Long ago I had come across this fascinating story of Coley's toxin and the development of his work into a burgeoning field of scientific study. A brief discussion with an acquaintance who is planning a presentation on immunotherapy and the recent interest in the use of bacterial DNA for cancer immunotherapy, made me revisit the article where I had first read about Coley's work. And I must say, the article by Frances Balkwill in Nature Reviews Cancer, tiled as "Tumor necrosis factor and cancer" manages to do a wonderful job at tracing the history of TNF (which is a ubiquitous factor in immunology jargon these days) and our present understanding of the same. It is a fascinating story that makes one really appreciate the hidden lessons in history and the sheer brilliance of scientific methodology. This story is also a great example for how serendipity knocks on our doors ever so often and then it is completely in our hands to make something out of the opportunity. William Coley did that and his life’s work is remembered long after he is gone as a landmark phenomenon we are still trying to understand. Such is the wonder of science and history plays a vital role in our understanding of science.
William Coley, a New York surgeon in the late 1800's was an expert surgeon and a very observant man. His fascinating work in 1890, at the start of his career laid the foundations of cancer immunotherapy and the role of bacterial toxins in the same. History says that in 1890, Coley was called in to treat a 17 year old woman who had a nagging pain in her right hand. However, in spite of Coley's expert surgical intervention, Elizabeth Dashiell died a few months later of an aggressive round cell sarcoma that disseminated at an alarming speed through out her body.
As an interesting footnote, Elizabeth Dashiell was a close friend of J D Rockefeller Jr and her death was an inspiration for the philanthropic work of his family which continues to this day in the form of the Rockefeller institute for medical research or the now Rockefeller University. It is amazing how much influence one person's death can sometimes indirectly have on history. Other than the extremely moving effects of Elizabeth's death on Rockefeller, its effect on Coley was also remarkable and this death heralded the beginning of our story. Dashiell's death had a profound effect on Coley as he immersed himself in pouring through hospital records to learn more about this rare but devastating malignancy.In his studies of the sarcoma induced deaths, Coley found an intriguing anecdote: the case of a German immigrant who 6 years previously had been dying of a large facial tumour. Fred Stein’s fate seemed to be sealed when a post-operative bacterial infection took hold but, as the fever subsided, the sarcoma has regressed. With dogged determination at this point, Coley searched the lower east side tenements for a man with a scar, and he found Stein alive and well 6 years after the surgery. Coley did not give up now. He began a line of enquiry which he pursued for is entire lifetime. Going by the case history of that one man, Coley first infected cancer patients with bacterial isolates, and then he made “Coley’s mixed toxins”, slightly less dangerous filtrates from cultures if Streptococcus pyogenes (the bacteria that causes Erysipelas) and Gram-negative endotoxin-producing Serratia marcasens. The work was controversial (not unexpected!) and few were able to reproduce the beneficial effects that Coley obtained but, if the published case histories are to be believed, Coley was able to obtain a rapid and sustained response in patients who would present a major challenge to the medical oncologists’ in the 21st Century.
With the developments in radiotherapy and chemotherapy, the interest in Coley’s toxins waned over time but some scientists were still attempting to reproduce his results in animal models of cancer and under the principle underneath. One of the earliest studies was in 1931, when Gratia and Linz showed that bacterial extracts caused tumour necrosis in guinea pig model of Sarcoma. In 1944, another report by Shear et al, isolated lipopolysaccharides from bacterial extracts and showed them to be responsible for the tumour regression seen in a mouse model of cancer. Work by O’Malley showed that the serum from endotoxin-treated animals was also capable of causing tumour necrosis, thus leading to the conclusion that it contained a “tumour necrotizing factor”. The entire field made a leap in understanding when in 1975 Carswell et al, reported that it was a factor made by host cells in response to endotoxin and not the bacterial endotoxin itself that destroyed the tumours. Thus, the term “tumor necrosis factor” was coined to describe this activity, reportedly produced by macrophages, which led to the necrosis of both mouse and human tumours.
