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Immunotherapies may be classified according to their dependence on antigen specificities within the preexisting TвЂђcell receptor repertoire or whether they introduce new specificities. Typically, these type of lineage or stageвЂђspecific antigens will not be recognized by the immune system. 28 Another feature of cancer cells is maturational arrest, resulting in a conserved phenotype marked by expression of normal (i.e., nonmutated, or self) proteins. This process is called the cancerвЂђimmunity cycle and was elegantly described by Chen and Mellman.

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In order for the immune response to lead to effective killing of cancer cells, a series of stepwise events must be initiated and allowed to proceed and expand iteratively. For CD8вЂђpositive (usually cytotoxic) T cells, this response typically involves the recognition of distinct peptides bound to major histocompatibility class I (MHC I) molecules on the cell surface. Some mutations result in the expression of neoantigens that can be seen by the immune system as nonself, with the resulting generation of a TвЂђcell response.

MECHANISMS AND OUTCOMES FOR DRUGS THAT HARNESS T CELLS IN THE IMMUNE SYSTEM TO FIGHT CANCERД¬ancer is characterized by the accumulation of a variable number of mutations that lead to the loss of normal cellular regulatory processes. 11, 13 The latter two observations have strongly influenced recent advances in immunotherapy. 12 Third, the functional competence of infiltrating lymphocytes may be compromised. 11 Second, specificity may be limited to private (i.e., nonshared) antigens resulting from novel mutations. First, infiltrating T cells may have specificity for tumor antigens. 10 However, it is important to highlight three seminal observations. Presence of tumorвЂђinfiltratingвЂђlymphocytes (TIL) has frequently been linked to prognosis, but given the functional heterogeneity of lymphocytes, the correlation is rarely straightforward. 9ДЄ key early event in this process is the attraction of immune cells into the tumor microenvironment. 8 More recently, Schreiber and colleagues have conceptualized the bidirectional interactions between neoplasia and the immune system as вЂњimmunoeditingвЂќ and consists of three phases, elimination, equilibrium, and escape. 6, 7 Several decades later, data from animals and humans emerged linking cellular immune deficiency syndromes, either inborn or acquired, with increased rates of cancers.

5 An immune surveillance theory was expanded by Burnet and Thomas. Ehrlich also proposed that the immune system could guard against the spontaneous development of cancer. 3, 4 In the early 20th century, Paul Ehrlich suggested that the immune system distinguished between self and nonself. Coley, a surgeon, observed regression of sarcoma in a patient who had developed erysipelas and then developed a вЂњtoxinвЂќ derived from the causative agent, Streptococcus pyogenes ( Figure вЂ‹ 1 1). The intentional deployment of the immune system to treat cancer was pioneered by William Coley in the late 19th century. From Coley Toxins to the Approval of Bispecific TвЂђCell Engaging Antibody Constructs for Cancer Immunotherapy.

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