A Snapshot of Early Immunotherapy

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Thucydides, a Greek historian, first recorded resistance to a specific disease in 430 B.C.

Edward Jenner, MD

Louis Pasteur, ScD

William Coley, MD

Over the past several years, immunotherapy has had a renaissance of sorts, emerging as one of the most active areas in cancer research. This pioneering line of cancer treatment has been around, in one form or another, for centuries.

Over the past several years, immunotherapy has had a renaissance of sorts, emerging as one of the most active areas in cancer research. For instance, we have seen the therapeutic promise of disrupting the programmed cell death protein 1 (PD-1) and its ligand (PD-L1) immune checkpoints in cancer, which has encouraged large clinical studies in this and other promising investigations in immune therapy. And although immunotherapy’s potential is now energizing the oncology community, this pioneering line of cancer treatment has been around, in one form or another, for centuries.

The First Clinical Trial

The early paradigm that shaped the development of most cancer therapies, until recently, was grounded in the observations based on infectious disease. And those observations began early in human history. Thucydides, a prominent Greek historian, first recorded resistance to a specific disease in 430 B.C. After the devastating plague of Athens, Thucydides, a survivor himself, noticed that the disease never attacked the same survivor twice. In his writings, he postulated that those surviving the plague had acquired some uncanny form of resistance to the disease, which is one of the first known observations of the immune system in action.

The first recorded immunotherapy trial was conducted in Newgate Prison, London, in 1721. During her travels, the Princess of Wales had heard of miraculous resistance following deliberate or accidental exposure to smallpox exposure. Fearing her children might contract the dreaded disease, she granted Charles Maitland, MD, permission to perform a trial on six condemned prisoners. The subjects were infected with pus from individuals who had smallpox, and then he exposed them to active cases. All of the prisoners on the “smallpox trial” survived; out of gratitude for their participation, they were released from prison 1 month later.

In 1796, the British physician, ­Edward Jenner, MD, demonstrated that the deliberate infection with the Vaccinia virus, which caused cowpox—an infection akin to smallpox but much weaker—was protective against smallpox. Building on Dr. ­Jenner’s work, Louis Pasteur, ScD, in the 1880s, demonstrated that immunity to one condition protected patients against reexposure to the same condition, without affording protection to an unrelated condition.

Dr. Pasteur’s experiments also showed for the first time that artificially mitigated pathogens could be effective protective agents against disease. Dr. Pasteur named these agents “vaccines” in honor of Dr. Jenner’s work with the Vaccinia virus. This groundbreaking research would lead to smallpox vaccinations, which eventually eradicated the scourge of smallpox, saving countless millions of lives.

Infectious Disease and Tumor Immunology

As our knowledge of the specifics of tumor immunology expands, we will be able to fully capitalize on the exquisite specificity of the immune system’s ability to treat cancer in highly targeted ways, with minimal side effects. The earliest reports of an immune response related to cancer came from the documents of a priest named Peregrine Laziosi, who was born around 1260, in northern Italy.

In his early 40s, Peregrine was conducting his business as a resident priest—converting and reconciling sinners—when he noticed a growth emerging on his leg. It was on his tibia, and the leading doctor of the day pronounced it as malignant. The lesion grew to the point where it broke through the skin and became severely infected, “giving off such a stench that it could be endured by no one sitting by him.”

His only option was to have the diseased leg amputated. A few days before the brutal procedure was to take place, the physician was astonished when he noticed that there was no sign of cancer. Naturally, the physicians in the 11th century did not ponder whether a spontaneous febrile immune response saved Peregrine; they concluded it was a miracle. The priest’s cancer never recurred, and he lived to the ripe old age of 85. Several centuries later, he was canonized as the patron saint of cancer.

Using the immune system to battle cancer began to gain traction in 1866, when noted German physician, ­Wilhelm Busch, MD, observed that some of his patients with sarcomas had tumor regressions after surviving postoperative wound erysipelas, an infection with a bacterial species of Streptococcus. Intrigued by this phenomenon, he deliberately infected a postoperative sarcoma with pus from another patient with postoperative erysipelas in an attempt to induce tumor regression. He did, but it was minimal and short-lived. Dr. Busch’s attempt at generating a spontaneous cancer-killing immune response was one of the earliest forays into cancer immunotherapy.

The Father of Immunotherapy

A physician named William Coley, MD, now regarded as the “Father of Immunotherapy,” took immunotherapy to the next level. Dr. Coley began his career as a young surgeon at New York Memorial Hospital. His search for new ways to treat patients with cancer began after the loss of his very first patient.

A 17-year-old woman who had injured her hand presented with persistent pain and inflammation. Dr. Coley diagnosed her lesion as a sarcoma of the bone and opted to amputate her right arm below the elbow. Despite no evidence of metastases, the young woman died of her disease 2 months after surgery, leaving Dr. Coley shaken by his clinical failure.

He spent months pouring through the literature; he discovered the record of an immigrant patient who presented with an egg-sized sarcoma on his left cheek. The tumor was excised twice but recurred after each surgery. The patient was considered terminal. However, a wound after the last surgery resulted in severe erysipelas infection, and the patient developed a very high fever. Little could be done to control the fever, yet after each spike, the tumor shrank and finally disappeared. The patient was discharged 4 months later.

Dr. Coley spent weeks searching the Lower East Side for the patient, eventually finding him. The man told Dr. Coley that he had no trace of cancer and felt fine since his discharge from the hospital, 7 years ago. Energized by this sarcoma patient’s success, Dr. Foley continued to search for more evidence, eventually discovering a number of cases in which patients with cancer went into spontaneous remissions after developing erysipelas infections and high fevers.

In 1891, Dr. Coley began injecting mixtures of live and inactivated Streptococcus pyogenes into his patients’ tumors. He achieved responses in several types of malignancies, including sarcoma, lymphoma, and testicular carcinoma. His further work in immunotherapy resulted in a vaccine called Coley’s Toxins, with which he treated hundreds of patients with cancer, with varying degrees of success. After an initial response to his vaccine, many of his patients died from the infections, as his experimental work predated the development of antibiotics.

Shortly before Dr. Coley’s death in 1936, Coley’s Toxins received an endorsement in the New and Nonofficial Remedies of the American Medical Association, which stated: “Its use as a prophylactic in conjunction with conservative or radical surgery’’ and ‘‘inoperable cases may be quite justified.”

However, the lack of a known mechanism of action for Coley’s Toxins and the risks of deliberately infecting cancer patients with pathogenic bacteria caused oncologists to adopt surgery and radiotherapy as standard treatments early in the 20th century.

Hit and Miss

Using attenuated bacteria to treat malignancies resurfaced in 1976, when a trial was conducted to test the tuberculosis vaccine Bacille Calmette-Guerin as an agent to prevent the recurrence of nonmuscle invasive bladder cancer. This therapy proved effective and is still used today.

However, although promising from a theoretical standpoint, several misfires occurred, and dedicated research in immunotherapy went into dormancy, as promising combination regimens and targeted therapies were developed. However, the promise of harnessing the immune system’s power to eradicate cancer cells was reinvigorated, and we have seen a decade of promising research.

This year, ASCO recognized immunology pioneer James P. Allison, PhD, awarding him the Society’s Science of Oncology award. Dr. Allison’s research focuses on new drug development that blocks checkpoints or stimulates the immune system. Dr. Allison, and many others in the oncology community, is confident that this line of therapy, which has stirred the interest of clinicians for centuries, will eventually prove be an invaluable tool in our fight against cancer.  ■