Epithelial Junction Opener Improves Oncolytic Adenovirus Therapy in Mouse Tumor Models
Roma Yumul1, Maximilian Richter1, Zhuo-Zhuang Lu1,2
11 Division of Medical Genetics, University of Washington , Seattle, Washington.
Abstract:
A central resistance mechanism in solid tumors is the maintenance of epithelial junctions between malignant cells that prevent drug penetration into the tumor. Human adenoviruses (Ads) have evolved mechanisms to breach epithelial barriers. For example, during Ad serotype 3 (Ad3) infection of epithelial tumor cells, massive amounts of subviral penton-dodecahedral particles (PtDd) are produced and released from infected cells to trigger the transient opening of epithelial junctions, thus facilitating lateral virus spread. We show here that an Ad3 mutant that is disabled for PtDd production is significantly less effective in killing of epithelial human xenograft tumors than the wild-type Ad3 virus. Intratumoral spread and therapeutic effect of the Ad3 mutant was enhanced by co-administration of a small recombinant protein (JO; produced in Escherichia coli) that incorporated the minimal junction opening domains of PtDd. We then demonstrated that co-administration of JO with replication-competent Ads that do not produce PtDd (Ad5, Ad35) resulted in greater attenuation of tumor growth than virus injection alone. Furthermore, we genetically modified a conditionally replicating Ad5-based oncolytic Ad (Ad5Δ24) to express a secreted form of JO upon replication in tumor cells. The JO-expressing virus had a significantly greater antitumor effect than the unmodified AdΔ24 version. Our findings indicate that epithelial junctions limit the efficacy of oncolytic Ads and that this problem can be address by co-injection or expression of JO. JO has also the potential for improving cancer therapy with other types of oncolytic viruses.
Insights
Adenoviruses can overcome tumor defenses by opening epithelial junctions. A protein called JO enhances this effect, improving oncolytic virus therapy for solid tumors.
Area of Science:
- Oncolytic virotherapy
- Tumor microenvironment
- Viral oncology
Background:
- Solid tumors present a significant challenge for cancer therapies due to epithelial junctions hindering drug penetration.
- Human adenoviruses (Ads) possess mechanisms to breach these epithelial barriers, facilitating tumor cell infection and spread.
- Adenovirus serotype 3 (Ad3) utilizes subviral penton-dodecahedral particles (PtDd) to transiently open epithelial junctions.
Purpose of the Study:
- To investigate the role of epithelial junctions in limiting oncolytic adenovirus efficacy.
- To evaluate the therapeutic potential of a recombinant protein (JO) derived from Ad3 PtDd for enhancing oncolytic virotherapy.
- To assess the efficacy of JO co-administration or expression with various oncolytic adenoviruses.
Main Methods:
- Comparison of wild-type Ad3 with a PtDd-deficient mutant in epithelial human xenograft models.
- Co-administration of recombinant JO protein with Ad3, Ad5, and Ad35.
- Genetic modification of an oncolytic Ad5 (Ad5Δ24) to express secreted JO and evaluation of its antitumor effect.
Main Results:
- An Ad3 mutant lacking PtDd showed reduced efficacy in reducing tumor size compared to wild-type Ad3.
- Co-administration of JO significantly enhanced the intratumoral spread and therapeutic effect of the Ad3 mutant.
- JO co-administration with Ad5 and Ad35 improved tumor growth attenuation.
- A JO-expressing Ad5Δ24 virus demonstrated superior antitumor activity over the unmodified Ad5Δ24.
Conclusions:
- Epithelial junctions represent a critical barrier to oncolytic adenovirus efficacy in solid tumors.
- Co-injection or tumor cell-specific expression of JO can overcome this barrier, enhancing therapeutic outcomes.
- JO holds promise for improving cancer treatment strategies involving oncolytic viruses beyond adenoviruses.
