CAR-T cells, oncolytic viruses, cytokine therapies, antibody therapies… The list of immune therapies seems to be ever expanding. With the 2018 Nobel prize going to the discoverers of immune checkpoint inhibitors, the topic of cancer immunotherapy seems hotter than ever. Are you interested to explore some of the landmarks in the history of cancer immunotherapy, to discover the state of the art today, and to see what lies in store in the future? If so, then read on…
The story of cancer immunotherapy starts with a certain gentleman named William B. Coley, an orthopedic surgeon working at the Hospital for the Ruptured and Crippled (yes, this is the 19th century). Over the span of his career, Coley would treat many sarcoma patients, for whom the finest treatment back then consisted of mere amputation. One of the first of such patients was eighteen-year-old Bessie Dashiell.
Bessie injured her hand by getting stuck between the seats of a passenger train. Over the subsequent weeks, the injury did not subside, and she noticed her injury became increasingly swollen and painful. Coley, only twenty-eight at the time, met Bessie during his first year of private practice. Coley expected the symptoms could best be explained by periostitis. However, Bessie’s injury still did not heal, while her symptoms only got worse over time. After performing a repeat biopsy and sending the specimen for pathology, it was revealed that Bessie suffered from sarcoma.
Coley did what any 19th century orthopedic surgeon could do. He amputated Bessie’s hand, while leaving her with some length of arm for daily functioning. Unfortunately, by that time the tumor had already metastasized. Bessie declined rapidly and in a dramatic way, with grotesque lumps appearing almost everywhere in her body. Bessie emaciated to become a skeletal form of her former self. There was nothing Coley could do in the way of a cure, and within 2 months Bessie died with Coley at her bedside.
Bessie’s story proved to be “quite a shock” for the young Coley. In fact, it would prove to be the impetus that set him off in his pursuit of what was to become history’s first cancer immunotherapy. Coley decided to analyze the medical files of all those patients in his hospital that had presented with a sarcoma similar to Bessie’s. In doing so, he hoped to find an exception to the inevitable decline that always seemed to accompany it. Although it took Coley seven years, he found his exception. His name was Fred Stein.
Although Fred had presented with a sarcoma much like that of Bessie, he had walked out of the hospital with no signs of remaining disease. He had been operated on five times, but every time the tumor came back with a vengeance. The operations had left him with open wounds, which became infected with Streptococcus pyogenes. While Fred almost died from this infection, it may have paradoxically saved his life. His body mounted an immune attack against the bacterium, and, together with the infection, the sarcoma disappeared as well.
Coley noticed the correlation. His hypothesis was that the bacterium released a certain toxin that caused the tumor to regress. A literature search revealed similar cases to Fred’s. In a bold move that would not easily pass medical ethics committees nowadays, he then decided to purposely infect sarcoma patients with S. pyogenes. The first of these lucky patients was a man named Zola. He suffered from a sizeable tumor in his right tonsil, and did not have much longer to live. Upon infecting the patient, the tumor likewise regressed. Zola lived another eight years.
Not all of Coley’s patients were so lucky, however. In fact, two of them died directly due to the infection. Coley then decided to change the ingredients, from live streptococci to a cocktail of two dead bacteria, named Coley’s toxins. Coley’s toxins were to be used against different types of cancer all the way from 1893 to 1963. However, there was much initial and enduring skepticism. The medical community much favored the new radiotherapy treatments that were born out of the physics of X-rays. One of Coley’s leading opponents, James Ewing, even favored radiotherapy over all other approaches to cancer. Indeed, Ewing actively suppressed the employment of Coley’s toxins in the treatment of sarcoma – ironically a sarcoma that would later come to bear his very own name.
Perhaps the greatest obstacle for the scientific and medical community to accept the approach taken by Coley was a lack of understanding. It was utterly unknown how Coley’s toxin worked to produce its clinical results. The underlying immunological mechanisms were not yet known. The connection between Coley’s toxins and immunology was all but lost on Coley’s contemporaries.
However, Coley’s legacy can hardly be overstated. From his initial observations, Coley gave the first impetus to the development a field, where discovery after discovery have led to a vast expansion in our fundamental understanding of immunology, and which would eventually culminate in the state-of-the-art cancer immunotherapies being researched and employed today. A similar strategy to Coley’s would re-appear in 1976. Bacillle Calmette-Guérin (BCG), a tuberculosis vaccine, was to become the standard of care in the treatment of bladder cancer, and remains so to this day.
Meanwhile, in 1909, Paul Ehrlich formulated the first hypothesis of cancer immunosurveillance. Ehrlich thought the host immune system may play a vital role in preventing neoplastic cells from progressing into full-blown cancers. It would not be until 1953, however, that the first hints of the mechanisms of such an immunosurveillance would surface. The late Lewis Thomas, physician and polymath, proposed that the immune system recognizes the expression of neo-antigens on the surface of tumor cells. Thus, our defense systems are able to recognize newly developing tumors and eliminate them. This was subsequently developed into a more full-fledged model by Frank Burnet.
The modern era of cancer immunotherapy finally took off. Some important landmarks were: the discovery of interferon (Isaacs/Lindemann); the founding of the New York Cancer Research Institute by Coley’s daughter, Helen Nauts; the first cancer vaccine study in humans in 1959 (Ruth/Graham); the identification of IL-2 in 1976, allowing T-cells to be cultured in vitro for the first time; the first-time production of monoclonal antibodies (Milstein/Köhler), realizing Ehrlich’s dream of creating ‘magic bullets’; the first discovery that CTLA-4 blocking antibodies could treat tumors in animal models in 1996 (Leach, Krummel and Allison); and the first immune checkpoint inhibitor, a CTLA-4 antibody (ipilimumab), receiving FDA approval in 2011 for the treatment of metastatic melanoma.
We are now living in the era of advanced immunotherapy combinations, CRISPR-CAS genome editing technology, third class immune checkpoint inhibitors, fourth generation CAR T cells, you name it… In the next installment of this series, I will tell the story of where the best of cancer immunotherapy is at today. What is the current state-of-the-art? What benefit can be expected from this for cancer patients? And what are the potential dangers?