BACKGROUND: Oncolytic adenoviruses (OAds) are the most clinically tested viral vectors for solid tumors. However, most clinically tested "Armed" OAds show limited antitumor effects in patients with various solid tumors even with increased dosages and multiple injections. We developed a binary oncolytic/helper-dependent adenovirus system (CAdVEC), in which tumors are coinfected with an OAd and a non-replicating helper-dependent Ad (HDAd). We recently demonstrated that a single low-dose CAdVEC expressing interleukin-12, programmed death-ligand 1 blocker, and HSV thymidine kinase safety switch (CAdTrio) induces significant antitumor effects in patients, including complete response. Similar to previous OAd studies, all patients primarily amplified Ad-specific T cells after treatment however, CAdVEC was still able to induce clinical responses even given at a 100-fold lower dose. METHODS: To address the mechanisms of CAdTrio-mediated antitumor effect in patients, we analyzed patients' samples using Enzyme-linked immunosorbent spot (ELISpot) to measure T-cell specificity and quantitative polymerase chain reaction (qPCR) to measure CAdVEC viral genome copies at tumor sites. We then evaluated potential mechanisms of CAdVEC efficacy in vitro using live-cell imaging. Based on those results, we developed a new CAdVEC additionally expressing a T-cell engager molecule targeting CD44v6 to redirect tumor-infiltrating irrelevant T cells against cancer stem cell populations (CAdTetra) for further improvement of local CAdVEC treatment. We tested its efficacy against different cancer types both in vitro and in vivo including Ad pre-immunized humanized mice. RESULTS: We found that HDAd-infected cells escape Ad-specific T-cell recognition with enhanced tumor-specific T-cell activity through immunomodulatory transgenes. Since CAdVEC treatment initially amplified Ad-specific T cells in patients, we re-direct these virus-specific T cells to target tumor cells by additionally expressing CD44v6.BiTE from CAdTetra. CAdTetra significantly controlled tumor growth, repolarizing local and systemic responses against cancer cells in both immunologically "hot" and "cold" tumor models and also induced immunologic memory against rechallenged tumors. CONCLUSIONS: Our results indicate that CAdTetra effectively induces adaptive T-cell responses against cancer cells by using tumor-infiltrating irrelevant T cells.