Abstract 4185: Neutralizing human IFN-β combined with anti-human PD-L1 and anti-human CTLA-4 treatment increased control of endometrial tumor growth in a novel HLA-A matched BLT humanized mice
Authors: Yuan Zhe , Zu Guorui , Sun Xiao , Papasavvas Emmanouil , Lu Lily , Cassel Joel , Lutes Peter L. , Cadungog Mark , Salvino Joseph , Montaner Luis J. 
Published: March 2024

High concentrations of type I interferon can induce growth arrest and apoptosis in cancer cells upon acute exposure, while low concentrations of the same can provide significant pro-survival benefits upon chronic exposure. In vitro data show the dependence of cancer cells on self-generated IFN-I leads to their demise if the IFN-β gene is disrupted, but they manage to persist when provided with IFN-β from an external source. Importantly, murine models show that inhibition of myeloid-associated INF-β can limit tumor growth. As blockage of type I interferon can also restore the CD8+ T cell function after chronic viral infection, we sought to determine the effects of neutralizing anti-human IFN-β antibody 7859 (N-anti-IFN-β) when added to T-cell directed immunotherapy in BLT humanized mice implanted with HLA-A matched human endometrial cancer PDX specimens. Specifically, we tested the combination of immunotherapy with N-anti-IFN-β combined with anti-human PD-L1 and anti-human CTLA-4. N-anti-IFN-β was first characterized for neutralizing activity to confirm specific neutralization of IFNβ and not human IFN-β. HLA-A matched genotyped CD34 stem cells and thymus (BLT humanized mice) and clinical endometrial tumors (PDX) were joined in BLT humanized mice before infusions with N-anti-IFN-β with or without anti-human PD-L1 and anti-human CTLA-4, anti-human PD-L1 and anti-human CTLA-4 alone, and IgG control antibodies intraperitoneally twice per week over three weeks. Tumor sizes were measured weekly and weighted at the end of the study. Human leukocytes infiltrating PDX were assessed by IHC and flow cytometry. Leukocyte subset activation, exhaustion, and tumor-specific T-cell function were measured. Anti-human PD-L1 and anti-human CTLA-4 reduced tumor growth by 82.9% (p&lt;0.0001), but quickly increased the T cell exhaustion markers PD-1 and LAG3. The addition of N-anti-IFN-β to immunotherapy significantly decreased the tumor growth rate by 96.2% (p&lt;0.0001) also significantly different from immunotherapy alone (p=0.0009) N-anti-IFN-β monotherapy reduced tumor growth rate by 42.4% (p=0.0032). While there was an increase in infiltrating CD4 and CD8 T-cells in combination therapy, reductions in expression of PD-1 and LAG3 were observed when compared to immunotherapy or N-IFN-β groups alone Analysis was done with Prism software. The use of a novel HLA-A matched BLT humanized mice with human tumor PDX model shows that neutralization of IFN-β can increase the T-cell anti-tumor activity and tumor repression of immunotherapy with anti-human PD-L1 and anti-human CTLA-4 treatment.

Citation Format: Zhe Yuan, Guorui Zu, Xiao Sun, Emmanouil Papasavvas, Lily Lu, Joel Cassel, Peter L. Lutes, Mark Cadungog, Joseph Salvino, Luis J. Montaner. Neutralizing human IFN-β combined with anti-human PD-L1 and anti-human CTLA-4 treatment increased control of endometrial tumor growth in a novel HLA-A matched BLT humanized mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4185.