In recent years, advances in immuno-oncology have generated a lot of excitement about the future of cancer care. From radical new therapies to combinations with existing approaches, the field is generating a remarkable amount of hope.
While the future looks bright, it is important to understand and revisit the history of immuno-oncology, which dates back to 19th century when William Coley, a prominent New York surgeon, began investigating the phenomenon of feverish infections in cancer patients correlating with cancer remission.
Coley Toxins, the Forerunners of Modern Immunotherapy
Dr. Coley noticed that a cancer patient went into complete remission after two attacks of erysipelas, which resulted in acute Streptococcus pyogenes infection. To experiment with this observation, he injected streptococcal cultures into cancer patients and remarked that tumor regression was achieved in some cases.
He published his landmark findings in 1893, and this paper has served as the foundation for modern immunotherapy. Over the course of more than four decades, Dr. Coley provided treatment to nearly 900 cancer patients with his so-called “Coley toxins.” Most of his patients struggled with inoperable sarcomas and the treatment achieved a cure rate over 10 percent.
Despite the demonstrable success of the treatment, most physicians did not accept Coley toxins as a viable option because of the severe fever induced by the therapy, which they believed was not worth the low cure rate. Immunotherapy gained little traction at this time because studies suggesting the real possibility of immunizing against tumors were called into question.
In these experiments, the tumor-specific immune response observed was actually targeting antigens expressed on healthy tissues. Thus, no theoretical framework existed to support Coley toxins. As a result, scientists generally accepted as fact that the immune system was unable to recognize malignant cells.
During the first few decades of the 20th century, the view that cancer immunizations were biologically impossible persisted. However, Coley toxins did lead to the use of bacilli Calmette-Guerin (BCG) as a cancer immunotherapy. In fact, BCG remains the most effective therapy for superficial bladder cancer to this day.
Frank Burnet, a Turning Point in Immuno-Oncology
Frank Burnet published a paper in 1949 that reinforced the traditional viewpoint. In the paper, he argued that lymphocytes capable of responding to self-tissues were deleted during prenatal development of the immune system. This assertion was later verified experimentally, so scientists accepted that the immune system was incapable of responding to malignant cells, since it was generally accepted that these cells are indistinguishable from healthy tissues.
This latter belief was called into question in the 1950s, when experimenters showed that the immune systems of animals with excised tumors would sometimes reject an injection of the same tumor cells. With these findings, it became evident that antigens must be associated with these tumor cells that are not present on healthy cells, which allowed the immune system to attack them.
During the 1960s, viewpoints on immuno-oncology clearly changed, largely due to additional work by Burnet. His research suggested that the immune system’s function includes the elimination of malignant cells. He hypothesized that lymphocytes continually patrol tissues to eliminate cells that have undergone transformation, a process he called immunosurveillance. Burnet’s ideas were reinforced by a study that examined homograft rejections and attributed them to aberrances in normal processes meant to eliminate tumors.
Changing Attitudes toward Cancer Immunotherapy
Scientists largely abandoned the immunosurveillance hypothesis during the early 1970s, and it did not return to favor until the mid-1990s. This shift occurred for a number of reasons. Theoretically, individuals were unwilling to believe that the immune system evolved to recognize and reject tumors, since acute infections are much more dangerous in the early years of life. Also, some experimental data was published that called the theory into question.
Perhaps the most convincing piece of evidence was the fact that T-cell deficient athymic mice had comparable incidence of tumors as the wild type. However, this experiment was later rejected after finding that the athymic mice actually had significant populations of functional T-cells. Scientists accepted the assertion that the rejection of transplanted tumors was actually tied to tumor-associated viruses, not tumor-specific antigens.
General opinion again began to shift in the mid-1980s, when it was discovered that malignant tumors are extremely genetically unstable. A single carcinoma can have up to 11,000 genomic alterations. This instability could lead to large numbers of novel tumor-associated antigens. Thus, tumor-specific T-cells are not required for an immune response.
Following the 1990s, the conversation has continued to explore the immunosurveillance hypothesis, with scientists attempting to discern why tumor cells would not initiate an immune response. Since 1995, the idea of tumor-specific immunity has remained a productive research area, with a growing body of evidence regarding its potential efficacy.
For example, studies have shown that dendritic cells can be activated and induced to elicit tumor-specific T-cell immunity through the use of tumor-derived peptides. These and other findings have led to the many clinical trials of the last two decades that continue to move the field of immuno-oncology forward.