Cancer therapy, from toxins to checkpoint inhibitors
Written by Rebecca J. Anderson, PhD
William Coley stood helplessly beside Elizabeth “Bessie” Dashiell’s hospital bed when she died on January 23, 1891.1–4 When he began treating 17-year-old Bessie four months earlier, he had just completed his surgical internship under two prominent surgeons (William T. Bull and Robert F. Weir) at New York Hospital and had already shown great promise as a surgeon himself.2–5
At first, Coley thought the small bump on Bessie’s right hand was just an infection. But a biopsy in November 1890 confirmed that it was a sarcoma (a malignant tumor of connective tissue).4 Coley’s only option was to amputate Bessie’s right arm below the elbow. Unfortunately, within a month, tumors appeared in her lungs, liver, stomach, and breasts. Then, tumors invaded her body from head to toe. She began vomiting large amounts of blood and wrenching in pain.2,4 Bessie died a few days later.1
An auspicious start
William Bradley Coley was born on a Connecticut estate that had been granted to the Coley family by King George III. His ancestors included religious leaders, schoolmasters, and large-land owners who had emigrated from western England.2–6 Coley developed into a slender, handsome young man of notoriously shy demeanor. Intelligent and deeply religious, he attended a private academy in Westport and then graduated from Yale. His two extracurricular passions were reading the classics and collecting rare books.4
Because he had spent the summer of 1886 accompanying his uncle on horse-and-buggy medical rounds, Coley entered Harvard Medical School’s three-year program as a second-year student.4,5 In parallel with his medical lectures, Coley was invited by some friends to cover for a New York Hospital doctor who was on sick leave. Not yet awarded his medical degree, Coley spent 6 weeks as an “active Junior Surgeon” at that major metropolitan hospital.4
In 1890, after his internship, Coley joined the surgical staff at New York Hospital. He also secured an appointment as a surgical instructor at the Postgraduate Medical School and was granted privileges at the Hospital for the Ruptured and Crippled (now the Hospital for Special Surgery).3,4
An amazing cure
Then (as now), sarcoma was a rare but aggressive form of cancer. Even amputation, as in Bessie’s case, usually failed to prevent its spread. All types of cancer were poorly understood, and Bessie’s rapid decline and death weighed heavily on Coley.3–5 To better understand sarcomas, Coley searched the past 15 years of medical records in the archives at New York Hospital.3,4 Of the 90 sarcoma cases that he found, one patient in particular captured his attention. Fred Stein, a German immigrant, had suffered from an aggressive, recurrent sarcoma, which amazingly disappeared following a serious bacterial skin infection.2,5
Stein had first been admitted eight years earlier with a large tumor on his neck. Over the next four years, William Bull had made multiple attempts to remove the tumor, but it always reappeared.2–4 The tumor eventually grew so large that Bull could not close the surgical wound, and several skin grafts failed to take.4
Following the last surgery, Stein developed a skin infection from Streptococcus pyogenes. The infection and accompanying fever were so severe that doctors feared Stein might die.2 Instead, the tumor miraculously disappeared, and a healthy scar formed in its place. Bull discharged Stein on February 26, 1885.3,4
Streptococcus pyogenes, a bacterium related to the organism that causes Strep throat, was a leading cause of postoperative infections and death in 19th century hospitals.2,4 S. pyogenes causes erysipelas, a skin infection characterized by hardened painful bright red rashes, a high fever, chills, and general malaise.7 In addition to being highly contagious, erysipelas rapidly spreads to underlying tissues and was often fatal.
At that time, documenting long-term outcomes was not part of medical practice, and Bull’s clinical notes ended with Stein’s discharge.4 Coley wanted to know what happened to Stein.
In the winter of 1891, he went door-to-door through the tenements of the Lower East Side of Manhattan, where the German immigrant community lived. After several weeks, he found Stein, who retained a prominent, jagged, crater-like scar down his neck (the result of his multiple surgeries).2–5 But he was cancer-free. Coley brought Stein to New York Hospital, where Bull examined and photographed him, to document the recovery. Stein continued to enjoy excellent health, and his cancer never returned.4
It was probably this case that impressed upon Coley the value of staying in touch with his patients.4 In any case, it became a hallmark of his treatment paradigm.
