Single-Agent NKTR-214 Produces a Large Increase in Tumor-Infiltrating Lymphocytes to Provide Durable Anti-Tumor Activity
Published on 07th June
New preclinical data for NKTR-214, an immuno-stimulatory CD-122 biased cytokine being developed by Nectar Therapeutics iscurrently being evaluated in cancer patients with solid tumors in a Phase I/II clinical trial being conducted at MD Anderson Cancer Centerand Yale Cancer Center.
The Phase I/II clinical study evaluates NKTR-214 in patients with advanced solid tumors, including melanoma, renal cell carcinoma and non-small cell lung cancer.The first stage of this study, which is expected to be complete in the second half of 2016, is evaluating escalating doses of single-agent NKTR-214 treatment in approximately 20 patients with solid tumors.The primary objective of the first stage of the study is to evaluate the safety and efficacy of NKTR-214 and to identify a recommended Phase II dose.In addition, the study will also assess the immunologic effect of NKTR-214 on TILs and other immune cells in both blood and tumor tissue, and it will also include TCR repertoire profiling.Dose expansion cohorts are planned to evaluate NKTR-214 in specific tumor types, including melanoma, renal cell carcinoma and non-small cell lung cancer.
The new preclinical data presented demonstrate that treatment with single-agent NKTR-214 mobilizes tumor-killing T cells into colon cancer tumors. In addition, mouse pharmacodynamics data demonstrated that a single dose of NKTR-214 can increase and sustain STAT5 phosphorylation (a marker of IL-2 pathway activation) through one week post-dose. These data were presented at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, IL from June 3-7, 2016.
“These latest data build upon our growing body of preclinical evidence demonstrating the unique mechanism of NKTR-214,” added Jonathan Zalevsky, PhD, Vice President, Biology and Preclinical Development at Nektar Therapeutics. “The studies presented at ASCO show that NKTR-214 promotes tumor-killing immune cell accumulation directly in the tumor, providing a mechanistic bais for its significant anti-tumor activity in multiple preclinical tumor models.The ability to grow TILs in vivo and replenish the immune system is exceptionally important. We’ve now learned that many human tumors lack sufficient TIL populations and the addition of the NKTR-214 TIL-enhancing MOA could improve the success of many checkpoint inhibitors and other agents, and allow more patients to benefit from immuno-therapy.”
In studies previously published for NKTR-214, when mice bearing established breast cancer tumors are treated with NKTR-214 and anti-CTLA4 (a checkpoint inhibitor therapy known as ipilimumab for human treatment), a large proportion of mice become tumor-free. Anti-tumor immune memory was demonstrated when tumor-free mice were re-challenged by implant with a new breast cancer tumor and then found to clear the new tumor, without further therapy. The new data presented at ASCO demonstrate that upon re-challenge, there is a rapid expansion of newly proliferative CD8 T cells and particularly CD8 effector memory T cells. Both cell populations were readily detectable in multiple tissues (blood, spleen, and lymph nodes) and likely contribute to the anti-tumor effect observed in these animals. Adoptive transfer studies confirmed the immune-memory effect as transplant of splenocytes from tumor-free mice into naïve recipients provided the ability to resist tumor growth.
“NKTR-214 provides a highly unique immune activation profile that allows it to access the IL-2 pathway without pushing the immune system into pathological overdrive,” said Dr. Steve Doberstein, Senior Vice President and Chief Scientific Officer. “NKTR-214’s unique immune-stimulatory profile and antibody-like dosing schedule positions it as a potentially important medicine within the immuno-oncology landscape.”
NKTR-214 is a CD122-biased agonist 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. 
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.Furthermore, the pro-drug design of NKTR-214 enables an antibody-like dosing regimen for an immuno-stimulatory cytokine.
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