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Oiseth et al. Cancer immunotherapy

rate was less than 10% . Combination therapy
[3]
with another immunotherapeutic agent shows even
greater promise, as seen when the addition of another
checkpoint inhibitor antibody, nivolumab, a monoclonal
antibody (mAb) which targets the PD-1 receptor on
T-cells, produced a 50% response rate in metastatic
melanoma [4,5] . CI has also shown effectiveness in other
types of malignances, and combinations with different
treatment modalities (“immuno-oncology”) are also
showing remarkable benefits [6,7] .

HISTORY OF OUR KNOWLEDGE OF THE
IMMUNE SYSTEM’S ROLE IN CANCER

It has been known for many years that the immune
system plays a major role in neoplastic development
and control, since patients who are immunosuppressed
have a higher risk of cancer, and spontaneous regression
of many types of malignant tumors is a rare but well-
recognized phenomenon-occurring in approximately 1
in every 60,000 to 100,000 cancer cases [8-10] .
Figure 1: An article in a major U.S. newspaper printed in 1908
Throughout history there are multiple accounts about reflects the widespread attention given to Coley’s toxins
tumorous growths regressing or disappearing after
an infectious and/or high febrile episode, having been cancer. Nonetheless, after no fewer than five marked
reported from ancient Egypt up to the early 18th shifts in attitude toward CI since the 1890s , Coley’s
[16]
century in Europe, but the scientific basis for attempts principles have been shown to be correct, and the use of
at modulating the immune system to treat cancer can bacteria finally found sound justification in 1976 when
find its modern roots only in the second half of the 18th [17]
century, when histologic confirmation of a malignancy Morales et al. established the effectiveness of
the bacterium Bacillus Calmette-Guérin (BCG) in
became possible. More than 135 years ago the German the treatment of superficial bladder cancer. The
physicians Busch and Fehleisen [12] independently underpinnings for this clinical trial include a 1959 study
[11]
noticed regression of tumors in cancer patients after [18]
accidental infections by erysipelas. In 1868, Busch by Old et al. showing the anti-tumor effects of BCG
was the first to intentionally infect a cancer patient with in a mouse model. Besides his work on BCG, Old
also performed extensive research on other CI-related
erysipelas and he noticed shrinkage of the malignancy. topics, and was a discoverer of tumor necrosis factor
[12]
Fehleisen repeated this treatment in 1882 and he also [19]
eventually identified Streptococcus pyogenes as the in 1975 . Due to their foundational discoveries and
causative agent of erysipelas [12,13] . In 1891, an American lifelong dedication to the field, Coley and Old have each
surgeon, William Coley, of the Bone Tumor Service been referred to as the “Father of Immunotherapy”, a
at Memorial Hospital in New York, followed up on his title which is perhaps best shared.
own independent observation of a long-term regression
of a sarcoma after an erysipelas infection by starting Even viral infections were believed to have a cancer-
a 43-year-old project involving the injection of heat- suppressive effect as far back as 1904 when George
inactivated bacteria (“Coley’s toxins”) into patients with Dock at the University of Michigan described a 42-year-old
inoperable cancers [14] . He reported a significant number woman with acute leukemia who experienced a temporary
of regressions and cures in more than 1,000 patients, remission after a presumed infection with influenza in
[20]
many or most with sarcomas, and the method started 1896 . At the same time, a better understanding of
gaining wide acceptance and notoriety [15] [Figure 1]. the immune system was being developed, including
His toxins gradually disappeared from use because discoveries about cellular and humoral immunity [Table 1].
of several factors, including his failure to follow good
scientific protocols and inability to consistently obtain THE IMMUNE SYSTEM’S ROLE IN ELIMINATING
reproducible results. The development of radiation OR CONTROLLING MALIGNANT CELLS
therapy and chemotherapy also contributed to the
loss of interest in using this type of therapy to treat As a brief background review, the immune system is
Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ October 31, 2017 251