Searching for confirmation
Impressed by Stein’s remarkable recovery, Coley combed through medical literature, looking for other cases of this phenomenon. He found a smattering of reports in which patients who accidentally contracted erysipelas enjoyed stunning cancer remissions.4,5,7 In addition, a German physician had intentionally injected a cancer patient with the Streptococcus organism to induce erysipelas, and he reported shrinking of the patient’s tumor.5
Coley was also aware of anecdotal suggestions that fever (a characteristic feature of infections) had a beneficial effect on malignant tumors.5
Altogether, Coley found 47 cases in the literature documenting infection-associated tumor remissions.5,7 Convinced that a serious infection could elicit an anti-cancer effect, “I determined to try inoculations [of bacteria] in the first suitable case.”4 That “suitable” patient was named Zola.
John D. Rockefeller, Jr., was a friend of young Bessie Dashiell and, like Coley, grief-stricken by her death. Rockefeller provided modest funds to finance Coley’s initial experiments—the first dollars that the Rockefellers spent on cancer research.4–6 Young Rockefeller subsequently focused all of his philanthropic efforts on conquering cancer.4
The test case
Back in 1890, Zola, a 35-year-old Italian immigrant, underwent an operation in Italy to remove a sarcoma in his throat, but it rapidly returned.4,7 In New York in April 1891, Bull removed part of the sarcoma, but the rest was deeply seated and inoperable. The aggressively growing tumor made it nearly impossible for Zola to eat, speak, or even breathe.2,4,7 A drug addict (probably due to painkillers he took for the cancer), Zola had only weeks to live.2,4
With no other alternatives, Coley proposed his erysipelas treatment to Bull, who agreed. He also explained the procedure to Zola, who consented. But hospitals were reluctant to allow the experiment, because erysipelas was so contagious and potentially dangerous.4
Instead, Coley and two other doctors, along with Zola’s niece who served as a nurse, administered the treatment in Zola’s apartment on the Lower East Side (the precautions were justified, because the nurse later contracted erysipelas from her uncle).4,7
On May 3, 1891, Coley made the first small cuts in Zola’s skin and rubbed the Streptococcus bacteria into them. He repeated the procedure for two weeks, but Zola developed only slight chills and a slight fever.2,4
Coley then obtained a stronger strain of the bacteria and injected larger amounts directly into the unhealed neck wound. There was intense local redness. Within eight hours Zola experienced severe chills, vomiting, and an intense headache. His temperature rose to 101°F.4,7
By June 2, 1891, the tumor had decreased in size, and Zola could swallow food again. Coley discontinued treatment in August after 16 injections. The tumor shrinkage was encouraging, but it was far from a cure.4
Despite several months of trying, Coley failed to generate the vigorous erysipelas infection he desired. Coincidentally, a friend, New York Hospital pathologist Farquhar Ferguson, was planning a trip to Europe, and Coley asked him to visit the Berlin lab of Robert Koch. Koch, the foremost bacteriologist in the world, provided a fresh S. pyogenes culture, which he obtained from a patient who had died from erysipelas.4
On October 8, 1891, Coley administered Koch’s bacteria, and both Zola and his niece developed raging infections.2,4 By this time, Zola’s tumors had returned to their previous size. Within an hour of the injection, Zola developed severe chills, which lasted for 40 minutes. He also experienced nausea, vomiting, and severe pain, along with a temperature of 105°F. Within 12 hours, the typical red patch of erysipelas appeared on his neck and spread across his face and head.4
By the second day, the neck tumor began to break down, liquify, and shrink. The tumor debris continued to slough off, and after two weeks, it had completely disappeared.2,4,7 Zola’s neck healed, and he gained weight. Coley continued to monitor Zola, who remained in good health, except for his continued addiction to morphine. Zola died six years later from a recurrence of the tumor, while living in his native Italy.7
Coley’s experience with the Stein and Zola cases established the routine he would follow for all of his subsequent infection-treated patients. Typically, those patients were referred to him because they had inoperable cancer and were expected to die.2,4,5 In addition to treating these patients, Coley tried to stay in touch with them and noted their long-term outcomes.
