Relaxin-expressing oncolytic adenovirus induces remodeling of physical and immunological aspects of cold tumor to potentiate PD-1 blockade

Abstract

BackgroundCurrently, several antibody (Ab)-based therapies have shown excellent therapeutic effects in the clinic. Nonetheless, Ab penetration into tumor tissues is limited due to abnormal vasculature, tumor interstitial pressure, and excessive extracellular matrix (ECM) accumulation, thus demanding novel strategies to overcome these barriers.MethodsThe intratumoral distribution of therapeutic Abs were detected by fluorescence microscopy or positron emission tomography in both human gastric xenograft and syngeneic pancreatic hamster tumor models. The antitumor efficacy by combination of oncolytic adenovirus (Ad), which coexpresses relaxin (RLX), interleukin (IL)-12, and granulocyte macrophage colony-stimulating factor (GM-CSF) (oAd/IL12/GM-RLX) and antibody against the programmed cell death protein 1 (αPD-1) was examined in hamster subcutaneous and orthotopic pancreatic tumor models. The immunological aspects of these combination therapy regimen were assessed by flow cytometry or immunohistochemistry in subcutaneous hamster tumor models.ResultsRelaxin-expressing oncolytic Ad effectively degraded tumor ECM and enhanced the tumor penetration of trastuzumab in comparison with trastuzumab monotherapy. Based on these results, an oAd/IL12/GM-RLX was used to enhance the potency of immune checkpoint blockade. The combination of the oAd/IL12/GM-RLX and αPD-1 promoted a concomitant degradation of the tumor ECM and amelioration of the immunosuppressive tumor niches, ultimately enhanced intratumoral infiltration of both αPD-1 and activated T cells. Of note, the combination therapy was able to elicit a potent and durable antitumor immune response against cold tumors that were refractory to immune checkpoint inhibitor monotherapy.ConclusionsOur findings are the first to demonstrate that expression of four genes (IL-12p35, IL-12p40, GM-CSF, and RLX) mediated by a single oncolytic Ad vector can promote remodeling of both physical and immunological aspects of the tumor niches to overcome the major limitations of Ab-based therapies that have emerged in recent clinical trials.

Agent-based computational modeling of glioblastoma predicts that stromal density is central to oncolytic virus efficacy

“…As OVs require cancer cells to proliferate and with a reduction in the source of their proliferation, it is intuitive that the treatment efficacy would drop in regions of low density. Fortunately, OVs can be genetically modified to express proteins that result in the breakdown of the ECM (such as matrix metalloproteinase-1 and -8 ( Cheng et al., 2007 ) and Relaxin ( Jung et al., 2020 ). Although these sorts of modifications are under experimental investigation, the impact of the breakdown of human patient stroma or ECM constituents in the clinical setting is missing.…”

Reshaping the Immune Microenvironment by Oncolytic Herpes Simplex Virus in Murine Pancreatic Ductal Adenocarcinoma

“…distribution of virus by promoting the degradation of ECM. 52 A mouse model that recapitulates the hallmarks of PDAC in both the immune suppression and the desmoplasia would be of necessity to understand the effect of the oncolytic virus on different components of the TME.…”

GM101 in Combination with Histone Deacetylase Inhibitor Enhances Anti-Tumor Effects in Desmoplastic Microenvironment

“…Despite major advances in cancer therapy, limited intratumoral distribution of anti-cancer therapeutics remains a major challenge toward maximizing the therapeutic potential. In this regard, aberrantly accumulated ECM in the tumor microenvironment has been identified as a key hindrance for the poor dispersion of cancer therapeutics in a tumor mass [ 36 , 37 ]. Additionally, there are therapy-specific obstacles, such as variable CAR expression levels of heterogenic tumor cell population, that attenuate the internalization and dispersion of Ad in tumor tissues.…”