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

Date 09 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Cancer Immunology and Immunotherapy
Presenter Deborah Charych
Citation Annals of Oncology (2016) 27 (6): 359-378. 10.1093/annonc/mdw378
Authors D.H. Charych, P. Kuo, M. Addepalli, V. Dixit, R. Pena, W. Rubas, U. Hoch, J. Langowski, S.K. Doberstein, J. Zalevsky
  • Research Biology, Nektar Therapeutics, 94158 - San Francisco/US

Abstract

Background

NKTR-214 is an agonist of the IL-2 pathway that provides a biased, sustained signal to the IL-2Rßɣ 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.

Methods

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).

Results

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.

Conclusions

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

Clinical trial identification

Legal entity responsible for the study

Nektar Therapeutics

Funding

Nektar Therapeutics

Disclosure

D.H. Charych, V. Dixit: Employee and stock holder of nectar therapeutics. P. Kuo: Employee and stock holder of Nektar. M. Addepalli: Employee and stock holder of nectar therapeutics. R. Pena, W. Rubas, U. Hoch, J. Langowski, S.K. Doberstein: Employee and stock holder of nectar. J. Zalevsky: Employee and stock holder of nectar. accepted travel reimbursement from Takeda within last two years.