Encouraging cases
Coley wanted to continue his experiments, but he needed an isolation ward, which would contain the highly contagious erysipelas. Through a close relationship with the stepson of Collis Huntington (one of the “Big Four” railroad robber barons of the 19th century), Coley received funds for construction of a special pavilion at Memorial Hospital: the New York Cancer Hospital (now Memorial Sloan Kettering Cancer Center). The funds represented the first endowment specifically for cancer research in the US, and it supported both Coley and other cancer researchers.4–6
Between 1891 and 1893, Coley attempted to elicit an erysipelas infection in 12 patients—all diagnosed with inoperable or incurable malignancies. Eight of them had sarcomas, and they all responded to treatment. In fact, in two of them, even the metastatic tumors disappeared. On the other hand, the four carcinoma patients failed to show a significant anti-tumor response.4,8
Interestingly, in some cases, his injections failed to produce the typical skin erysipelas, but the patients did exhibit other signs of infection (short-term nausea, vomiting, headache, malaise, and fever). In most of these cases, Coley nevertheless saw signs of tumor regression.8 These results gave him a valuable hint on how to optimize his treatment. He surmised that the beneficial anti-tumor effect was due to toxins produced by the Streptococcus organism, rather than the bacteria itself.8
Coley used two methods for separating the bacteria from its toxins. In his first experiments, in 1892, he heated the bacterial cultures, which killed the bacteria but left the bacterial toxins unharmed.8 In the other method, his friend Alexander Lambert filtered the cultures, which trapped the bacterial cells but allowed the toxin-containing liquid to pass through.8
The toxin-laden liquid triggered fevers in the range of 103.5°F but had only a modest, temporary effect on the tumors of patients with inoperable sarcomas.4,8 Something more powerful was needed.
Then Coley learned that researchers at the Pasteur Institute in Paris had intensified the virulence of erysipelas by growing Streoptococcus pyogenes in the presence of Bacillus prodigiosus (now called Serratia marcescens).8,9 S. marcescens is a gram-negative bacterium, and it produces an endotoxin that is one of the most powerful inducers of an immune response. It stimulates production of tumor necrosis factor (TNF), interferon, and interleukins.4
The combo is better
Coley soon had the opportunity to test the efficacy of the combined toxins, which he called the “toxic products” of S. pyogenes and Serratia marcescens. A New York physician had referred 16-year-old John Ficken to Coley. The large inoperable tumor attached to Ficken’s abdominal wall had been diagnosed as malignant sarcoma.4
Starting on January 24, 1893, Coley injected the toxins directly into the boy’s tumor in gradually increasing doses every 2–3 days, until they provoked a strong inflammatory reaction.8 At the 10-week point, Ficken developed violent chills, nausea, vomiting, headache, fever, and local redness and swelling at the injection site. These symptoms appeared within an hour after injection and disappeared by 24 hours.8
Ficken’s general condition improved, and Coley halted treatment on May 13, 1893. A month later, the tumor no longer protruded from Ficken’s abdomen, and he was discharged. Coley stayed in touch with Ficken, who died in Grand Central Terminal in 1919 after suffering a heart attack while riding the subway. He was 47 years old and had remained cancer-free for 26 years.4
Buoyed by the Ficken success, Coley treated five more patients in early 1893. In 1894, he published his first results of the combined toxins. The results of the other patients were encouraging but unfortunately less impressive than Ficken’s.4,8
Coley’s Toxins
Bertram H. Buxton at the Loomis Laboratory in New York found that growing the two bacterial organisms together, followed by heat-treatment and filtering, intensified the toxin combo’s virulence.8 Coley continued giving the “toxic products” (prepared by Buxton) as his standard treatment at New York Cancer Hospital.5,8
Later, Martha Tracy and S. P. Beebe of the Huntington Cancer Research Fund, using dogs, showed that the toxin produced by Serratia marcescens had inherent curative properties against sarcoma—not just that it enhanced the virulence of the S. pyogenes toxin.8 In 1908, Tracy introduced a modification that made it possible to standardize the dosage, and the toxin combo was subsequently referred to as “Coley’s Toxins.”5,8,9
In 1899, Parke, Davis & Co. began selling the toxins under the label, “Coley’s Mixture.”5 At that time, no drug company had the technical expertise to mass-produce a sophisticated biological product, and Parke-Davis invested little effort in quality control.4,7
All physicians had access to the Parke-Davis product. At least 42 of them in Europe and North America reported successful outcomes, especially in patients with bone and soft-tissue sarcomas.4,5,7 But in the hands of practitioners who lacked Coley’s insight and skill, the commercial product performed inconsistently at best.
