Abstract
Oncolytic viruses (OVs) have been shown to induce anti-cancer immunity and enhance cancer immunotherapies, such as immune checkpoint inhibitor therapies. OV therapies can be further improved by arming OVs with immunostimulatory molecules, including various cytokines or chemokines. Here, we have developed a novel adenovirus encoding two immunostimulatory molecules: cluster of differentiation 40 ligand (CD40L) and tumor necrosis factor receptor superfamily member 4 ligand (OX40L). This novel virus, designated VALO-D102, is designed to activate both innate and adaptive immune responses against tumors. CD40L affects the innate side by licensing antigen-presenting cells to drive CD8+ T cell responses, and OX40L increases clonal expansion and survival of CD8+ T cells and formation of a larger pool of memory T cells. VALO-D102 and its murine surrogate VALO-mD901, expressing murine OX40L and CD40L, were used in our previously developed PeptiCRAd cancer vaccine platform. Intratumoral administration of PeptiCRAd significantly increased tumor-specific T cell responses, reduced tumor growth, and induced systemic anti-cancer immunity in two mouse models of melanoma. In addition, PeptiCRAd therapy, in combination with anti-PD-1 immune checkpoint inhibitor therapy, significantly improved tumor growth control as compared to either monotherapy alone.
Highlights
Cancer immunotherapies, including antibodies targeting immune checkpoint molecules, such as PD-1, PD-L1 and CTLA-4, have emerged as an unprecedented breakthrough for the treatment of cancer that can induce long-term tumor regression
Novel oncolytic adenovirus (OAd) VALO-D102 produces high levels of biologically active human cluster of differentiation 40 ligand (CD40L) and OX40L VALO-D102 (Ad5/3-D24-OX40L-CD40L) is a serotype 5 oncolytic human adenovirus where the serotype 5 knob has been replaced by a serotype 3 knob for enhanced gene delivery into tumor tissue.[16]
High levels of functional CD40L activity produced by VALO-D102 suggest that the A2 self-cleaving peptide sequence between the OX40L and CD40L genes was able to efficiently uncouple the translation between the two transgenes (Data S1)
Summary
Cancer immunotherapies, including antibodies targeting immune checkpoint molecules, such as PD-1, PD-L1 and CTLA-4, have emerged as an unprecedented breakthrough for the treatment of cancer that can induce long-term tumor regression. The use of immune checkpoint inhibitor (ICI) antibodies can create durable responses in only a small minority of cancer patients, the response rate being 10%–25% in a majority of cancers.[1] The common feature among patients responding to ICI therapy is that they have an existing antitumor immune response with immune cell infiltration in the tumor tissue prior to ICI therapy.[2,3] These immune cell-infiltrated tumors are called “hot” tumors. The remaining 75%–90% of patients are not responding due to a lack of anti-tumor immune responses or other immune-suppressive aspects of the tumor microenvironment (TME). These tumors that have not been recognized by the immune system or have not provoked a spontaneous immune response are collectively called “cold” tumors
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