Abstract
Oncolytic viruses (OVs) preferentially infect and selectively replicate in cancer cells. OVs have been tested in clinical trials as monotherapy or in combination with chemotherapy, radiotherapy, and immunotherapy. However, the dense extracellular matrix hampers the intratumoral spreading and efficacy of OVs. Previously we described VCN-01, an oncolytic adenovirus expressing a soluble version of human sperm hyaluronidase (hyal) PH20, which exhibited enhanced intratumoral distribution and antitumor activity in different models. Here, we present two oncolytic adenoviruses designed to increase the secretion of PH20 compared to VCN-01. ICO15K-40SAPH20, encoding PH20 under an Ad40 splice acceptor, and ICO15K-E1aPH20 expressing PH20 fused to the E1A gene by P2A peptide. We demonstrate that increased hyal activity improves antitumor efficacy in both a sensitive immunodeficient model and an immunocompetent model. Moreover, we show that hyal activity impacts T cell accumulation in tumors, highlighting the value of a hyaluronidase-expressing virus for combinations with other immunotherapies in cancers involving dense stroma.
Highlights
Solid tumors are complex organ-like structures consisting of cancer cells, vasculature, extracellular matrix (ECM), stromal, and immune cells
Generation of oncolytic adenovirus (OAd) with enhanced hyal activity compared to VCN-01 and preserved oncolytic properties We have previously reported the generation of OAd ICOVIR15K18 and VCN-01 expressing a soluble version of the human PH20 hyal under IIIa splice acceptor[19] (Figure 1A)
Effect of enhanced hyal activity expressed by oncolytic adenoviruses in tumors The Sk-mel-28 model was selected to test the efficacy of the hyal-expressing viruses, as we previously reported that these tumors are rich in hyaluronic acid (HA) content.[21]
Summary
Solid tumors are complex organ-like structures consisting of cancer cells, vasculature, extracellular matrix (ECM), stromal, and immune cells. Oncolytic viruses (OVs) have the ability to selectively replicate in cancer cells without harming normal tissues.[9,10] OVs lyse tumor cells and trigger a pro-inflammatory response that may induce antitumor immunity, making them attractive for immunotherapy combinations.[11] their intratumoral spread is hampered by the ECM, which acts as a physical barrier for viral distribution.[12] ECM-degrading enzymes are commonly exploited to enhance viral penetration in solid tumors.[13] Our group generated a hyaluronidase-expressing oncolytic adenovirus (OAd), called VCN-01.14 VCN-01 has exhibited a favorable toxicity profile and potent antitumor efficacy in different models of cancer.[14,15,16,17] VCN-01 is currently under clinical trial investigation to treat advanced pancreatic cancer (NCT02045602, NCT020455 89), retinoblastoma (NCT03284268),[16] and head and neck cancers (NCT03799744). We generated OAds with higher hyal activity to assess the impact of HA degradation on antitumor efficacy and immune response
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