Immunological Effects and Viral Gene Expression Determine the Efficacy of Oncolytic Measles Vaccines Encoding IL-12 or IL-15 Agonists

Abstract

Tumor-targeted immunomodulation using oncolytic viral vectors is currently being investigated as a promising strategy in cancer therapy. In a previous study, we showed that a measles virus Schwarz vaccine strain (MeVac) vector encoding an interleukin-12 fusion protein (FmIL-12) is an effective immunotherapy in the MC38cea murine colon adenocarcinoma model. We hypothesized that MeVac encoding interleukin-15 may mediate enhanced T and NK cell responses and thus increase the therapeutic efficacy, especially in NK cell-controlled tumors. Therefore, we generated MeVac vectors encoding an interleukin-15 superagonist, FmIL-15. Replication and oncolytic capacity, transgene expression, and functionality of MeVac FmIL-15 vectors were validated in vitro. Effects on the tumor immune landscape and therapeutic efficacy of both FmIL-12 and FmIL-15 vectors were studied in the MC38cea and B16hCD46 tumor models. Treatment with MeVac FmIL-15 increased T and NK cell infiltration in both models. However, MeVac FmIL-12 showed more robust viral gene expression and immune activation, resulting in superior anti-tumor efficacy. Based on these results, MeVac encoding a human IL-12 fusion protein was developed for future clinical translation.

Measles Vaccines Designed for Enhanced CD8+ T Cell Activation

“…Furthermore, transgenes providing "signal 3" for CD8 + T cell activation, such as pro-inflammatory cytokines [62], could be incorporated into the vector. For instance, measles vaccine vectors encoding IFNβ and interleukin-12 have been developed previously [20,22,63]. Additional transgenes to promote DC function, CTL induction, proliferation, differentiation and to prevent CTL exhaustion can be inserted into the measles vaccine vector.…”

“…Additional transgenes to promote DC function, CTL induction, proliferation, differentiation and to prevent CTL exhaustion can be inserted into the measles vaccine vector. Previous examples include granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-15 as well as immune checkpoint blocking antibodies [17,19,22,23].…”

“…Recombinant measles viruses (MeV) of the Schwarz vaccine strain (MeVac) were generated using the reverse genetics system originally described by Radecke et al [36] with the modifications described previously [22,37]. MeVac encoding enhanced green fluorescent protein (eGFP) has been described previously [20].…”

“…The advantages of oncolytic measles vaccines include the well documented safety record, genomic stability, and the versatility of the reverse genetics system [2,14,15]. Insertion of immunomodulatory genes encoding cytokines, chemokines or immune checkpoint antibodies into the oncolytic vector can enhance anti-tumor immunity [16][17][18][19][20][21][22][23].…”

Oncolytic Virus Encoding a Master Pro-Inflammatory Cytokine Interleukin 12 in Cancer Immunotherapy

“…As IL-12 is a master anti-tumor cytokine and has distinct multifaceted anti-cancer properties [1][2][3]6,8,10], IL-12 expression by OVs is not limited to OHSVs. Several other OVs encoding IL-12 have been developed ( Table 2), including adenoviruses [18,42,[46][47][48][49][133][134][135][136][137][138], measles virus [20,50], maraba virus [51], Newcastle disease virus [52], Semliki forest virus [53][54][55][56][139][140][141], vesicular stomatitis virus [57,142], and Sindbis virus [58]. In these above-mentioned studies, IL-12 is expressed either alone [18,20,51,57,[137][138][139] or co-expressed alongside with GM-CSF [134][135][136], pericellular matrix proteoglycan decorin [47], tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) [133], IL-2 proinflammator...…”