Hands down, cancer immunotherapy is one of the most exciting ones. News media reports on blockbuster cancer immunotherapy results are thick and fast these days. A newcomer could be forgiven for thinking such a close overlap between cancer and immunology has always been par for the course but nothing could be further from the truth. As recently as the 1970s, an immunologist choosing to study immune responses against tumors was committing career suicide. Instead then tumor immunology was a ‘a seedy intellectual neighborhood of fantasy and wishful thinking, a landscape littered with the hulks of abandoned hypotheses and charred reputations‘ ().
20th century prospects of immune treatments for cancer started out on a very different note. Hardly anything known about immune function, yethad spectacular success treating a great variety of tumors in thousands of patients using , a mish-mash of bacterial cultures and toxins he called Mixed Bacterial Vaccine (MBV). His daughter painstakingly tracked down many of the patients he treated, showing they survived for years, even 88 years in one case ( ). All this with just Coley’s MBV, no surgery or radiation. But after his death, MBV Rx rapidly faded.
The 1961 thalidomide tragedy inspired the Kefauver Harris Amendment, i.e., stricter scrutiny for new Rx. This changed regulatory landscape incentivized patentable products for drug licensing. A natural substance, MBV wasn’t patentable. In the vacuum, chemotherapy and radiotherapy quickly rose to dominate from the 1960s. At the same time, knowledge of immune responses improved by leaps and bounds. Yet such knowledge only convinced immunologists that the immune system had nothing whatsoever to do with cancer. After all, in their hands, it pretty much seemed to ignore tumors.
Thus today’s spectacular results, albeit in a handful of patients, are the result of a rapid pendulum swing from one end to the other, a swing made possible by exponential technological advancements that changed how immune function was perceived. Starting in the 1990s, it became clearer how innate immunity got the ball rolling. Technical improvements made using them to jump-start T cell responses easier. Appreciation of what T cells were capable of expanded. With such data, T cells driven to attack tumor cells was no longer a heretical notion. That was on the T cell side. On the B cell side,and ‘s Nobel worthy technical achievement, the monoclonal antibody, was tailor-made for fighting tumors. Exquisite specificity and sensitivity of antibodies for their targets could be exploited for anything from directly glomming onto tumors and destroying them to helping reverse the brakes tumors place on immune cells. T and B cell attack on tumors thus became feasible. Field’s moved so fast, in <10 years we have >30 companies focused on cancer immunotherapy.
Brings us back full circle to Coley. How did he hit upon the notion that bacterial toxins could be used to cure tumors? No obvious connection between the two. Genesis for Coley’s idea starts at a rather unlikely place. Spontaneous cancer remissions. Rare enough to be well reported in medical literature, since the 18th century, fever and cancer remission were known to be linked. By Coley’s time, such fevers were known to be infectious in origin, specifically bacterial. Reviewing these cases Coley hit upon the idea of using bacterial extracts to induce the same ‘fever’ effect, believing it would yield the same outcome, cancer remission. Modern cancer immunotherapy works to the same end, only it doesn’t mimic an acute bacterial infection but rather recreates its effect, a highly activated immune response. Biggest difference is Coley’s crude extracts could only do much before they ran out of steam while an amped up immune response could be self-sustaining once in the body. Thus the cautionary note is too much collateral damage may dim the promise with inevitable backlash still very much a possibility.
1. Kienle, Gunver S. “Fever in cancer treatment: Coley’s therapy and epidemiologic observations.” Global advances in Health and Medicine 1.1 (2012): 92-100.