The Parke-Davis product was likely inferior to the preparations that Tracy and Buxton made for Coley. One patient who went home to inject himself with the toxins wrote Coley, “You know, I have to use eight times the dose of the Parke-Davis product to get the same reaction that I get with a small dose of the Tracy.”4 Coley urged Parke-Davis to get in touch with Martha Tracy, and the company did change its product. The results were then a little better, but not much.4
Optimizing treatment
The inflammatory reaction induced by the combined toxins corresponded exactly to that seen at the beginning of an erysipelas attack. But they produced a more powerful response than that of the Streptococcus toxin alone, and the effect on the tumor was much greater.8
Through trial, error, and keen observations, Coley intuitively optimized treatment for each patient. He judged how much each critically ill patient could tolerate, knowing that if he delivered the toxins improperly, they could result in significant morbidity and even death.4,9,10
The infection-induced fever was a key efficacy signal. Coley titrated the dose to achieve a fever of 104–113°F, which appeared to elicit an optimal effect.9–11
Coley also experimented with the site and route of administration, eventually finding that intravenous injection was the most effective.9 He started with injections daily, or every other day, for a month or two. Then, to prevent tumor recurrence, he administered weekly injections for at least six months.10
Little was known about the immune system at that time, and Coley could only speculate about the toxins’ mechanism of action.9 But because he could elicit an anti-tumor response, even when the injection site was far from the tumor, he concluded that the toxins triggered a systemic immune response. What exactly was happening, though, was unclear.
A stellar reputation
Coley became a highly regarded cancer surgeon and rose to Chief of the Bone Tumor Service at Memorial Hospital.7 In 1909, he was appointed clinical professor of surgery at Cornell University Medical School, and in 1915 he was appointed clinical professor of cancer research at Cornell. In 1924, he was named Surgeon in Chief at the Hospital for Special Surgery, along with holding a staff surgeon position at New York Cancer Hospital.3
Coley enjoyed a reputation as an empathetic physician, as well as a superb surgeon. He counted in his circle of professional colleagues some of the medical giants of his generation, including William Welch at Johns Hopkins, Harvey Cushing at Harvard, and the Mayo brothers.4
But in addition, for some 40 years, he treated inoperable patients with Coley’s Toxins.5,7 The cases covered a wide variety of malignant diseases including lymphomas, osteosarcomas, Ewing’s sarcomas, and malignant melanomas. He also treated cervical, ovarian, testicular, renal, breast, and colorectal cancers. But by far, the best response was achieved in patients with inoperable soft tissue sarcomas.9
By the end of his career, Coley had written over 150 papers describing his toxin therapy, and he had treated almost 1000 patients.5
Although these patients had been referred to Coley in the final stages of their disease, some of them made remarkable recoveries.10 Had he been able to treat them earlier, he said, the results might have been even better.8
Skeptics prevail
Being based in New York City, Coley garnered public recognition as a leading cancer expert. But in the medical community, he was a target of criticism, because his breakthrough treatment was built upon a shaky foundation.7
Many doctors simply did not believe his results.5 Spontaneous tumor regression remains a very rare phenomenon, with an incidence rate of 1 per 60,000 to 100,000 cases.3 Skeptics said that those “cured” patients had been misdiagnosed and really didn’t have cancer in the first place.3,7 To address this criticism, Coley began employing microscopic analysis, histochemical techniques, and a pathologist’s assessment to confirm that the tumors were malignant.8
Many doctors found it hard to reconcile the Hippocratic oath of “Do no harm” with a treatment that induced a very high fever and potentially fatal infection in patients already weakened by cancer.2,3,7
In addition, despite Coley’s enthusiasm and dogged persistence, he was not trained in scientific methods, and it showed. His experiments were not well controlled, and factors such as length of treatment, site of injection, and magnitude of the fever were not adequately documented.2,4,7 That made it even harder for skeptics to trust his results.
