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PROMISE OF IMMUNOTHERAPY

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The ability of the immune system to recognize and eradicate cancer was first postulated in the 19th century; however, proof of principle remained elusive until the 20th century. The effect of infection on tumor regression was observed as early as 1884 by Anton Chekov (1); following this, William Coley developed a mixture of killed bacteria that were used to treat various types of cancer between the 1890s and 1960s with mixed clinical benefit. In addition, the concept of using bacterial elements was validated with Food and Drug Administration (FDA) approval of intravesical administration of BCG, which is an FDA-approved therapy that leads to nonspecific inflammatory immune responses and clinical benefit for patients with superficial bladder cancer (2). The discovery of the major histocompatibility complex (MHC) and T-cell receptor (TCR) in the 1980s provided insight into T-cell function that led to a number of clinical trials (3,4). Unfortunately, many of the early clinical trials failed due to incomplete understanding of T-cell function. Further research led to understanding of costimulatory and coinhibitory molecules, which led to improved strategies in the field of cancer immunotherapy, including chimeric antigen receptor (CAR) T cells and immune checkpoint therapies, resulting in clinical success that turned the tide in favor of immunotherapy.

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The basic principles that guide cancer immunology are (a) immune surveillance, (b) immune editing, and (c) immune tolerance (5). Immune surveillance involves scanning and eliminating the transformed nascent cells by the immune system. This theory was bolstered by the finding of tumor-specific antigen that could be identified by cytotoxic T cells (6). Immune editing is a process that involves elimination in which the immune system acts as an extrinsic tumor suppressor (similar to the original concept of immunosurveillance); second, equilibrium occurs, in which tumor cells survive but are held in check by the immune system; and third, in escape, tumor cell variants with either reduced immunogenicity or the capacity to attenuate or subvert immune responses grow into clinically apparent cancers. Escape theory also gave credence to the concept of immune tolerance by which cancer cells exploit the body’s immune system and use it for their continuous immune evasion and subsequent growth and proliferation.

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The immune compartments that aid in tumor elimination and promote tumor evasion are listed in Table 48-1. The guiding theory for development of immunotherapy is to promote antitumor immune factors and attenuate protumor factors.

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Table Graphic Jump Location
Table 48-1Anti and Protumor Arms of the Immune System

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