The next two decades marked the identification of this elusive tumour necrosis factor and it was soon realised that this protein belonged to a family of related cytotoxic proteins. By the 1990s, in addition to the TNF, the genes for the two receptors which bind to TNF were also cloned. By mid 1990s, it was becoming clear that neutralizing antibodies and soluble receptor fusion proteins targeting this cytokine TNF would be successful treatments for a range of human inflammatory diseases and the cytokine itself was under investigation as a cancer therapeutic. In good agreement with the research done for the previous 40 years, recombinant TNF induced necrosis of both syngeneic and xenografted tumours. TNF was injected locally and repeatedly and it managed to cause a regression except in the periphery where there was a risk of regrowth. The tumour necrosis caused by TNF was found to be haemorrhagic in nature with major destruction of the vascular bed which was believed to lead to increased tissue concentrations of the administered chemotherapy.
However, the course of scientific research never really runs smooth and by around 1987, intriguing reports started to emerge which demonstrated increased presence of TNF mRNA and protein in cancer biopsies and blood plasma of the patients. There were also these paradoxical observations that suggested that TNF might actually stimulate tumour growth. By the early 1990s however the entire TNF saga was one giant cauldron of confusion as reports found TNF to contribute to oncogene activation and DNA damage. Long term TNF treatment was found to result in transformation of immortalized cells. These studies thus raised the possibility that TNF might actually be a target instead of a treatment and that it might be beneficial to neutralize TNF activity in cancer patients. This was tried in Phase I and II clinical cancer trials with TNF antagonists as single agents, with some evidence of clinical activity. Even today the role of TNF antagonists in cancer prevention is not clear as some of the studies suggest a role for TNF in the promotion of early cancers, but then given our current understanding of the role of TNF in regulating innate immunity, the increased risk of infection precludes the wider use of the current TNF antagonists. However, TNF antagonists are being used for the treatment of chronic inflammatory diseases like rheumatoid arthritis and the incidence of cancer under these conditions is being monitored closely.
Our current understanding of TNF is quite a mixed bag and as the TNF timeline moves into the future a number if questions remain to be answered. How can we explain the apparent efficacy of Coley’s missed toxins and the long but anecdotal history of cancer regression associated with acute bacterial infection? Can the tumour necrosis ability of TNF be harnessed without promoting cancer or inducing a cytokine storm? Will TNF antagonists have a more important role in cancer therapy and if so then under what conditions must it be administered?
Our understanding of Coley’s work although still not completely clear has had some significant strides. We now realise that Coley’s mixed toxins must have been powerful stimulants of TLRs thereby inducing a range of inflammatory mediators, not just TNF. As a closest recent approximation to Coley’s work, bladder cancer was reportedly successfully treated with Bacillus-Calmette-Guerin. The current thinking is that probably both the BCG and the Coley’s toxins trigger an inflammatory response through the TLRs which not only stimulates macrophages to kill the tumour cells but also promotes the development of sustained and effective adaptive immunity to the tumour. This type of a response may also contribute to a more successful chemo or radiotherapy as dying tumour cells were able to cross-present the antigen to the dendritic cells in a TLR4 the efficacy of chemotherapy and radiotherapy was reduced.
Interestingly, in 1949, Coley’s daughter, Helen Colet-Nauts reviewed the case histories of the 484 patients who were treated with the toxin preparations an recorded that approximately 50% of his patients were alive 5 years after the treatment began. The toxins were given both locally and systemically for maximum effectiveness and the treatment was continued for long periods ranging from months to even years.
The history of TNF is interesting in many ways. It began with a serendipitous discovery and with the dogged determination of one man. TNF shows us how inflammation can have both positive and negative effects on cancer and how its effects will have to be controlled and manipulated to attain the desired effects (In an anthropomorphic explanation, TNF like us has a good and bad side and it depends on the situations and the context as to where which instinct dominates!). The kind of work done by Coley is certainly no longer possible in a world dictated by social rules and norms (as it is today) but despite all the legal and ethical obligations, one must remember the preliminary insight which was provided by Coley which has laid the foundations of an entire field of cancer immunotherapy. It was his preparedness to observe and analyze, his dogged determination and his ingenuity that has opened new vistas and no matter in what time scale we live, these are the qualities that propel science forward.
