Viral Vectors Expressing Interleukin 2 for Cancer Immunotherapy

Abstract

Interleukin 2 (IL-2) plays a crucial role in T cell growth and survival, enhancing the cytotoxic activity of natural killer and cytotoxic T cells and thus functioning as a versatile master proinflammatory anticancer cytokine. The FDA has approved IL-2 cytokine therapy for the treatment of metastatic melanoma and metastatic renal cell carcinoma. However, IL-2 therapy has significant constraints, including a short serum half-life, low tumor accumulation, and life-threatening toxicities associated with high doses. Oncolytic viruses (OVs) offer a promising option for cancer immunotherapy, selectively targeting and destroying cancer cells while sparing healthy cells. Numerous studies have demonstrated the successful delivery of IL-2 to the tumor microenvironment without compromising safety using OVs such as vaccinia, Sendai, parvo, Newcastle disease, tanapox, and adenoviruses. Additionally, by engineering OVs to coexpress IL-2 with other anticancer transgenes, the immune properties of IL-2 can be further enhanced. Preclinical and clinical studies have shown promising antitumor effects of IL-2-expressing viral vectors, either alone or in combination with other anticancer therapies. This review summarizes the therapeutic potential of IL-2-expressing viral vectors and their antitumor mechanisms of action.

Keywords: cancer; immunotherapy; interleukin 2; local delivery; oncolytic virus; proinflammatory cytokine; viral vectors; virotherapy.

Figure 1.

Proinflammatory effects of IL-2 and its mechanisms of action. (1) High-affinity IL-2 signaling is mainly produced in response to antigen stimulation. First, through trans presentation, IL-2 derived from dendritic cells binds to CD25 (a.k.a. IL2Rα) expressed on activated dendritic cells. Then, the ligand–receptor complex will bind to IL2Rβ and IL2Rγ receptors on adjacent T cells to trigger downstream mechanisms. (2) Upon cis presentation of high-affinity IL-2 to the trimeric IL-2R receptor (i.e., IL-2Rα, IL2-Rβ, and IL-2Rγ), downstream signaling cascade is triggered. (3) IL-2 binds with low–moderate affinity to the dimeric IL-2R to induce downstream mechanisms. Notably, the monomeric IL-2 receptor (not pictured) does not result in downstream signaling. The three major IL-2 downstream mechanisms include activation of the PI3K-AKT pathway, JAK-STAT pathway through STAT5 dimerization, and the MAPK pathway. All the listed pathways will result in transcription of target genes downstream. While IL-2 is mainly associated with antigen-stimulated CD4⁺ T cells, which can differentiate into multiple subtypes (i.e., Th1, Th2, Th17, and Tregs), IL-2 is also associated with CD8⁺ T cells, NK cells, and cytotoxicity. IL-2, interleukin 2; MAPK, mitogen-activated protein kinase; NK, natural killer; PI3K, phosphoinositide 3-kinase; Treg, regulatory T-cell.

Figure 2.

Summary of IL-2-expressing viruses as potential cancer therapeutics. Referring to IL-2-expressing virus (depicted in green), there are multiple combination therapies to treat cancer demonstrating promising activity in preclinical models. (1) IL-2 in combination with sunitinib demonstrated therapeutic activity in RCC, pancreatic neuroendocrine tumors, and GIT stromal tumors through an increase in CD8⁺ T cells and NK cells; (2) IL-2 in addition to an immune checkpoint blockade induced tumor eradication in 90% of mice through modulation of the αβ T cell receptor; (3) IL-2 in addition to murine TNF-α in combination with ACT will increase CD8⁺ T cells and is known to hinder the growth of melanoma tumors; and, lastly; (4) IL-2 in addition to human TNF-α in combination with ACT will increase TILs and immunogenic memory, which will ultimately decrease HapT1 tumor growth.^, TILT-123 in an oncolytic adenovirus encoding IL-2 and TNF-α (depicted in blue), (1) TILT-123 in combination with ACT eliminates postconditioning and preconditioning in melanoma and pancreatic tumors through high CD8⁺ T cell levels, elevated B cells, an increase in M1-like macrophages, and proliferation of dendritic cells, which ultimately results in high antitumor effect and low toxicity profile;^, (2) TILT-123 in pancreatic cancer induced T cell-stimulating factors that promote T cell proliferation; (3) TILT-123 in ovarian cancer increased overall TIL activation as evidenced by increased CD69, CXCL10, and IFN-γ. TILT-123 in ovarian cancer is also associated with a decrease in functional signatures of infiltrating Tregs and MDSCs.^,, ACT, adoptive cell therapy; GIT, gastrointestinal; MDSCs, myeloid-derived suppressor cells; RCC, renal cell carcinoma; TIL, tumor-infiltrating lymphocyte; Tregs, regulatory T cells.