Abstract 3258: THOR-707, a novel not-alpha IL-2, elicits durable pharmacodynamic responses in non-human primates and efficacy as single agent and in combination with anti PD-1 in multiple syngeneic mouse models
Authors: Joseph Ingrid B. , Ma Lina , Ptacin Jerod L. , Caffaro Carolina E. , Aerni Hans R. , Jose Kristine M. San , Pena Michael J. , Herman Robert W. , Pavlova Yelena , Chen David B. , Bragstad Ken , Li Shukuan , Nguyen Jasmine , Shawver Laura K. , Koriazova Lilia K. , Milla Marcos E. 
Published: August 2019

Aldesleukin is a recombinant form of IL-2 approved for metastatic melanoma and renal cell carcinoma that induced complete, durable remissions in certain patients. Yet, its use is infrequent because of vascular leak syndrome (VLS), a severe dose-limiting adverse event stemming from the engagement of the high affinity IL-2 receptor (IL-2R) alpha chain in type 2 innate lymphoid cells, eosinophils and vascular endothelial cells. THOR-707 is a site-directed, singly pegylated form of IL-2 completely lacking IL-2R alpha chain engagement yet retaining normal binding to the intermediate affinity IL-2R beta-gamma signaling complex expressed by natural killer (NK) and CD8+ T tumor-killing cells. We studied THOR-707 pharmacokinetics (PK) and pharmacodynamics (PD) in non-human primates (NHP) to evaluate peripheral biomarkers of immune cell activation (expansion of NK, CD8+ T and CD4+ regulatory T (Treg) cells and the induction of pSTAT5 and the proliferation marker Ki67). Here we show that in NHP, THOR-707 elicits the expansion of peripheral CD8+ T cells and the persistence of that response with different administration regimes. We also show that in the mouse syngeneic colon tumor model CT-26, THOR-707 induced Ki67 and the expansion of peripheral NK and CD8+ T cells. Within the tumor, THOR-707 promoted an increase in the numbers of infiltrating tumor-killing NK and CD8+ T cells without expansion of suppressive CD4+ Treg cells. Immunohistochemical (IHC) analysis showed that in THOR-707 treated animals, CD8+ T cells were mostly seen around the edges of the tumor and at areas of necrosis. Evaluation of T cell receptor (TCR) clonality revealed that treatment with THOR-707 increased intra-tumoral T cell diversity compared to the untreated animals. THOR-707 induction of CD8+ T cell tumor infiltration resulted in single agent dose-dependent anti-tumor efficacy, and additive efficacy in combination with PD-1 checkpoint inhibitor, increasing the survival of CT-26 tumor-bearing mice over either group alone. The pharmacodynamics, T cell infiltration and clonality, and efficacy of THOR-707 in two additional syngeneic models, have also been studied. Filing of an investigational new drug application for THOR-707 is expected in the second quarter of 2019 and thereafter initiation of a Phase 1/2 clinical trial in multiple tumor types as a single agent and in combination with an immune checkpoint inhibitor.

Citation Format: Ingrid B. Joseph, Lina Ma, Jerod L. Ptacin, Carolina E. Caffaro, Hans R. Aerni, Kristine M. San Jose, Michael J. Pena, Robert W. Herman, Yelena Pavlova, David B. Chen, Ken Bragstad, Shukuan Li, Jasmine Nguyen, Laura K. Shawver, Lilia K. Koriazova, Marcos E. Milla. THOR-707, a novel not-alpha IL-2, elicits durable pharmacodynamic responses in non-human primates and efficacy as single agent and in combination with anti PD-1 in multiple syngeneic mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3258.