Cytokines in Cancer Immunotherapy

Abstract

Cytokines that control the immune response were shown to have efficacy in preclinical murine cancer models. Interferon (IFN)-α is approved for treatment of hairy cell leukemia, and interleukin (IL)-2 for the treatment of advanced melanoma and metastatic renal cancer. In addition, IL-12, IL-15, IL-21, and granulocyte macrophage colony-stimulating factor (GM-CSF) have been evaluated in clinical trials. However, the cytokines as monotherapy have not fulfilled their early promise because cytokines administered parenterally do not achieve sufficient concentrations in the tumor, are often associated with severe toxicities, and induce humoral or cellular checkpoints. To circumvent these impediments, cytokines are being investigated clinically in combination therapy with checkpoint inhibitors, anticancer monoclonal antibodies to increase the antibody-dependent cellular cytotoxicity (ADCC) of these antibodies, antibody cytokine fusion proteins, and anti-CD40 to facilitate tumor-specific immune responses.

Figure 1.

Interleukin (IL)-2, IL-15, IL-21, granulocyte macrophage colony-stimulating factor (GM-CSF), and type 1 interferons (IFNs) have been evaluated in clinical trials for the immunotherapy of cancer. Targets of anticancer trials are shown at the bottom with those approved by the U.S. Food and Drug Administration (FDA) in bold. IFNAR, Interferon-α/β receptor; JAK, Janus kinase; STAT, signal transducers and activators of transcription; TYK, tyrosine kinase.

Figure 2.

Model of interaction of interleukin (IL)-2 and IL-15 with their receptors. IL-2 is predominantly a secreted cytokine that binds to preformed high-affinity heterotrimeric receptors. In contrast, IL-15 is a membrane-associated molecule that signals as part of an immunological synapse between antigen-presenting cells and natural killer (NK) cells, γΔ, and CD8 T cells. IL-15Rα on the surface of activated monocytes or dendritic cells (DCs) presents IL-15 in trans to cells that express IL-2/IL-15Rβ and γ chain (γc), thereby allowing signaling through these complexes. (Based on figures in Waldmann 2006.)

Figure 3.

Different approaches to change interleukin (IL)-2 conformation to favor effector over negative regulatory function. One strategy for selectively modulating the effects of IL-2 is the development of cytokine-directed antibodies that bias activity toward specific T-cell subsets. The anti-IL-2 antibody S4B6 blocked the IL-2:IL-2Rα interaction while also conformationally stabilizing the IL-2:IL-2Rβ interaction, thus stimulating all IL-2-responsive immune cells, particularly IL-2Rβ^hi effector cells favored over IL-2Rα expressing regulatory T (Treg) cells. The right side shows a different mutational approach to generate a distinct IL-2R superkine variance, which uses mutations to stabilize IL-2, including a flexible helix in the IL-2Rβ-binding site, into an optimized receptor-binding confirmation resembling that when bound to CD25 (IL-2Rα) (Levin et al. 2012). The evolved mutations in super-2 recapitulated the functional role of CD25 by eliciting potential phosphorylation of signal transducers and activators of transcription 5 (STAT5) and vigorous proliferation of T cells irrespective of CD25 expression. Compared to IL-2, super-IL-2 induced superior expansion of cytotoxic T cells, leading to improved antitumor responses in vivo and eliciting proportionally less expansion of Treg cells and reduced pulmonary edema. WT, Wild type.

Figure 4.

A series of approaches has been developed to block γ chain (γc) cytokine, Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling in T-cell malignancies and autoimmune disorders. Such therapeutic approaches include targeting the γc cytokines directly, agents that block cytokine receptor interactions, and JAK kinase inhibitors. H9-RETR, the RETR mutant of H9 super-IL-2. (This figure was previously published as Figure 4 in Waldmann et al. 2017. It is now reproduced with permission.)

Figure 5.

Modified interleukin (IL)-2 to simultaneously inhibit IL-2 and IL-15 action. Two modifications of IL-2 have been generated that block binding of normal IL-2 and IL-15 to IL-2/IL-15Rβ and γ chain (γc), thereby simultaneously inhibiting the actions of both IL-2 and IL-15. BNZ-1 (left) binds only to the γc but not IL-2/IL-15Rβ (Nata et al. 2015). In parallel, the RETR mutant of H9 superkine IL-2 (H9-RETR, right) binds tightly to IL-2/IL-15Rβ but not γc (Mitra et al. 2015). Both agents prevent the heterodimerization of IL-2Rβ with γc, which is required for signaling.