Abstract
The notion of developing variants of the classic interleukin 2 (IL-2) cytokine has emerged from the limitations observed with the systemic use of human IL-2 in the clinic: severe adverse events accompanied by low therapeutic response rate in treated patients. Modifications made in the IL-2 receptor-binding structure leads to preferential binding of IL-2 variant cytokine to receptors on effector anti-tumor lymphocytes over T regulatory (TReg) cells. Because of their inherent immunogenicity, oncolytic adenoviruses are useful for expression of immunomodulatory molecules in tumors, for induction of a pro-inflammatory state in the tumor microenvironment. In the present study, we constructed an adenovirus coding for an IL-2 variant (vIL-2) protein, Ad5/3-E2F-d24-vIL2. Functionality of the new virus was tested in vitro, and anti-tumor efficacy and mechanism of action studies were performed in immunocompetent hamsters bearing pancreatic tumors. Ad5/3-E2F-d24-vIL2 treatment elicited efficient anti-tumor response, with 62.5% monotherapy complete response. Moreover, it promoted substantial repression of genes associated with myeloid cells mediated immunosuppression (CD11b, ARG1, CD206). This was seen in conjunction with upregulation of genes associated with tumor-infiltrating lymphocyte (TIL) cytotoxicity (CD3G, SAP, PRF1, GZMM and GZMK). In summary, Ad5/3-E2F-d24-vIL2 demonstrates therapeutic potential by counteracting immunosuppression and in efficiently coordinating lymphocytes mediated anti-tumor response in immunosuppressive tumors. Thus, Ad5/3-E2F-d24-vIL2 is a promising candidate for translation into clinical trials in human immunosuppressive solid tumors.
Highlights
Recombinant human interleukin 2 (IL-2), known as aldesleukin, was the first immunomodulatory protein approved for cancer treatment [1]
The vIL-2 gene was inserted in the partially deleted E3 gene region, resulting in a construct where vIL-2 expression is linked to virus replication (Figure 1A)
VIL-2 virus showed similar oncolytic capability in human and hamster cancer cells when compared to unarmed virus (Figures 1B–D). These results demonstrate that the virus intrinsic lytic capability was not compromised by the insertion of the vIL-2 transgene
Summary
Recombinant human interleukin 2 (IL-2), known as aldesleukin, was the first immunomodulatory protein approved for cancer treatment [1]. IL-2 therapy introduced a new perspective on cancer treatment: instead of affecting cancer cells directly, it promotes anti-tumor responses through the stimulation of the host immune system [2, 3]. Effector CD8+ cytotoxic and CD4+ helper lymphocytes exert anti-tumor effects upon T-cell receptor (TCR) recognition of antigens and proliferative stimulation by IL-2 protein [4]. Retrospective clinical data on metastatic renal cell carcinoma patients who received high-dose IL-2 therapy showed an overall objective response rate of only 20%, including complete and partial responders [5]. High dose IL-2 therapy is associated with severe toxicity, which has limited its broader use in the clinic [6]
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