Nektar Reports Preclinical Data Presented at AACR, Showed Combining NKTR-214 with Checkpoint Blockade is Superior to Dual Checkpoint Inhibition

Nektar Therapeutics

today announced new preclinical data for the company's investigational immuno-stimulatory cytokine therapy, NKTR-214, which demonstrate both its activity as a single-agent and its synergistic activity with checkpoint blockade. In a TCR repertoire analysis conducted to assess both anti-tumor T cell clonality and T cell tumor infiltration (TIL clonality and infiltration), the combination of NKTR-214 and a checkpoint inhibitor resulted in dramatically higher increases for both parameters as compared to dual checkpoint inhibition. These data were presented at the American Association for Cancer Research (AACR) Annual Meeting in New Orleans, LA on April 17, 2016. TIL clonality establishes the frequency of T cells with a specific TCR Vβ and TCR Jβ chain usage at the tumor site, which suggests increased CD8-positive effector T cell function against the specific tumor.1 The concomitant presence of both TIL clonality and infiltration has been significantly correlated with clinical response and better survival outcomes in patients.1 In a CT26 colon carcinoma model, sequencing for TCRs in the tumor was conducted using Adaptive Biotechnologies' ImmunoSEQ platform. Measurements of TIL clonality and infiltration were assessed seven days after treatment. NKTR-214 as a single-agent led to superior increases in TIL clonality and infiltration as compared to either anti-CTLA-4 or anti-PD-1 therapy alone. The combination of NKTR-214 with either mode of checkpoint inhibition led to superior increases in both TIL clonality and infiltration relative to the combination of CTLA-4 and PD-1 inhibitors. The highest increases occurred when NKTR-214 was added to an anti-PD-1 therapy. "We are particularly excited by these new preclinical data for the combination of NKTR-214 with a checkpoint inhibitor which show an induced oligoclonal T cell response along with high TIL infiltration, "said Dr. Jonathan Zalevsky, Vice President of Biology at Nektar Therapeutics. "These data demonstrate that the addition of NKTR-214 to either an anti-CTLA-4 or anti-PD-1 agent could improve T cell clonality differences over checkpoint blockade therapies." NKTR-214 is an investigational CD122-biased agonist currently in Phase 1/2 clinical development. NKTR-214 is designed to stimulate the patient's own immune system to kill tumor cells by preferentially activating production of specific immune cells which promote tumor killing, including CD8-positive T cells and Natural Killer (NK) cells, within the tumor micro-environment. CD122, which is also known as the Interleukin-2 receptor beta subunit, is a key signaling receptor that is known to increase proliferation of these types of T cells.2 In studies conducted in multiple established tumor models presented at AACR, NKTR-214 demonstrated activity as both a single-agent and when co-dosed with either an anti-PD-1 agent or an anti-CTLA-4 agent. In a tumor re-challenge study conducted in an EMT6 colon carcinoma model, sequential dosing of anti-CTLA-4 followed by NKTR-214 resulted in durable immunity, with complete responders resisting a tumor re-challenge. Following a second re-challenge, 100% of the animals remained tumor-free without additional treatment. "Our latest preclinical findings continue to show that treatment with NKTR-214 either as a single-agent or in combination with checkpoint blockade is superior to single or dual checkpoint inhibition in multiple models," added Steve Doberstein, PhD, Senior Vice President and Chief Scientific Officer of Nektar Therapeutics. "These new data emphasize the cellular mechanisms underlying the remarkable efficacy of NKTR-214 in our preclinical models of cancer." The data presentation at AACR entitled, "Durable antitumor activity of the CD122-biased immuno-stimulatory cytokine NKTR-214 combined with immune checkpoint blockade," can be accessed at http://www.nektar.com/product_pipeline/oncology_nktr-214.html In preclinical studies, NKTR-214 demonstrated a highly favorable mean ratio of 450:1 within the tumor micro-environment of CD8-positive effector T cells relative to regulatory T cells.3 Furthermore, the pro-drug design of NKTR-214 enables an antibody-like dosing regimen for an immuno-stimulatory cytokine.4