Recombinant Newcastle disease virus (NDV/Anh-IL-2) expressing human IL-2 as a potential candidate for suppresses growth of hepatoma therapy

Abstract

Newcastle disease virus (NDV) have shown oncolytic therapeutic efficacy in preclinical study and are currently approved for clinical trials. NDV Anhinga strain which is a mesogenic strain should be classified as lytic strain and has a therapeutic efficacy in hepatocellular cancer. In this study, we evaluated the capacity of NDV Anhinga strain to elicit immune reaction in vivo and the possibility for using as a vaccine vector for expressing tumor therapeutic factors. Interleukin-2 (IL-2) could boost the immune response against the tumor cells. Therefore, we use NDV Anhinga strain as backbone to construct a recombinant virus (NDV/Anh-IL-2) expressing IL-2. The virus growth curve showed that the production of recombinant NDV/Anh-IL-2 was slightly delayed compared to the wild type. The NDV/Anh-IL-2 strain could express soluble IL-2 and effectively inhibit the growth of hepatocellular carcinoma in vivo. 60 days post-treatment, mice which were completely cured by previous treatment were well protected when rechallenged with the same tumor cell. From the H&E-stained sections, intense infiltration of lymphocyte was observed in the NDV Anhinga strain treated group, especially in NDV/Anh-IL-2 group. The NDV Anhinga strain could not only kill the tumor directly, but could also elicit immune reaction and a potent immunological memory when killing tumor in vivo. In conclusion, the Anhinga strain could be an effective vector for tumor therapy; the recombinant NDV/Anh-IL-2 strain expressing soluble IL-2 is a promising candidate for hepatoma therapy.

Exploring the Prospects of Engineered Newcastle Disease Virus in Modern Vaccinology

“…Other approaches used to enhance the oncolytic efficacy of NDV include reprogramming the virus to constitutively express certain interferons and proinflammatory cytokines [134]. A recombinant NDV expressing soluble IL-2 has been shown to effectively regress hepatocellular carcinoma in mice and lead to the establishment of strong immunity that completely protected the cured mice from future challenge with cancerous cells [139]. Furthermore, co-expression of IL-2 and IL-12 on the NDV backbone led to enhanced anti-hepatoma activity in mice.…”

Armed oncolytic viruses: A kick-start for anti-tumor immunity

“…In these murine studies, reduced tumor growth and increased T cell infiltration of the tumors was reported. No distress was observed in mice and IL-2 production was limited to the tumor site, which might indicate less side-effects when administrated to humans [53][54][55]. Also, mice were protected from re-challenge with tumor cells suggesting induction of long term tumor specific immunity and thus show promise as vectorized immune modulator [52][53][54][55].…”

“…AdV [108] Neuroblastoma [45], Glioma [43], Prostate [48], Squamous Cell Carcinoma [46,47], Melanoma [108] Infiltration of macrophages, T helper, CTL and NK cells [43,45,47,48] No signs [44,46,47] HSV [30,[43][44][45]47,48] Improved survival [108] and protective against rechallenge [47] VSV [46] IL-2 NDV [52][53][54][55][56] Melanoma [54,55], Hepatoma [52,53], Squamous Cell Carcinoma [51] Infiltration of T helper and CTL [51][52][53][54][55][56] No signs [53,54] HSV [51] Immunity against rechallenge with tumor cells [51][52][53][54]…”

“…Systemic treatment with IL-2 is associated with major adverse side effects in humans [24]. Therefore, local delivery of IL-2 by OVs has been tested by several research groups [51][52][53][54][55][56]. In these murine studies, reduced tumor growth and increased T cell infiltration of the tumors was reported.…”

Development of oncolytic virotherapy: from genetic modification to combination therapy

“…M032 is an oncolytic HSV expressing IL-12 [128] and is being assessed in the clinical trial for the treatment of GBM (the results of which have not yet been reported). Other cytokines, such as IL-2 [129] and IL-15 [130], can also be inserted to improve antitumor efficiency. However, some secreted cytokines have systemic toxicity [131].…”