A chimeric poxvirus with J2R (thymidine kinase) deletion shows safety and anti-tumor activity in lung cancer models

Abstract

Oncolytic viruses have shown excellent safety profiles in preclinical and clinical studies; however, in most cases therapeutic benefits have been modest. We have previously reported the generation of a chimeric poxvirus (CF33), with significantly improved oncolytic characteristics, through chimerization among different poxviruses. Here we report the sequence analysis of CF33 and oncolytic potential of a GFP-encoding CF33 virus (CF33-GFP) with a J2R deletion in lung cancer models. Replication of CF33-GFP and the resulting cytotoxicity were higher in cancer cell lines compared to a normal cell line, in vitro. After infection with virus, cancer cells expressed markers for immunogenic cell death in vitro. Furthermore, CF33-GFP was safe and exerted potent anti-tumor effects at a dose as low as 1000 plaque forming units in both virus-injected and un-injected distant tumors in A549 tumor xenograft model in mice. Likewise, in a syngeneic model of lung cancer in mice, the virus showed significant anti-tumor effect and was found to increase tumor infiltration by CD8+ T cells. Collectively, these data warrant further investigation of this novel chimeric poxvirus for its potential use as a cancer bio-therapeutic.

Replicative conditioning of Herpes simplex type 1 virus by Survivin promoter, combined to ERBB2 retargeting, improves tumour cell-restricted oncolysis

“…Accordingly, we evaluated anti-tumour efficacy in immune-competent transgenic mice, tolerant to human ERBB2, harbouring ectopic, established tumours based on ERBB2-positive LLC1 murine cancer cells 27 . The LLC1 established tumours raised in syngeneic C57B6 mice are poorly responsive to oncolytic virotherapy and to immune checkpoint blockade monotherapy 27,48,49 . Mice injected with ERBB2-positive LLC1 cancer cells, upon appearance of tumours > =100 mm 3 in volume were randomized and subjected to placebo, or to anti-PD1 antibody (days 0, 3, 7, 10, 14, 17 from appearance of tumour), or to combined anti-PD1 treatments (schedule as above) with either R-LM113 or SurE_oHSV viruses (0.5 × 10 8 PFU at days 0, 2, 4, 7) (Fig.…”

Oncolytic poxvirus CF33-hNIS-ΔF14.5 favorably modulates tumor immune microenvironment and works synergistically with anti-PD-L1 antibody in a triple-negative breast cancer model

“…Cell lysates were collected at 24-, 48-and 72-h post-infection and virus titer in the lysates were determined by standard plaque assay on CV1 cells as described previously. 21 To determine the cytotoxic potential of the virus, 3000 cells were seeded per well of 96-well culture plates in 100 uL cell culture medium. The following day, cells were either mockinfected or infected by CF33-hNIS-ΔF14.5 at MOIs 0.01, 0.1 or 1.…”

“…Construction of CF33 has been described previously. 21 The virus CF33-hNIS-ΔF14.5 is deleted of the genes J2R and F14.5L and it encodes human sodium iodide symporter (hNIS) gene. CF33-hNIS-ΔF14.5 was amplified in CV1 cells and purified on sucrose gradients.…”

“…CF33-hNIS-ΔF14.5 is a chimeric poxvirus which has demonstrated strong oncolytic effect against several tumor models at relatively low doses. 21,[24][25][26] We have previously reported that CF33-hNIS-ΔF14.5 induces immunogenic cell death and increases CD8+ T cells infiltration in tumors. 21 Here, we studied the therapeutic potential of CF33-hNIS -ΔF14.5 in combination with an anti-PD-L1 (α-PD-L1) antibody in a triple-negative breast cancer model.…”

“…20 For example, OVs have been shown to induce immunogenic cell death which plays an important role in the induction of adaptive immunity. [21][22][23] Furthermore, OVs can modulate cytokine/chemokine in TME leading to increased tumor infiltration by CD8+ T cells and other immune cells. 9 However, CD8+ T cells within the TME may be blocked by cancer cells through checkpoint proteins such as PD-L1 in which case addition of ICIs should be helpful.…”