Abstract CT122: Phase I study of potentially "best-in-class" survivin-responsive conditionally replicating adenovirus for advanced sarcoma actually demonstrates potent and long-term efficacy and high safety

[Background] Recent approvals of oncolytic virus (OV) by FDA and EMA attract the worldwide oncologists and anticancer market. We developed the first platform technology to efficiently construct diverse types of a next-generation conditionally replicating adenovirus (CRA), i.e., CRAs that target and/or treat tumor cells with multiple factors (m-CRAs), which can increase tumor-specificity (i.e., safety) and efficacy (Gene Ther 2005). Using this platform technology, we have generated and tested numbers of m-CRAs as anticancer agents, and found that one of the best was survivin-responsive m-CRAs (Surv.m-CRAs). In preclinical studies, Surv.m-CRAs induced more potent cytotoxic effects against most of malignant tumors than other competing CRAs, and exhibited not only stronger but also more cancer-selective phenotypes than telomerase reverse transcriptase (Tert)-responsive m-CRAs (Cancer Res 2005). Moreover, Surv.m-CRAs induced increased effectiveness against cancer stem cells, which are resistant to conventional therapies (J Trans Med 2014). Preclinical analyses suggested that Surv.m-CRA is the “best-in class” CRA. [Trial protocol] We submitted an IND in March, 2016 and have been performing the first-in-human investigator-initiated ICH-GCP clinical trial for refractory malignant bone and soft tissue tumors (Phase I). Three doses (low: 1×10^10 viral particle [vp], mid: 1×10^11 vp, high: 1×10^12 vp) are planned. Adverse effects were graded according to CTCAE v4.0. Viral shedding into blood, urine and saliva was monitored by PCR. Efficacy was assessed by CT according to RECIST and Choi criteria. [Results] Three patients underwent a single intratumoral injection of low dose Surv.m-CRA-1. Treatment-related adverse events included asymptomatic and temporal leukopenia (grade 3, n=1), CPK elevation (grade 1, n=1), fever (grade 1, n=1) or other mild events (no grade 4 events). Viral shedding into saliva was found in the first case only at 3 hours after injection and was negative in other two cases. Clinical efficacy for target lesion was observed in all three cases (PR or better). First case showed PR by Choi criteria at 4 weeks and PR by RECIST (reduction rate, 50%) at 28 weeks; surprisingly the antitumor efficacy continued for more than one year. In the second case, tumor necrosis (PR by Choi criteria) was found at 4 weeks and subsequently, bone formation (beneficial remodeling) was observed at 12 weeks after the injection. Since no DLT was observed in the low dose coho