Enhancing Therapeutic Efficacy of Oncolytic Herpes Simplex Virus-1 with Integrin β1 Blocking Antibody OS2966

Abstract

Integrin b1 receptor, expressed on the surface of tumor cells and macrophages in the tumor microenvironment (TME), has been implicated in both tumor progression and resistance to multiple modalities of therapy. OS2966 is the first clinical-ready humanized monoclonal antibody to block integrin b1 and was recently orphan designated by the FDA Office of Orphan Products Development. Here, we tested therapeutic potential of OS2966-mediated integrin b1 blockade to enhance the efficacy of oncolytic herpes simplex virus-1 (oHSV) through evaluation of virus replication, tumor cell killing efficiency, effect on the antiviral signaling pathway, co-culture assays of oHSV-infected cells with macrophages, and in vivo bioluminescence imaging on mammary fat pad triple-negative breast cancer xenograft and subcutaneous and intracranial glioma xenografts. OS2966 treatment decreased interferon signaling and proinflammatory cytokine induction in oHSV-treated tumor cells and inhibited migration of macrophages, resulting in enhanced oHSV replication and cytotoxicity. OS2966 treatment also significantly enhanced oHSV replication and oHSV-mediated antitumor efficacy in orthotopic xenograft models, including triple-negative breast cancer and glioblastoma. The results demonstrated the synergistic potential of the combinatory treatment approach with OS2966 to improve antitumor efficacy of conventional oHSV therapy.

The Current State of Oncolytic Herpes Simplex Virus for Glioblastoma Treatment

“… 145 Blockade of ITGB1 with OS2966 (a humanized CD29 blocking antibody) overturned bevacizumab-induced resistance. 145 Although OS2966 enhanced oHSV replication and GBM cell cytotoxicity in vitro, 146 systemic OS2966 delivery did not enhance the anti-tumor efficacy of oHSV (rHSVQ1-IE4/5-Luciferase) in vivo. Insufficient delivery of OS2966 to the brain may have contributed to the failure to obtain a combination effect.…”

“…To overcome this issue, OS2966 was directly injected intracranially into GBM xenograft 2 days prior to oHSV treatment, and this time, the combination significantly extended survival compared to monotherapies. 146 In contrast to OS2966, systemic delivery of cilengitide (another integrin inhibitor) significantly enhanced the anti-glioma efficacy of RAMBO compared to single treatments. 147 Cilengitide has been evaluated in GBM patients 148 and could be a better choice than OS2966 for combination studies.…”

Clinically Explored Virus-Based Therapies for the Treatment of Recurrent High-Grade Glioma in Adults

“…Integrin-mediated entry has also been utilized to improve both viral tropism and replication [ 93 , 94 ]. Lee et al showed that the β1 integrin blockade improved replication of an HSV variant and promoted antitumor efficacy in patient-derived primary glioblastoma-bearing mice [ 95 ].…”

The Role of the Tumor Microenvironment in Developing Successful Therapeutic and Secondary Prophylactic Breast Cancer Vaccines

“…Oncolytic viruses (OV) transform immunotherapy from a sterile immunity to a pathogen-associated-like immunity, as these viruses replicate preferentially in tumor cells and release TAAs and PAMPS [ 132 , 133 ]. In this emerging in situ vaccination strategy in breast cancer models, pox- [ 134 , 135 ], reo- [ 136 ], herpes simplex [ 137 , 138 , 139 ], adeno- [ 140 , 141 , 142 , 143 ], Newcastle disease [ 144 , 145 ], Vesicular stomatitis [ 146 ], and measles [ 147 , 148 , 149 ] viruses have been employed to make breast tumors more immunogenic and more responsive to immunotherapies by priming the TME to signs of infection and releasing TAAs [ 150 ]. Moreover, these viruses can be engineered to express various TAAs to further prime an immunological response from TME.…”