At least 13 different formulations of the toxins were produced by different labs. And the different formulations had different levels of potency.7,11 Even for the supportive physicians who were willing to administer his toxins, the treatment paradigm was labor-intensive, time-consuming, and expensive.2,3,6,11
Furthermore, each patient reacted unpredictably, and some of them died. Despite Coley’s skill and extensive experience, even his results were inconsistent. He could not explain why his toxins worked—and why they sometimes didn’t.2,3,7,12
But the main factor that doomed Coley’s Toxins was the emergence of radiation therapy.5,6
Radiation therapy
By 1901, radiation treatment had shown great promise.2,5 It resulted in immediate tumor destruction and pain relief. And unlike Coley’s Toxins, radiation (and later chemotherapy) produced clear and consistently effective results in nearly every patient.10,11
Coley’s most vocal critic was James Ewing, a highly respected cancer pathologist and a stanch supporter of radiation therapy.5–7 Ewing repudiated any other theories for cancer treatment. As Medical Director of Memorial Hospital, he was, in effect, Coley’s boss and exercised considerable influence over the research and publications emanating from the hospital.4,5,7,11
Coley and Ewing were complete opposites. Coley cultivated a genial, civil, and highly-social disposition, eloquent if somewhat long-winded, and an Anglophile adherent to the “moral virtues.” Ewing was endowed with a crisp, sharp-tongued, incisive intellect, and he was a bit mean-spirited.4
Ewing refused to give Coley permission to use his toxins at the hospital.4,5,7,11 This was ironic because Coley had more experience and success than any other surgeon in the country in treating the small round blue cell sarcoma that is still called “Ewing’s sarcoma.”5
To his credit, Coley purchased and used two X-ray machines.2 But after several years, he concluded that radiation therapy (still primitive at that time) was localized, temporary, and a non-curative treatment. He acknowledged that radiation was useful in some cases, but Ewing and many other clinicians advocated it for essentially every cancer patient.2,11
By 1896, many physicians had concluded that Coley’s Toxins were worthless.4 His notion that cancer could be treated by mounting an immune response and an accompanying fever disappeared as a treatment strategy.3
Despite the criticism and lack of support, Coley tenaciously and stubbornly continued to use his toxins. He was convinced that they were an effective means of destroying cancer.7
In 1914, he published a 172-page monograph listing the case histories of more than 80 patients with various types of cancer who had been treated with his toxins.8 Many of these patients also received radiation and/or surgery.
Coley continued treating terminally ill patients until his death in 1936.4 But every other clinician employed radiation and chemotherapy, which they thought would eventually lead to a cure for cancer.10 Interestingly, these “modern” treatments are highly immunosuppressive—the exact opposite of Coley’s immunotherapy approach.
