1078P - Combining complementary mechanisms of immune activation: NKTR-214, a biased IL-2 pathway agonist and immune checkpoint antagonists

Abstract

NKTR-214 is an agonist of the IL-2 pathway that provides a biased, sustained signal to the IL-2R&bgr;γ complex resulting in expansion of CD8+ T cells compared to regulatory T cells in the tumor. (1) NKTR-214 is currently in an outpatient Phase 1 clinical trial to evaluate MTD, pharmacokinetics, pharmacodynamics and mechanism in solid tumors. Here we describe T-cell clonality and formation of tumor-reactive immune memory after administering NKTR-214 and checkpoint inhibitor antibodies in murine tumor models. Mice bearing subcutaneous established EMT6 breast or CT26 colon tumors were treated with single agent NKTR-214 (q9d), murine anti-CTLA4 or anti-PD1 (twice weekly), or their combinations. Anti-tumor memory was assessed by 1) rechallenging tumor-free mice and 2) transferring splenocytes from tumor-free animals into tumor-bearing recipients. Immune cell enumeration used flow cytometry; T-cell clonality used the ImmunoSEQ platform (Adaptive Biotechnologies). While EMT6 and CT26 were refractory to single agent regimens, NKTR-214 achieved synergistic anti-tumor activity with antiPD1 or antiCTLA4 superior to both antibodies combined. Tumor rechallenge demonstrated anti-tumor memory was durable, specific, and marked by vigorous proliferative memory T cells. The two antibodies produced significant increases in T cell density but modest increases in T cell clonality. In contrast, when NKTR-214 combined with either checkpoint antibody, a greater increase in both T cell density and clonality was observed. NKTR-214 delivers a long-lived, biased activation of the potent IL-2 pathway, favorable pharmacokinetics and mechanistic complementarity to checkpoint inhibition. The combination increases T cell clonality paralleling improved efficacy. The data support the concept of enhancing anti-tumor immunologic memory by combining agonist and antagonist mechanisms, providing increased T cell density and clonality in the tumor. 1. Charych et al., NKTR-214, an Engineered Cytokine with Biased IL2 Receptor Binding, Increased Tumor Exposure, and Marked Efficacy in Mouse Tumor Models. Clinical Cancer Research, 22, 680-690, 2016