OCT 18, 2021 3:00 AM PDT

The History of Immunotherapy: Toxins, Targets & T Cells

WRITTEN BY: Katie Kokolus

Cancer immunotherapy, a treatment that directly enhances a patient’s immune system, is typically perceived as a modern innovation. However, scientific attempts to modulate the immune response to combat cancer occurred as early as the nineteenth century. Indeed, the discovery, development, and improvement of cancer immunotherapy embody a rich history.

Early indications of immune modulation impacting cancer growth involved the use of bacterial toxins. Two German physicians, W. Busch and Friedrich Fehleisen, independently noted spontaneous tumor regressions in patients accidentally infected with erysipelas, a bacterial infection of the skin.  Following these anecdotal observations, Busch noted tumor shrinkage after intentionally infecting a cancer patient with erysipelas in 1868. By 1882, Fehleisen identified the specific bacterial toxin, Streptococcus pyogenes, which caused erysipelas, resulting in tumor regression patients with several cancer types.   

Following these discoveries, attempts alter the immune system for cancer treatment began in the United States.  William Coley inoculated a sarcoma patient, Signor Zola, with bacteria. Remarkably, Zola lived an additional eight months due to this treatment.  Coley’s work encompassed over 1,000 tumor regressions and cures of patients with various malignancies, including lymphoma, sarcoma, and testicular cancer. “Coley’s toxins” became commercially available in 1899; however, many oncologists feared infecting their patients with bacteria, rendering toxin-driven immune-based therapies all but forgotten by the medical community for decades.  

The mid-1900s saw the discovery of critical immune mediators known as T cells.  A team in Australia, first described T cell functions in mice in 1967. It wasn’t until 1982 that James Allison and his colleagues Bradley McIntyre and David Bloch characterized T cells receptors. Nine years later, a team in Belgium published the first account of T cell recognition of human melanoma antigens. In 1996, Allison’s team discovered that blockade protein called CTLA-4, which downregulates the immune response to prevent auto-immunity, caused tumor rejections in mice. Researchers correlated another subset of T cells that confer long-lasting immune memory with clinical response in colorectal cancer patients a decade later.  

Immune checkpoint inhibitors (ICI) have emerged as a promising approach to treat many cancers. ICIs target specific markers on immune or tumor cells allowing the immune system to attack cancer cells. In 2011, the Federal Drug Administration (FDA) approved the first ICI, a CTLA-4 inhibitor called Ipilimumab. The discovery and development of this therapy won Allison a Nobel Prize in 2018. In 2016, two additional ICIs, anti-PD-1 (pembrolizumab) and anti-PD-L1 (atezolizumab), were FDA approved.

Chimeric antigen receptor T (CAR T) cells are showing significant promise in treating many cancers, including leukemia. After extracting T cells from a patient, CAR T cells are engineered to recognize and target markers found on cancer cells. These therapies are revolutionizing the therapeutic landscape.

While immunotherapies can generate long-lasting immunity in cancer patients, notably even patients with late-stage and hard-to-treat malignancies, still, only a small number of patients respond. However, immunotherapies are at the forefront of cancer research, and scientists report encouraging developments regularly. The next era of immunotherapy is poised to generate tremendous advances and novel treatment options for cancer patients.  

Sources: W. Busch and Friedrich Fehleisen, erysipelas, William Coley, Australia, Belgium, blockade, CTLA-4, memory, ICI, Ipilimumab, Nobel Prize, anti-PD-1, anti-PD-L1, CAR T

About the Author
Doctorate (PhD)
I received a PhD in Tumor Immunology from SUNY Buffalo and BS and MS degrees from Duquesne University. I also completed a postdoc fellowship at the Penn State College of Medicine. I am interested in developing novel strategies to improve the efficacy of immunotherapies used to extend cancer survivorship.
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