Enter—Helen Nauts
Coley’s papers were stored in a barn on the family’s Connecticut property: his medical records, case reports, professional and personal diaries, as well as correspondence with the Mayo brothers and Joseph Lister. His daughter, Helen Coley Nauts, intended to write her father’s biography and hauled it all back to her New York home.2–4
She spent three years patiently reading the entire archive.4 Although she had no formal medical training, Nauts soon realized that Coley’s Toxins had (occasionally, at least) produced some remarkable results.7,13 She spent more than a decade teaching herself oncology, immunology, and record-keeping so that she could understand, analyze, and properly interpret the results.13 Of Coley’s nearly 1,000 treated patients, Nauts identified 896 cases of microscopically confirmed cancers that had been treated with Coley’s Toxins.11,13
Unfortunately, Coley’s records lacked details that were needed to prove efficacy. She supplemented his medical notes, systematically tracking down patients, contacting coroners, and collecting death certificates to confirm the patients’ outcomes.4,11 Several patients who received Coley’s Toxins were still alive. One of them was Dr. William Curtis, a retired radiologist in Seattle. At the age of 12 in 1921, Curtis’s bone cancer had been successfully treated with the toxins.4
Unlike Coley’s haphazard and disorganized medical record-keeping, Nauts turned out to be much better at organizing and analyzing the data. She tabulated each patient’s responses and categorized the results by cancer type.4,5 She also correlated the results with 15 different toxin formulations.4
Several things stood out in her analysis. She noted the importance of personalizing treatment with Coley’s Toxins: the individual adjustments he made to ensure the treatment was safe and maximally effective for each patient. Treatment success correlated with the length of treatment and the magnitude of the fever induced by the toxins. The longest remissions, including many cures, were associated with repeated long-term toxin treatment. Some treatments lasted 3–4 years.4
Nauts’s extensive analysis showed that her father had achieved an impressive success rate in treating certain tumors. In fact, many patients fared better with Coley’s Toxins than the standard treatments at that time.3 More than 500 of the approximately 1,000 cases showed near-complete tumor regression.5,7
Nauts published 18 articles and monographs, detailing the use of Coley’s Toxins and related topics, such as the role of fever in cancer remission.4,5,7 Her data compilations were so precise that they are still consulted by cancer researchers for clues about the disease.13
In 1953, Nauts published the results of 30 patients with inoperable cancer who had been treated with Coley’s Toxins.13–15 Amazingly, 20 of those 30 patients had survived more than 20 years.14
Convinced that this was a viable approach, she urged mainstream cancer researchers to reappraise her father’s work and tirelessly championed research on cancer immunotherapy.7,11,13 In 1953, with a $2,000 grant from Nelson Rockefeller, Coley established the nonprofit Cancer Research Institute (CRI) to support scientists and projects that followed up on Coley’s work.2,11,13
CRI has since become a highly respected leader in funding research in immunology and cancer immunology at universities and hospitals worldwide. Virtually every major research institution working in immunology and immunotherapy now has scientists on staff who have been or are currently being funded by CRI.2–4,13
Independent confirmation
Parke-Davis discontinued supplying Coley’s Toxins in 1952.5,7 In 1962, despite Nauts’s advocacy, the Food and Drug Administration (FDA) refused to acknowledge Coley’s Toxins as a proven drug and made it illegal to use for cancer treatment. In 1963, Coley’s Toxins was assigned “new drug” status, which forced anyone interested in this treatment to obtain an Investigational New Drug authorization. That greatly discouraged general practitioners from using Coley’s Toxins.10,11
Despite the new regulatory hurdles, Nauts and the CRI rekindled the medical community’s interest in the link between cancer and the immune system.13 Over the next few decades, researchers explored immunotherapy and went back and forth, arguing whether the immune system could mount an anti-tumor response.7
In 1962, Barbara Johnston and colleagues at Bellevue Hospital used Coley’s Toxins to treat a group of patients who had inoperable metastatic cancers.16 About half of the treated patients showed “some improvement,” in contrast with no change in the control patient group.16
The Johnston group also published a second study to determine which types of cancer responded to the therapy.17 In their conclusion, they noted, “…Coley’s toxin has definite oncolytic properties and is useful in treating certain types of malignant diseases.”17
In 2007, a Phase I trial in Frankfurt, Germany, showed that Coley’s Toxins both induced a fever and caused a robust surge in the patients’ cytokines.11 Half of those patients had a prolonged overall survival.
