Oncolytic viruses (OVs) are promising candidates for innovative cancer treatment technologies as two products have been approved in developed countries. In early 90’s (at the dawn of gene therapy), we first developed a combination suicide gene and cytokine gene therapy, which became part of the underlying principles of OV immunotherapy that efficiently induced systemic anti-tumor immunity. To further develop OV in Japan, we developed an original platform technology of “Conditionally replicating adenovirus that regulated with multiple factors” (m-CRA). Survivin-responsive m-CRA (Surv.m-CRA), which we developed using the technology, demonstrated innovative therapeutic effects, 1) superiority over competing technologies in both therapeutic efficacy and safety, 2) cancer-specific technology that can be administered systemically, and 3) ability to effectively treat cancer stem cells that are resistant to conventional therapies (advantage over existing technologies). For the clinical development of the first generation Surv.m-CRA-1, which does not yet carry a therapeutic gene, we conducted ICH-compliant non-clinical development (GMP manufacturing, GLP safety testing) and regulatory compliance (Cartagena, PMDA consultation). We completed the First-In-Human phase I clinical trial of Surv.m-CRA-1 (no transgene) for malignant tumors in bone or soft tissue region that were resistance to standard therapy. A protocol of low, intermediate, and high dose groups was used, with confirmed safety and suggested efficacy in 9 patients. Based on these positive results, a multicenter, investigator-initiated clinical trial (Phase II) is currently underway, aiming for early approval (orphan, regenerative medicine product) for malignant bone tumors. We are also developing two types of second-generation Surv.m-CRA-2s, which are armed with immune genes, and which efficiently induced systemic anti-tumor immunity and effectively inhibited metastasis in animal models. Furthermore, we are developing new third- and fourth-generation m-CRAs technologies and drugs. Here we present our basic research on recombinant virus and drug discovery, non-clinical development, and First-In-Human clinical trials. We would be happy if our presentation could contribute to the discussion of issues in the development of new modalities of gene therapy.