Abstract 3675: Novel immune oncology strategy for targeted cytotoxic lymphocyte activation
Authors: Lazier Eric , Hein Sarah , Westwick John , Watkins Dan , Krupnick Alexander S. 
Published: July 2017

High-dose interleukin 2 (IL2) therapy was the first FDA-approved immunotherapy, and still has an exceptionally high true long-term cure rate for metastatic cancer. However, IL2 therapy has fallen out of favor due to systemic toxicity and off-target side effects. We have recently described a novel fusion cytokine comprised of a mutant form of IL2 with inhibited α-receptor binding and an NKG2D-binding viral decoy protein called Orthopox Major Histocompatibility Complex Class I-like Protein (OMCP). Unlike wild-type IL2, our fusion cytokine (OMCP-mutIL2) binds to and activates only NKG2D expressing cytotoxic lymphocytes. This targeted IL2 activity results in superior efficacy and decreased toxicity over wild-type IL2 therapy. Here, we present data which further establishes the superior efficacy of OMCP-mutIL2 therapy as measured by biomarkers such as systemic cytokine production and tumor lymphocyte infiltration. Additionally, we present data which evaluates OMCP-mutIL2 therapy as a potentiator of PD1 checkpoint inhibitor therapy.

To evaluate tumor lymphocyte infiltration mice with established Lewis Lung Carcinoma (LLC) flank tumors were treated for three days with either saline, wild type IL2, or OMCP-mutIL2 and tumor infiltrating lymphocytes evaluated flow cytometrically.

A trend for increased tumor infiltrating NK cells was evident for both IL2 and OMCP-mutIL2 treated groups over saline controls, and OMCP-mutIL2 tended to increase tumor infiltrating CD8+ T cells over either IL2 or saline controls was evident as well. Additionally, tumor infiltrating CD8+ T cells in IL2-treated mice had a higher level of exhaustion over OMCP-mutIL2 treated mice as measured by PD-1 expression. Tumor infiltrating CD4+ T cells also showed a trend toward a Foxp3 regulatory phenotype in IL2 treated mice over OMCP-mutIL2. To study cytokine serum profile mice were treated with high dose OMCP-mutIL2 with or without NK depletion and serum cytokine levels measured by cytometric bead array. Serum cytokine analysis of mice treated with supra-therapeutic doses of OMCP-mutIL2 did not reveal an increase in pro-inflammatory cytokines TNF-α, IFN-γ, and IL-6. A significant increase in serum levels of G-CSF was evident in NK cell sufficient mice treated with OMCP-mutIL2. Combination immunotherapy was initiated by the addition of PD-1 blockade (clone RMPI-14) to OMCP-mutIL2 therapy in a lung LLC tumor model. Combination therapy led to near complete control of LLC growth in the lung compared to OMCP-mutIL2 or PD-1 blockade alone.

The data presented here suggest that in addition to our previously published data suggesting increased safety of OMCP-mutIL2 over high-dose IL2 therapy, OMCP-mutIL2 therapy may be functionally superior to classic high-dose IL2 therapy. Continued development of OMCP-mutIL2 is ongoing.

Citation Format: Eric Lazier, Sarah Hein, John Westwick, Dan Watkins, Alexander S. Krupnick. Novel immune oncology strategy for targeted cytotoxic lymphocyte activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3675. doi:10.1158/1538-7445.AM2017-3675