in the United States today include some form of immunotherapy.

“I’ve been [at the Cancer Research Institute] for 28 years, and I have never seen the excitement in the field like this,” O’Donnell-Tormey says. “In the last few years, it’s all come together. Scientific understanding has helped build a rational case of how this works, and now we can couple that with clinical results.”

The momentum started building in 2010 when the FDA approved Provenge, a cancer vaccine that rallies male patients’ immune systems to attack prostate cancer cells, allowing patients with an advanced form of the cancer to live several months longer. Provenge proved to researchers that it is possible to get an active immunotherapy approved by the FDA.

The next year, the FDA approved another immunotherapy agent, ipilimumab, to treat melanoma. The drug blocks CTLA-4, a protein receptor on the surface of T-cells that serves as a molecular stop sign, preventing the immune system from going into overdrive. Ipilimumab counters the CTLA-4 signal, allowing T-cells to launch a full-scale attack on cancer cells.

Although Coley couldn't explain precisely why or how his toxins worked, modern immunotherapy treatments help T-cells in the immune system to recognize specific cancer cells and attack them. Mike Werner/Science S

“That’s when Big Pharma started sniffing around and really got interested in immunotherapy,” says Jeffrey Schlom, chief of the National Cancer Institute’s Laboratory of Tumor Immunology and Biology.

BioMed Valley Discoveries in Kansas City is one of those pharmaceutical companies hot on the immunotherapy trail. One of BioMed’s projects involves an unorthodox way to penetrate cancer’s armor, and the team’s approach would no doubt make Coley smile. The BioMed team successfully treated rats, dogs and one human by injecting tumors with a weakened version of Clostridium novyi, a toxic bacterium that lives in the soil. Like Coley’s initial bacteria of choice, C. novyi also has a dark side: It can cause flesh-ravaging, potentially fatal infections in its natural state. But the researchers’ version of C. novyi was stripped of its ability to produce a particular toxin. Injecting spores of C. novyi into dogs resulted in rapid reduction of tumor sizes, and even completely eradicated tumors in three of 16 trial dogs. When the team injected the first human with the bacteria, it was as if researchers had traveled back in time to Zola’s New York apartment.

“Coley injected his first patient a century ago, and what he saw was almost identical to what we saw in our first patient,” says Saurabh Saha, a partner with Atlas Venture, former BioMed Valley researcher and senior author of the study. “Within the same time frame observed by Coley, our patient developed a fever, the tumor started swelling, and then it started to shrink.”

C. novyi is really a two-pronged weapon against cancer: It germinates in tumors and releases cancer-killing enzymes, and it may also trigger an immune response similar to Coley’s Toxin. Since C. novyi survives only in oxygen-poor environments — tumors can be notoriously void of oxygen — the bacteria die when they reach healthy, oxygen-rich tissues, sparing collateral damage. Essentially, the injections perform highly precise biosurgery from the inside out.

Immunotherapy's Resurgence BioMed Valley’s intriguing C. novyi treatment is still in its early stages of testing and research, and it’s just one of many ascending immunotherapy treatments. In December 2014 the FDA approved Opdivo (nivolumab), which, like ipilimumab, is another checkpoint inhibitor to treat melanoma. (Opdivo just applies the brakes in a different way.) As a follow-up act, the FDA in September 2015 gave the green light to the first cancer therapy to combine nivolumab and ipilimumab to treat certain patients with metastatic melanoma.

Researchers are also experimenting with another form of immunotherapy called adoptive cell transfer, which harvests and then reintroduces patients’ tumor-infiltrating lymphocytes — cells with anti-tumor capabilities that dig deep behind enemy lines. The idea is that these cells may be present in the body, but their population isn’t large enough to exert an anti-tumor effect. So scientists choose the lymphocytes with the greatest tumor-fighting activity, grow a large population of them in the lab, then infuse them back into the patient.

Schlom, of the National Cancer Institute, says the next challenge for researchers is to find ways to combine different immunotherapy drugs into single treatments and measure their efficacy in clinical trials. He says different immune system-enhancing drugs, when combined, can result in better anti-tumor effects. The same rings true when immunotherapy is paired with other cancer treatments like chemotherapy, for example. But testing new combinations presents an entirely different problem. “A lot of these drugs are being made by different companies, and getting them to work together will be difficult,” says Schlom.

More than a hundred years after that fateful day in 1891, Coley’s legacy may be more relevant than ever. Today’s immunotherapy researchers not only will need to borrow the methods once popularized by Coley, but also his implacable personality. But the tide is certainly turning, and persistence is paying off.

“I most admire Coley’s tenacity and stubbornness. He kept moving forward with what he thought was an effective means to destroy cancer, despite his colleagues’ lack of support,” says Saha. “It’s unfortunate he was once pushed to the background, but the field has been resurrected 100 years later.”

[This article originally appeared in print as "Germ of an Idea."]