Preclinical evaluation of naturally derived viral nucleic acids in combination cancer immunotherapy

Abstract Effective cancer immunotherapy often requires coordinated activation of innate and adaptive immune responses. While the previous studies have primarily focused on whole oncolytic viruses, synthetic or engineered viral nucleic acids, or inactivated viral particles, the therapeutic potential of purified, naturally derived viral nucleic acids has remained largely unexplored. Here, we performed a preclinical evaluation of naturally derived viral RNA- and DNA-based combination immunotherapy in the murine Renca renal adenocarcinoma model. BALB/c mice-bearing subcutaneous tumors received intratumoral treatment with CpG plus anti-OX40, CpG plus 3p-hpRNA, 3p-hpRNA alone, influenza virus RNA (IV-RNA) plus anti-OX40, or porcine parvovirus DNA (PPV1-DNA) plus anti-OX40. Several treatment regimens were associated with improved survival and delayed tumor progression compared with PBS-treated controls. The greatest survival benefit was observed with CpG plus anti-OX40 (70% survival at day 38), followed by IV-RNA plus anti-OX40 (60%) and 3p-hpRNA alone (50%). IV-RNA combined with anti-OX40 demonstrated therapeutic activity comparable to that observed with CpG plus anti-OX40. In addition, treated tumors exhibited well-demarcated morphology and a markedly lower incidence of metastasis (13–38%) than PBS-treated controls (78%), consistent with improved local tumor control. Overall, these findings provide preclinical evidence that naturally derived viral nucleic acids may represent promising components of combination cancer immunotherapy. Although the underlying mechanisms remain to be elucidated, the observed therapeutic activity and reduced incidence of metastasis support further investigation of naturally derived viral nucleic acids in preclinical cancer immunotherapy.