Cancer Immunotherapy and Coley’s Toxins

New-generation “immune checkpoint inhibitor” drugs work in many cancer types, particularly the skin cancer malignant melanoma . Instead of killing cancer cells directly, they support the patient’s immune system, enabling it to function.

Although these drugs are new, the idea of treating cancer by activating immunity is old, belonging to a young surgeon willing to think differently 100 years ago.

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The young surgeon’s name was William Coley. In late summer 1890, he was preparing to examine a new patient in New York, unaware this young woman would change his life and cancer research’s future.

Elizabeth Dashiell, known as Bessie, was 17 and came with a hand wound. It seemed minor, with a small swelling, but would not heal and was very painful. Other doctors had failed to diagnose it correctly.

Coley initially thought infection, but biopsy revealed an advanced malignant cancer called sarcoma.

Little could be done then. This was before radiotherapy and chemotherapy . Coley therefore did the only thing possible, amputating Bessie’s right arm below the elbow to stop spread. It failed; within 1 month cancer spread to her lungs, liver and whole body through metastasis .

Bessie’s painful final days were heartbreaking. Coley was with her when she died on 23 January 1891. Her death deeply affected young surgeons.

It spurred Coley to act. Little was known about cancer, so he reviewed dozens of old records at New York Hospital, seeking anything to explain this ruthless, aggressive disease.

Coley believed that whenever an exceptional biological situation occurred, he should ask, “Why did this happen?”

He found such an exception in German immigrant Fred Stein, a New York Hospital patient 8 years earlier. Repeated neck tumor removals had failed as it returned after each operation, and doctors expected him to die.

Stein then contracted a streptococcal bacterial skin infection with fever . His days seemed numbered, but he survived; his tumor disappeared and he was discharged. Coley wondered whether he remained alive years later.

In winter 1891, surgeon William Coley became detective William Coley, searching German immigrant neighborhoods on Manhattan’s Lower East Side door to door for Stein with his conspicuous neck scar. After weeks, he found him alive and cancer-free.

He questioned why cancer disappeared and never returned after bacterial infection, thinking streptococcus had reversed it. What would happen if he reproduced this by injecting bacteria into patients?

He tried in seriously ill patients, first Italian immigrant Zola, with sarcoma like Bessie. Throat tumors made eating, talking and even breathing difficult. Coley spent months trying to induce streptococcal infection but obtained insufficient response.

He then used stronger bacteria. Zola developed a severe febrile infection that could easily have killed him. Within 24 hours, his orange-sized tumor began shrinking.

Zola recovered completely. Coley knew he had found something and continued research and bacterial use. He called this cancer treatment through febrile infection Coley’s toxins .

It was exciting; unprecedented successes were applauded in America and abroad. Others also found febrile infections useful (Busch 1866, Fehleisen 1883, Eschweller 1898, Schmidt 1910, Wolffheim 1921, Braunstein 1929, Engel 1934, Sinek 1936, Schulz 1969). Nobody, including Coley, understood why toxins sometimes worked and sometimes failed. Later it became clearer that febrile infection triggered mechanisms activating and regulating immunity, similarly to today’s immunotherapies, but through different mechanisms.

The immunity-cancer relationship remained mysterious until the 1990s. Overshadowed by directly cell-killing chemotherapy, immunity’s importance began emerging after the 90s through Professor Dr. James Allison’s work.

Radiotherapy’s development in the early 1900s overshadowed interest in the toxins. After Coley’s death in 1936, daughter Helen Coley Nauts reviewed his notes for a biography, concluding he had treated many patients. However, subsequent studies could not clearly reproduce these successes.

Researchers since learned more about immunity and developed modern immunotherapies, now yielding successful cancer outcomes. Beyond melanoma, immune-powered treatments can be used in kidney, lung, head and neck, stomach, leukemia and bladder cancers.

For every treatment harnessing immunity against cancer, respect is due to Willim Coley’s work begun 100 years ago.

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