Combination Therapy with NHS-muIL12 and Avelumab (anti-PD-L1) Enhances Antitumor Efficacy in Preclinical Cancer Models

Abstract

To determine whether combination therapy with NHS-muIL12 and the anti-programmed death ligand 1 (PD-L1) antibody avelumab can enhance antitumor efficacy in preclinical models relative to monotherapies. BALB/c mice bearing orthotopic EMT-6 mammary tumors and μMt mice bearing subcutaneous MC38 tumors were treated with NHS-muIL12, avelumab, or combination therapy; tumor growth and survival were assessed. Tumor recurrence following remission and rechallenge was evaluated in EMT-6 tumor-bearing mice. Immune cell populations within spleen and tumors were evaluated by FACS and IHC. Immune gene expression in tumor tissue was profiled by NanoString® assay and plasma cytokine levels were determined by multiplex cytokine assay. The frequency of tumor antigen-reactive IFNγ-producing CD8 T cells was evaluated by ELISpot assay. NHS-muIL12 and avelumab combination therapy enhanced antitumor efficacy relative to either monotherapy in both tumor models. Most EMT-6 tumor-bearing mice treated with combination therapy had complete tumor regression. Combination therapy also induced the generation of tumor-specific immune memory, as demonstrated by protection against tumor rechallenge and induction of effector and memory T cells. Combination therapy enhanced cytotoxic NK and CD8 T-cell proliferation and T-bet expression, whereas NHS-muIL12 monotherapy induced CD8 T-cell infiltration into the tumor. Combination therapy also enhanced plasma cytokine levels and stimulated expression of a greater number of innate and adaptive immune genes compared with either monotherapy. These data indicate that combination therapy with NHS-muIL12 and avelumab increased antitumor efficacy in preclinical models, and suggest that combining NHS-IL12 and avelumab may be a promising approach to treating patients with solid tumors. .

The antibody-based delivery of interleukin-12 to solid tumors boosts NK and CD8+T cell activity and synergizes with immune check-point inhibitors

“…L19-mIL12 exhibited potent single agent activity, which was enhanced by combination with immune checkpoint inhibitors. In keeping with our findings, the combination of NHS-IL12 (an IL12 fusion based on an antibody directed against DNA released from necrotic tumor cells in full IgG format) with PD-L1 blockade had also revealed a synergistic activity 64 . However, no biodistribution studies with IL12 fusions in IgG format have been published so far and it is therefore difficult, at this stage, to assess whether these molecules have equivalent activity.…”

The antibody‐based delivery of interleukin‐12 to solid tumors boosts NK and CD8+ T cell activity and synergizes with immune checkpoint inhibitors

“…In keeping with our findings, the combination of NHS-IL12 (an IL12 fusion based on an antibody directed against DNA released from necrotic tumor cells in full IgG format) with PD-L1 blockade had also revealed a synergistic activity. 62 However, no biodistribution studies with IL12 fusions in IgG format have been published so far and it is therefore difficult, at this stage, to assess whether these molecules have equivalent activity. In principle, the tandem diabody format (used in this work) should promote an easier extravasation and tumor targeting process, while rapidly clearing from circulation.…”

Immuno‐oncology gene expression profiling of formalin‐fixed and paraffin‐embedded clear cell renal cell carcinoma: Performance comparison of the NanoString nCounter technology with targeted RNA sequencing

“…Until now, there are only a few studies that employed either the nCounter‐based Pan Cancer Immune Profiling panel (NanoString Technologies) 25‐27 or the Ion Torrent semiconductor RNA‐Seq based Oncomine Immune Response Research Assay (Thermo Fisher Scientific) 28,29 in a few cancer entities including melanoma and head and neck cancer. To the best of our knowledge, our study is the first to compare these two technical platforms and to validate their performance using real‐world FFPE clear cell RCC cases.…”