What is the role of innate immune system activation in immunotherapeutic targeting in pediatric oncology?

Updated: Mar 20, 2018
  • Author: Crystal L Mackall, MD; Chief Editor: Jennifer Reikes Willert, MD  more...
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Answer

William Coley, MD, a pioneering surgeon who practiced medicine at Memorial Hospital in New York City from 1890 to 1936, is regarded as the father of cancer immunotherapy. [10, 11] In his practice, he focused on the treatment of sarcomas and developed a firm belief that activation of endogenous immune responses could induce remission of tumors. This conviction arose from reports and direct observations of spontaneous tumor remissions that were temporally related to bacterial infections and were primarily observed in patients with sarcoma.

Coley subsequently produced crude bacterial extracts that were eventually termed “Coley toxins” and were administered to patients with cancer. In some cases (albeit relatively infrequently), dramatic antitumor effects were observed. Ewing sarcoma was one of the tumors in which Coley observed antitumor responses using this approach. [10, 12]

During the same period in which Coley was observing dramatic tumor responses with Coley toxins, the spectacular radiosensitivity of Ewing sarcoma was observed by James Ewing, MD, the physician-in-chief at Memorial Hospital. This led to a rivalry between advocates of immunotherapy (in the form of Coley toxins) and advocates of radiotherapy (such as Ewing). [11] For various reasons, not the least of which was difficulty in standardizing the toxins, immunotherapy was eventually abandoned in favor of cytotoxic radiotherapy, a legacy that persists to this day.

Today, bacteria are known to be potent inducers of the body’s first-line defense, the innate immune system. Activation of innate immunity can not only induce direct antitumor effects but also boost adaptive immunity (especially T-cell responses) and assist in improving tumor antigen presentation. [13] As knowledge of the innate immune system has advanced, the possibility of generating a modern Coley toxin that could incorporate specific activators of innate immunity has increased.

Innate immunity refers to cellular components that serve as the first-line immunologic defense that participates in rapid, nonselective protection without resulting immunologic memory. Stimulation of toll-like receptors (TLRs), which recognize highly conserved structural and molecular patterns on pathogens, is critical to initiating activation of antigen-presenting cells (APCs), which have recently been found to be involved in the efficacy of radiation therapy. [14]

Coley toxins likely work through stimulation of TLRs; accordingly, many investigators currently seek to optimize TLR activation as a means for potent, reproducible activation of innate immunity.


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