On December 9, 2019 Nektar Therapeutics (NASDAQ: NKTR) reported three presentations at the 61st American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition for its IL-15 agonist and investigational candidate, NKTR-255 (Press release, Nektar Therapeutics, DEC 9, 2019, View Source [SID1234552160]). Data were presented from a number of preclinical studies conducted in collaboration with researchers from the Dana-Farber Cancer Institute and the Fred Hutchinson Cancer Research Center.
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NKTR-255 is an interleukin-15 (IL-15) receptor agonist, which is currently being evaluated in a Phase 1 clinical study in patients with multiple myeloma (MM) and non-Hodgkin’s lymphoma (NHL). NKTR-255 is designed to work by selectively targeting the IL-15 pathway to expand both natural killer (NK) cells and memory CD8 T cell populations.
"The preclinical data being recognized at ASH (Free ASH Whitepaper) demonstrate NKTR-255’s promise in hematological malignancies through its potential to restore both NK cell and memory CD8 T cell compartments in patients," said Loui Madakamutil, Ph.D., Senior Vice President and Head of Discovery and Research at Nektar Therapeutics. "In studies presented by the laboratory of Dr. Nikhil Munshi at Dana-Farber, NKTR-255 enhanced the number and function of NK and CD8+ effector memory T cell populations in peripheral blood and bone marrow from patients with multiple myeloma and, also increased expression of activating receptors found on those NK cells. Separately, researchers from the laboratory of Dr. Cameron Turtle at Fred Hutchinson demonstrated NKTR-255 prevented tumor growth and increased survival of CAR T cells when added to a CD19-targeted CAR T cell regimen in models of B cell lymphoma. This preclinical data reinforces the basis of our ongoing clinical trial evaluating the potential of NKTR-255 in patients with multiple myeloma and non-Hodgkin’s lymphoma."
Details of the preclinical data presentations at ASH (Free ASH Whitepaper) are as follows and are available on the scientific section of Nektar’s website at View Source
Abstract 2866: "Combination of NKTR-255, a polymer conjugated human IL-15, with CD19 CAR T cell immunotherapy in a preclinical lymphoma model," Chou, C., et al. (This study was conducted in collaboration with the Turtle Laboratory in the Fred Hutchinson Cancer Research Center.)
Session: 625. Lymphoma: Pre-Clinical – Chemotherapy and Biologic Agents: Poster II
Date: Sunday, December 8, 2019, 6:00 p.m. – 8:00 p.m. Eastern Standard Time
CAR T cells treated with NKTR-255 demonstrate increased proliferation and survival both in vitro and in vivo which may in part be due to increased expression of bcl-2.
Tumor bearing mice treated with NKTR-255 and CAR T cells have decreased tumor burden and increased survival compared to mice treated with CAR T cells alone.
Tumor-bearing mice previously treated with NKTR-255 and CAR T cells are able to reject tumor re-challenge supporting persistence of functional CAR T cells.
Abstract 4398: "Restoring innate and adaptive immune repertoire in multiple myeloma for therapeutic application," Fernandez, R., et al. (This study was conducted in collaboration with Dr. Nikhil C. Munshi at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute.)
Note: Dr. Rafael Fernandez was recognized with a 2019 ASH (Free ASH Whitepaper) Abstract Achievement Award for this abstract.
Session: 652. Myeloma: Pathophysiology and Pre-Clinical Studies, Excluding Therapy: Poster III
Date: Monday, December 9, 2019, 6:00 p.m. – 8:00 pm. Eastern Standard Time
Multiple myeloma patients are known to experience impaired innate immunity and a decline in function of NK cells along with lower expression of activating receptors found on these cells.
Treatment with NKTR-255 enhanced the number and function of both NK and CD8+ effector memory T cell populations in peripheral blood from healthy donors and MM patients in a dose dependent manner.
NKTR-255 was also able to revert the inhibitory status of NK cells from MM patients and showed synergy with daratumumab and elotuzumab to significantly increase status of NK susceptibility of the MM cells.
Findings suggest NKTR-255 delivers a significant impact on the activation of effector cell function to efficiently target MM cells.
Details of the Trials in Progress poster presentation are as follows:
Abstract 4459: "A Phase 1, Open-Label, Multi-Center, Dose Escalation and Dose Expansion Study of NKTR-255 As a Single Agent in Relapsed or Refractory Hematologic Malignancies and in Combination with Daratumumab As a Salvage Regimen for Multiple Myeloma," Shah, N., et al.
Session: 704. Immunotherapies: Poster III
Date: Monday, December 9, 2019; 6:00 p.m. – 8:00 p.m. Eastern Standard Time
About the Phase 1 Study of NKTR-255 (NCT04136756)
NKTR-255 is currently being evaluated in an open-label Phase 1, dose escalation and dose expansion study in patients with select hematological malignancies (relapsed or refractory NHL or MM). The dose escalation phase of the study will evaluate the safety and tolerability of NKTR-255 as monotherapy in approximately 40 patients in order to establish a recommended Phase 2 dose (RP2D) for NKTR-255. The dose expansion phase of the study will enroll patients with MM or NHL (relapsed/refractory salvage) to evaluate the NKTR-255 RP2D in combination with targeted antibodies, including anti-CD38 monoclonal antibody, daratumumab in MM and anti-CD20 monoclonal antibody, rituximab in NHL. These studies are designed to assess pharmacokinetic and pharmacodynamic effects, anti-tumor activity and a range of biomarker assessments associated with NK and memory T cell populations.
About NKTR-255
NKTR-255 is an IL-15 receptor agonist designed to activate the IL-15 pathway and expand NK cells and promote the survival and expansion of memory CD8+ T cells without inducing suppressive regulatory T cells. Through optimal engagement of the IL-15Rα/IL-2Rβγ receptor complex, NKTR-255 enhances functional NK cell repopulation and formation of long-term immunological memory, which may lead to sustained anti-tumor immune response. NKTR-255 is uniquely designed to overcome the challenges of recombinant IL-15 and other IL-15 agonists, which are rapidly cleared from the body and have shown diminishing response to successive doses.1 Designed using Nektar’s polymer conjugation technology to extend circulating half-life, NKTR-255 can be dosed every 14 or 21 days.