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. 2012 Feb 13;209(2):201-9.
doi: 10.1084/jem.20112275.

Immunotherapy earns its spot in the ranks of cancer therapy

Drew Pardoll  1 , Charles Drake
Affiliations

Immunotherapy earns its spot in the ranks of cancer therapy

Drew Pardoll et al. J Exp Med. .

Abstract

Since it became clear that all cancer cells express tumor-specific and tumor-selective antigens generated by genetic alterations and epigenetic dysregulation, the immunology community has embraced the possibility of designing therapies to induce targeted antitumor immune responses. The potential therapeutic specificity and efficacy of such treatments are obvious to anyone who studies the exquisite specificity and cytocidal potency of immune responses. However, the value assigned to a therapeutic modality by the oncology community at large does not depend on scientific principle; all that matters is how patients respond. The bar for the ultimate acceptance of a therapy requires more than anecdotal clinical responses; rather, the major modalities of cancer therapeutics, including surgery, chemotherapy, radiation therapy, and, more recently, drugs targeting oncogenes, have earned their place only after producing dramatic frequent clinical responses or demonstrating statistically significant survival benefits in large randomized phase 3 clinical trials, leading to FDA approval. Although tumor-targeted antibodies have certainly cleared this bar, immunotherapies aimed at harnessing antitumor cellular responses have not-until now.

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Figures

Figure 1.
Figure 1.
Various immune checkpoint receptors inhibit effector T cell function and boost T reg cell function. Checkpoint receptors such as CTLA-4, PD-1, and LAG-3 are expressed on activated effector T cells, but are constitutively expressed on T reg cells. In the presence of cognate ligands for these receptors, effector T cell function is diminished, whereas T reg cell function and/or proliferation are enhanced. In this figure, the strength of T cell function and/or proliferation is proportional to the size of the cell.
Figure 2.
Figure 2.
Multiple immune inhibitory and co-stimulatory pathways in the tumor microenvironment are targets of therapeutic manipulation by antibodies or drugs. Cells in the tumor microenvironment express multiple inhibitory cytokines, ligands, and cognate receptors (red) that down-modulate the antitumor activity of immune effector cells including cytotoxic T lymphocytes (CTL). Some of these inhibitory proteins are expressed by tumor cells themselves and others are expressed by tumor-infiltrating suppressive cells including T reg cells and myeloid derived suppressor cells (MDSCs). T reg cells inhibit antitumor CTL activity by producing soluble factors such as IL-10 and TGF-β, whereas MDSCs inhibit immunity through metabolic enzymes such as IDO and arginase. These inhibitory signals are counterbalanced by signals that enhance immune activation (green), a number of which are transduced by members of the TNFR family (CD40, CD137, OX40, and CD27). Blocking antibodies or drugs are in development or clinical testing for each of the inhibitory molecules depicted in the figure, and agonist antibodies are in development or clinical testing for each of the activating TNFR family members depicted (Table 1). DC/Mφ, DCs/macrophages.
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