7.1.2 Interleukin-2
IL-2 is viewed as a key cytokine in promoting the expansion of natural killer (NK) cells and T lymphocytes.Thus, it is widely used in protocols of adoptive transfer for both expanding lymphocytes in culture and increasing the persistence of transferred cells in cancer patients.The infusion of this cytokine at high doses is currently approved for the treatment of metastatic RCC and metastatic melanoma.However, the systemic administration of this cytokine at the recommended dose is hampered by its toxic profile, which includes frequent grade 3 and 4 adverse effects.Second-generation IL-2-based therapies with improved pharmacokinetic and pharmacodynamic profiles are being developed.Improvement of the pharmacokinetic profile is achieved through covalent binding of IL-2 to moieties that increase the half-life in circulation, such as the Fc domains of immunoglobulins or PEG molecules, or by chimerisation with antibodies that target the cytokine to the TME.Improvement of the pharmacodynamic properties is attained by using biotechnology tricks to reduce binding to the high-affinity IL-2 receptor while maintaining binding to the medium-affinity IL-2 receptor to increase the amount of cytokine that is available to stimulate NK and T cells.
The IL-2 receptor is composed of three different complexes formed by three chains (Figure 7.1).The low-affinity receptor is composed of the IL-2Rα chain alone but does not trigger an intracellular signal cascade.Thus, the two receptors that induce signal transduction are the medium-affinity and the high-affinity receptors.The medium-affinity receptor is composed of the IL-2Rβ chain and the common γ chain; when the IL-2Rα chain is also present in the receptor complex, IL-2 is bound with high affinity.IL-2Rα is highly expressed on T regulatory (Treg) cells and therefore the high-affinity IL-2 receptor skews IL-2 activity towards the expansion of Treg cells, while limiting the bioavailability of the cytokine to stimulate anti-tumor effector NK and T lymphocytes.
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Figure 7.1 Interleukin (IL)-2 receptors.IL-2 is recognised by three types of receptor complex expressed on natural killer (NK) and T lymphocytes.The non-signalling, low-affinity receptor is composed of the IL-2Rα chain alone.The medium-affinity receptor is composed of the IL-2Rβ chain and the common γ chain.Finally, the high-affinity IL-2 receptor is composed of the IL-2Rα,the IL-2Rβ chain and the common γ chain.Ligand binding to the medium-affinity and high-affinity receptors leads to the phosphorylation of Janus kinase-1 (JAK1) and JAK3 and the recruitment and subsequent phosphorylation of signal transducer and activator of transcription-3 (STAT3) and STAT5, and ensuing transcriptional changes.(Please scan the QR code on the Preface to get original color figures.)
Source: Berraondo P, Sanmamed M F, Ochoa M C, Etxeberria I, Aznar M A, Pérez-Gracia J L, Rodríguez-Ruiz M E, Ponz-Sarvise M, Castañón E, Melero I.“Cytokines in Clinical Cancer Immunotherapy”.BritishJournalofCancer, 2019, 120(1):6-15.
Several of these second-generation IL-2-based compounds engineered to avoid binding to IL-2Rα/CD25 have reached clinical trials.NKTR-214 is composed of recombinant IL-2 together with multiple molecules of PEG .Directed PEGylation generates an inactive cytokine with a long half-life in circulation.The PEG groups are progressively released, yielding IL-2 molecules with double or single PEGylation that can interact with the medium affinity IL-2 receptor but not with the high-affinity IL-2 receptor.
This modified cytokine is being evaluated in clinical trials in combination with the immune checkpoint inhibitors atezolizumab (NCT03138889), nivolumab (NCT02983045, NCT03282344 and NCT03435640) and nivolumab plus ipilimumab (NCT02983045).As reported at the American Society of Clinical Oncology (ASCO) annual meeting in 2018, NKTR-214 has undergone dose-escalation studies and has also been used in combination with nivolumab to treat 214 patients,showing promising response rates in immunotherapy-naive patients suffering from melanoma, RCC or NSCLC.In terms of safety, the combination was tolerated, and comparative randomized studies will be performed to confirm benefit over nivolumab single-agent therapy.