Oncolytic viruses engineered to deliver therapeutic transgenes are attractive for targeted intratumoral immunomodulation. TROCEPT is an oncolytic adenovirus type 5 platform in which the native binding interactions mediated by coxsackie and adenovirus receptor, αvβ3/5 integrins, and coagulation factor X have been ablated. Tumor selective targeting is achieved by incorporating the high affinity αvβ6-integrin binding A20 peptide into the fiber knob protein of the viral capsid. These modifications de-target to avoid healthy cells such as the liver, and re-target to specifically infect and replicate in tumor cells that express αvβ6 integrin. avβ6 integrin in an attractive target with high expression in numerous solid tumor types with poor prognoses and high unmet need. ATTR-01 is a first-in-class TROCEPT variant that, following infection of permissive tumor cells, expresses an anti-PD-L1 antibody payload. Intratumoral generation of the anti-PD-L1 checkpoint inhibitor locally, may lead to higher tumor localized concentrations compared to systemic delivery by IV infusion, thus, limiting systemic T-cell exhaustion, increasing efficacy, and reducing off-tumor toxicity.

In-vitro cell and immunohistochemistry (IHC) assays and in-vivo murine αvβ6 xenograft models, were conducted to assess the oncolytic effects of TROCEPT, with a focus on its αvβ6 integrin dependent specificity and its impact on tumor growth.

In-vitro experiments demonstrated that viral replication, transgene expression, and oncolytic cell death following infection with ATTR-01 was highly selective for αvβ6 integrin positive tumor cells compared to a panel of normal human primary cells. IV administration in in-vivo xenograft mouse models demonstrated virus distribution, replication and increasing transgene expression in tumors over time. IHC confirmed αvβ6 integrin expression in tumors in-vivo. Tumor regression and survival was observed in all indication tested: ovarian, pancreatic, bladder, colorectal and lung. The engineering of ATTR-01 led to viral delivery into the tumor with more than a 100-fold improvement in tumor-to-liver ratio compared to parental Ad5, as well as a good safety profile.

This data confirms tumor selectivity, anti-tumor activity, and a positive non-clinical safety profile of ATTR-01, demonstrating the potential therapeutic benefit of the platform for a wide range of indications. A phase 1 study, ATTEST, is evaluating safety and preliminary efficacy of ATTR-01 IV delivery in patients with selected epithelial tumors expressing high levels of αvβ6 integrin, at multiple UK and Spanish sites.

Thanks to the following authors who also contributed significantly to this study: S Shahreza, NK. Boparan, S. Hardy, A Di Mambro, HK. Uusi-Kerttula, LM. Williams, SL. Moore, BK. Jakobsen Consent statement: All animal studies and human tissues had appropriate ethical approvals.