To improve the efficacy of oncolytic viruses, De Lucia et al. modified a human HER2 (hHER2)-retargeted oncolytic herpes simplex virus (oHSV) to express both mIL-12 and mGM-CSF (double arm R123). In a PD-1-non-responsive, hHER2-transgenic mouse model bearing large, established tumors, intratumoral monotherapies (GM-CSF or IL-12 single arm oHSVs) were poorly effective, but the combination of double arm R123 oHSV with anti-PD-1 resulted in 100% efficacy. Efficacy of the combination was T cell-dependent and long lasting. When delivered systemically, the combination controlled lung metastases, suggesting translational opportunities.
Contributed by Katherine Turner
ABSTRACT: Oncolytic viruses (OVs) are novel anti-tumor agents with the ability to selectively infect and kill tumor cells while sparing normal tissue. Beyond tumor cytolysis, OVs are capable of priming an anti-tumor immune response via lysis and cross-presentation of locally expressed endogenous tumor antigens, acting as an "endovaccine." The effectiveness of OVs, similar to other immunotherapies, can be hampered by an immunosuppressive tumor microenvironment. In this study, we modified a previously generated oncolytic herpes simplex virus (oHSV) retargeted to the human HER2 (hHER2) tumor molecule and encoding murine interleukin-12 (mIL-12), by insertion of a second immunomodulatory molecule, murine granulocyte-macrophage colony-stimulating factor (mGM-CSF), to maximize therapeutic efficacy. We assessed the efficacy of this double-armed virus (R-123) compared to singly expressing GM-CSF and IL-12 oHSVs in tumor-bearing mice. While monotherapies were poorly effective, combination with _-PD1 enhanced the anti-tumor response, with the highest efficacy of 100% response rate achieved by the combination of R-123 and _-PD1. Efficacy was T cell-dependent, and the induced immunity was long lasting and able to reject a second contralateral tumor. Importantly, systemic delivery of R-123 combined with _-PD1 was effective in inhibiting the development of tumor metastasis. As such, this approach could have a significant therapeutic impact paving the way for further development of this platform in cancer immunotherapy.
Author Info: (1) Nouscom S.r.l., Via Castel Romano 100, 00128 Rome, Italy. (2) Nouscom S.r.l., Via Castel Romano 100, 00128 Rome, Italy. (3) Nouscom S.r.l., Via Castel Romano 100, 00128 Rome, I
Author Info: (1) Nouscom S.r.l., Via Castel Romano 100, 00128 Rome, Italy. (2) Nouscom S.r.l., Via Castel Romano 100, 00128 Rome, Italy. (3) Nouscom S.r.l., Via Castel Romano 100, 00128 Rome, Italy. (4) Nouscom S.r.l., Via Castel Romano 100, 00128 Rome, Italy. (5) Nouscom S.r.l., Via Castel Romano 100, 00128 Rome, Italy. (6) Nouscom S.r.l., Via Castel Romano 100, 00128 Rome, Italy. (7) Nouscom S.r.l., Via Castel Romano 100, 00128 Rome, Italy. (8) Nouscom S.r.l., Via Castel Romano 100, 00128 Rome, Italy. (9) Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40126 Bologna, Italy. (10) CEINGE-Biotecnologie Avanzate S.C. aR.L., via Gaetano Salvatore 486, 80145 Naples, Italy. Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universit degli Studi di Napoli Federico II, Via Sergio Pansini 5, 80131 Napoli, Italy. (11) CEINGE-Biotecnologie Avanzate S.C. aR.L., via Gaetano Salvatore 486, 80145 Naples, Italy. Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universit degli Studi di Napoli Federico II, Via Sergio Pansini 5, 80131 Napoli, Italy. (12) CEINGE-Biotecnologie Avanzate S.C. aR.L., via Gaetano Salvatore 486, 80145 Naples, Italy. Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universit degli Studi di Napoli Federico II, Via Sergio Pansini 5, 80131 Napoli, Italy. (13) Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40126 Bologna, Italy. (14) CEINGE-Biotecnologie Avanzate S.C. aR.L., via Gaetano Salvatore 486, 80145 Naples, Italy. Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universit degli Studi di Napoli Federico II, Via Sergio Pansini 5, 80131 Napoli, Italy. (15) Nouscom S.r.l., Via Castel Romano 100, 00128 Rome, Italy. (16) Nouscom S.r.l., Via Castel Romano 100, 00128 Rome, Italy.