In 2012, researchers in Rostock, Germany, systematically analyzed the tumor-killing and immunostimulatory effects of a Coley’s Toxins preparation, which they made by heat-inactivating S. pyogenes and Serratia marcescens.8,18 The treatment resulted in an antitumor effect, along with stimulation of innate immune mechanisms, indicating that the heat-inactivated bacterial mixture was responsible for both effects.8,18
Those who scrutinized Coley’s results had little doubt that the bacterial toxins were highly effective in some cases.11 As Frances Balkwill, a researcher at the Imperial Cancer Research Fund in London, said, “I can’t explain why Coley got the results he did, but I’m convinced he got them.”4
Modern immunology
As late as 2001, despite occasional reports confirming Coley’s results, many oncologists remained skeptical that immunological intervention could induce cancer regression.3 But as basic research caught up to Coley, the cellular and molecular mechanisms of inflammation and immunity increasingly indicated that the immune system could, indeed, fight cancer.3,4,7,12
In the mid-2010s, immunotherapy was the hottest area of cancer research, and biotech firms heavily invested in immunotherapy research. About 40% of the 6,000 cancer clinical trials in the US involved some form of immunotherapy.7
Instead of suppressing immunity, cancer immunotherapies activate the patient’s immune system to fight cancer. Scientists have explored various immune-enhancing strategies, including activating immune cells, triggering hormones, CAR-T-cell therapy, and manufacturing new antibodies.11,12
Among the most exciting immunotherapy approaches has been the use of checkpoint inhibitors.12,19 Cancer cells coat their surface with “checkpoint” proteins, which effectively turn off T cells and prevent the patient from mounting an immune response. Checkpoint inhibitor drugs block those checkpoint proteins, thus releasing the brakes on the immune response and allowing a full-scale attack on tumor cells.7,12
In 2011, FDA approved ipilimumab (Yervoy) to treat melanoma.7,12 Metastatic melanoma is an especially aggressive cancer, and 90% of patients treated with standard chemotherapy drugs die within a few years.12 Ipilimumab, a checkpoint inhibitor, blocks a tumor checkpoint protein called CTLA-4. In clinical trials, 20% of the melanoma patients receiving ipilimumab survived for more than five years.12,20
Another checkpoint protein is the programmed cell death protein-1 (PD-1), which resides on T cells and acts as an “off switch,” preventing overactive immune responses. Checkpoint inhibitors that block PD-1 allow the T cells to continue targeting the tumor. In 2014, the PD-1 checkpoint inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo) were approved by FDA.12
Because blockers of checkpoint proteins (like CTLA-4 and PD-1) unleash the immune system (specifically T cells), these treatments theoretically provide clinical benefit for all cancer patients, regardless of tumor type.20 Data showing clinical benefit convinced FDA to approve checkpoint inhibitor drugs to treat melanoma, renal cell carcinoma, bladder cancer, gastric cancer, head and neck cancer, non-small cell lung cancer, Hodgkin’s disease, and even tumors defined by genetic mutations.19–21
Checkpoint inhibitors cause fewer side effects than traditional cancer treatments, but like all drugs, they can cause adverse reactions.21 The aggressive immune response sometimes targets healthy tissues and triggers an autoimmune reaction such as colitis, hepatitis, or thyroiditis. These side effects can be mitigated by early treatment with immune suppressants, which do not appear to hamper the anti-tumor effects.12
In 2018, James Allison and Tasuku Honjo received the Nobel Prize in Physiology or Medicine for their discovery of checkpoint inhibitors to CTLA-4 and PD-1, respectively. Researchers are currently investigating other proteins on tumor cell surfaces that might also be good targets for development of checkpoint inhibitors.12,19
Coley found that his toxins were most effective when used as an adjunct to surgery or radiation and thought that they prevented recurrence of the cancer.11 Similarly, investigators suspect that a multi-pronged approach that combines surgery, radiation, and/or chemotherapy with checkpoint inhibitors will be even more effective than using the checkpoint inhibitors alone.12,20,21
Thanks to Coley
Michael Osband, chief of pediatric hematology-oncology at Boston University School of Medicine, said, “When you look at the history of cancer immunotherapy, I think, to be blunt, we are not much farther along in comparison to Coley…That 20 percent to 40 percent of patients will respond to Coley’s Toxins is, in my mind, incontrovertible, and the same percentage of patients—probably the same actual patients—who would respond to any effective immunotherapy.”4
We still don’t know specifically how Coley’s Toxins worked and probably never will, now that more specific immune modulators are available.4 Those modulators, which include cancer vaccines and a repertoire of other antibody-based therapies, along with the checkpoint inhibitors, hold great promise in expanding treatment options for patients.13 All thanks to William Coley, who is now regarded as the “Father of Cancer Immunotherapy.”
