Assessing cytokine therapies

Cytokine and anticytokine therapies for cancer treatment
Cancer is a major public health problem worldwide. Numerous basic studies and clinical trials have shown that immunotherapy is one of the most effective and promising therapeutic approaches for cancer treatment. Cancer immunotherapy activates the body’s immune system and enhances the antitumour immune response to fight cancer cells. It consists of several strategies, including cytokine therapies, immune checkpoint inhibitors, therapeutic monoclonal antibodies targeting tumour antigens, cell therapies (e.g., CAR-T cells), and cancer vaccines. With the intensive studies of cytokines in cancers, targeting cytokines or cytokine receptors have also emerged as a potential cancer immunotherapy.
Cytokines are a class of small proteins (typically <30 kDa) possessing various biological activities and being synthesised and secreted by immune cells and some nonimmune cells (e.g., endothelial cells, epidermal cells, and fibroblasts). Cytokines mediate intercellular communication in an autocrine or paracrine manner, thereby regulating the proliferation, differentiation, survival, and effector functions of immune cells. Depending on their functions, cytokines can be classified into interleukins (ILs), interferons (IFNs), tumor necrosis factors (TNFs), colony-stimulating factors (CSTs), and chemokines.

Cytokine network in the tumour microenvironment

The tumour microenvironment (TME) is a complex integrated system of endothelial cells, fibroblasts, immune cells, the extracellular matrix, and cytokines covering the cancer cells. Cancer cells constantly interact with the surrounding microenvironment. Remarkably, cytokines mediate intercellular communication between these various cells in the TME in an autocrine or paracrine manner (Figure 1)[1].
In the TME, some specific cytokines, such as IFNγ, IL-2, IL-12, and IL-15, demonstrate antitumour effects by directly inhibiting cell growth or enhancing the cytotoxic effects of lymphocytes and/or myeloid cells. Meanwhile, some aberrantly expressed cytokines exhibit tumour-promoting effects through several ways, such as immunosuppression, neoangiogenesis, cancer cell survival promotion, stemness, and proliferation. These atypical cytokines can be produced by immune cells, stromal cells, and even malignant cells, and they could be involved in all stages of cancer occurrence and progression.
Depending on the antitumour or protumour effects of various cytokines, two opposing cytokine-based immunotherapy strategies are used for cancer treatment: (1) cytokine therapy, in which recombinant cytokines or cytokine derivatives with antitumor effects are used directly to fight cancer cells, and (2) anticytokine therapy, in which the antagonists of cytokines or cytokine receptors are harnessed to inhibit the protumour effects of cytokines.

Cytokine therapy

Over the past 40 years, numerous preclinical and clinical studies have attempted to directly harness cytokines with antitumor effects for cancer treatment, and some have shown promising results. At present, two cytokine drugs have been approved for the clinical treatment of cancer: IFN alfa-2b (Intron A) and aldesleukin (Proleukin) (Table 1). Intron A was licensed for treating hairy cell leukemia, malignant melanoma, follicular lymphoma, and AIDS-related Kaposi’s sarcoma [2], whereas Proleukin was authorized for treating metastatic renal cell carcinoma (RCC) and metastatic melanoma [3].
Many other cytokines are identified as potential cytokine therapies. For example, as an antitumor cytokine, IL-12 promotes the proliferation and cytotoxic activity of natural killer cells and T cells, while enhancing IFNγ production and TH1 cell differentiation. In various clinical trials, recombinant IL-12 has shown modest antitumor effects. However, its toxicity and short half-life hinder its approval for clinical application. At present, multiple strategies, such as protein conjugation with polyethylene glycol and antibody-cytokine fusion proteins, are being applied for IL-12 engineering to prolong its half-life and reduce its toxicity.
In these studies, recombinant cytokines of high purity and activity are indispensable for various functional assays, such as cytotoxicity assay and control experiment of the cytokine drug candidates. Sino Biological provides a broad collection of recombinant cytokines covering all the high-activity, high-purity, and multilabel cytokine families (Figure 2).

Anticytokine therapy

Anticytokine therapies, especially those targeting TNF and IL-6, are widely used in the clinical treatment of some inflammatory and autoimmune diseases. The tremendous success of anticytokine therapies in the field of immunology has greatly contributed to its extensive use in the field of oncology. According to numerous preclinical studies, neutralizing monoclonal antibodies or antagonists targeting the cytokines with protumor effects or their receptors exhibit anticancer activities.
Moreover, TNF is a proinflammatory cytokine with tumour-promoting effects. Hence, antibodies to TNF are used to bind aberrantly expressed TNF for cancer treatment. Infliximab is an anti-TNF monoclonal antibody approved for multiple autoimmune diseases. A phase I clinical trial revealed that infliximab was well tolerated and had no dose-limiting toxic effects in patients with advanced cancer [4]. In two sequential phase II clinical trials, three of 37 patients with RCC achieved partial response and 14 patients achieved stable disease [5]. Therefore, inflixmab may be effective for RCC. However, it needs to be validated in further clinical trials.
IL-6 plays proinflammatory and tumour-promoting roles in the TME. Therefore, agents targeting IL-16 or its receptor may be potential cancer drugs. For example, siltuximab, an approved monoclonal antibody to IL-6, was used in a phase II clinical trial of18 patients with platinum-resistant ovarian cancer [6]. Among these patients, one had a partial response and seven had stable disease. In addition, siltuximab treatment significantly reduced the plasma levels of CCL2, CXCL12, and VEGF.
Sino Biological has developed a full range of high-quality reagents, including recombinant cytokine and receptor proteins, antibodies, and ELISA kits, to support anticytokine therapies (Figure 3). These high-quality reagents have been validated using various methods to provide consistent and reproducible results.
[1] Propper DJ, Balkwill FR. Harnessing cytokines and chemokines for cancer therapy. Nat Rev Clin Oncol. 2022;10.1038/s41571-021-00588-9. doi:10.1038/s41571-021-00588-9
[2] PRODUCT INFORMATION INTRON A (Interferon alfa-2b)., accessed January 21, 2022. Reference ID: 4160510
[3] PRODUCT INFORMATION PROLEUKIN (aldesleukin)., accessed January 21, 2022. Reference ID: 3165255
[4] Brown ER, Charles KA, Hoare SA, et al. A clinical study assessing the tolerability and biological effects of infliximab, a TNF-alpha inhibitor, in patients with advanced cancer. Ann Oncol. 2008;19(7):1340-1346. doi:10.1093/annonc/mdn054
[5] Harrison ML, Obermueller E, Maisey NR, et al. Tumor necrosis factor alpha as a new target for renal cell carcinoma: two sequential phase II trials of infliximab at standard and high dose. J Clin Oncol. 2007;25(29):4542-4549. doi:10.1200/JCO.2007.11.2136
[6] Coward J, Kulbe H, Chakravarty P, et al. Interleukin-6 as a therapeutic target in human ovarian cancer. Clin Cancer Res. 2011;17(18):6083-6096. doi:10.1158/1078-0432.CCR-11-0945

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