Using the immune system to fight cancer and other diseases is a not a new concept. In the late 1800s, injection of Streptococcus bacteria into tumors was found by German physicians W. Busch and Friedrich Fehleisen and confirmed in 1909 by American surgeon William B. Coley, MD, to reduce tumor burden in sarcoma and melanoma patients. For Coley’s report on the early use of bacteria to treat cancer and what became known as Coley’s Toxins, read more here.
Around the same time in Berlin, Paul Ehrlich developed the “side chain,” or “receptor” theory, suggesting that cells had proteins that could recognize and bind to molecules he termed “antigens.” His theory paved the way for the concept of drug-specific receptors and thus, immunotherapy [Diagrams of the Side-Chain Theory]. Ehrlich is responsible for postulating that a host immune defense may prevent neoplastic cells from developing into tumors in 1909.
Diagrams of the Side-Chain Theory
Source: Maehle AH. Endeavour. 2009;doi: 10.1016/j.endeavour.2009.09.001. Wellcome Library, London.
Several decades later in the early 1950s, Lewis Thomas first introduced the idea that the immune system could recognize cancer from neoantigens on and released by tumor cells, and Ludwick Gross later demonstrated the ability to mount an immune response against sarcoma in mice via intradermal immunization. Sir Frank Mac Farlane Burnet further developed the immune surveillance theory. Burnet and Thomas are both credited with contributing to the immune surveillance theory in cancer.
In a seminal paper published in 1975 in Nature, Argentinian Cesar Milstein, PhD, and his German post-doctoral student Georges Kohler announced the discovery of monoclonal antibodies. Recall from Module 1, “The Immune System,” antigens are foreign substances that induce immune response. Antibodies are proteins produced by immune cells (lymphocytes) in response to and counteracting antigens. In cancer therapy, monoclonal antibodies are laboratory-produced molecules designed to recognize and bind to a neoantigen. Monoclonal antibodies function in multiple ways. For example, some monoclonal antibodies block the link between cancer cells and proteins that may promote cancer cell growth, while other monoclonal antibodies may carry chemotherapeutic drugs directly into a cancer cell. Milstein and Kohler won the Nobel Prize in physiology and medicine in 1984 for their contribution to science.
Around the same time Milstein and Kohler were publishing data on their discovery of monoclonal antibodies, Donald L. Morton, MD, completed his study of 151 melanoma patients treated with Bacillus Calmette-Guerin (BCG). BCG is an attenuated version of a bacteria (Mycobaterium bovis) that is related to the bacteria that causes tuberculosis. Adjuvant injections of BCG directly into tumors resulted in regression of melanoma in 91% of patients. BCG was also successfully administered in non-muscle invasion bladder cancer patients and is still used today.
Cytokines are soluble proteins that are secreted by different types of cells, both immune and nonimmune, that have an impact on the immune system and are thought to be involved with immune surveillance. Cytokines are pleiotropic, meaning that each cytokine has multiple biological properties, and redundant, meaning they may share biological actions. Many different families of cytokines have been identified for potential use as cancer therapy, starting with discovery of the first interferons in the late 1950s and interleukins in the 1970s. Other cytokine families include tumor necrosis factor, transforming growth factor beta and the extended IL-1 families. Of note, in the 1980s, the first immunotherapy cancer treatment IL-2 was approved by the FDA for the treatment of kidney cancer and melanoma.
Various approaches to immune therapy continue to be developed. Adoptive cell therapy uses a patient’s own blood and tumor to fight cancer. T cells from the blood and tumor are treated in the lab with substances to help them better target the cancer cells. Chimerical antigen receptor T cell (CAR T) and tumor infiltrating lymphocyte (TIL) are two types of adoptive cell therapy. In addition to adoptive cell therapies, immune checkpoint inhibitors and cancer vaccines are at the forefront of cancer immunotherapy, with research advances changing standard practice at an unprecedented rate.
In 2018, James P. Allison, PhD, and Tasuku Honjo, MD, PhD, received a Nobel prize “for their discovery of cancer therapy by inhibition of negative immune regulation.” Their pioneering work on the CTLA-4 (Allison) and PD-1 (Honjo) immune checkpoints in the 1990s proved that these pathways act as “brakes” on the immune system. Their research showed that inhibition of these checkpoint pathways allows T cells to more effectively eradicate cancer cells. This led to the development of immune checkpoint inhibitors, the first class of immunotherapeutic drug that showed clinical benefit across a wide range of cancers, including both solid tumors and hematologic malignancies.
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