On January 9, 2019 NantKwest Inc. (Nasdaq:NK), a leading, clinical-stage, natural killer cell based therapeutics company, reported the launch of a novel triple combination, phase II clinical trial in Merkel cell carcinoma (MCC) (Press release, NantKwest, JAN 9, 2019, https://ir.nantkwest.com/news-releases/news-release-details/nantkwest-announces-launch-merkel-cell-carcinoma-phase-ii-trial?field_nir_news_date_value[min]=2019 [SID1234532598]).

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NantKwest’s phase II immunotherapy trial builds upon the company’s earlier phase II single-combination study using its proprietary, off-the-shelf aNKTM natural killer cell therapy and IL-15/Fc superagonist (N-803), which produced an objective responses in 3 of 7 patients.

In this new clinical trial, patients will be dosed with: (i) the novel chemotherapy-free combination of our haNK cell therapy, which are aNK cells that are genetically engineered to express the high-affinity variant of the CD16 receptor (V158 FcγRIIIa), (ii) avelumab, a PD-L1 targeting checkpoint inhibitor, and (iii) N-803, a superagonist IL-15/Fc cytokine therapy, in a regimen designed to synergistically optimize the therapeutic potential of each agent.

Commenting on the initiation of this novel triple combination trial in MCC, Patrick Soon-Shiong, MD, Chairman and CEO of NantKwest said, "Even in a heavily pretreated patient population, including patients who have failed checkpoint inhibitor therapy, we were encouraged to see our combination of aNK cell and N-803 therapy exhibit preliminary clinically meaningful antitumor activity, including objective response in this resistant setting."

Dr. Soon-Shiong continued, "Building upon this human clinical trial data, we are pleased to announce the transition of this earlier study to include haNK cell therapy in combination with the IL-15 superagonist N-803 and the PD-L1 checkpoint inhibitor avelumab, which we believe, when used together, will offer synergies and the potential to improve response rates for patients with MCC that may also potentially translate to a number of additional solid tumor indications."

In preclinical and human clinical studies conducted by NantKwest, the combination of haNK cells with a number of different therapeutic antibodies, including avelumab, led to enhanced tumor cell killing when compared to the use of the antibody alone. The IL-15/Fc superagonist N-803, developed by NantCell, Inc., an affiliate company, has been shown to synergistically activate NK and T cells and enhance cancer cell killing in both single agent and combination therapy. The PD-L1 checkpoint inhibitor avelumab, a monoclonal antibody developed by Merck KGaA and approved in 2017 by the FDA, targets the programmed death-ligand 1 protein (PD-L1), commonly expressed on a wide range of cancer cells. Avelumab works by blocking PD-L1 from binding PD-1 receptors on T-cells, resulting in an increase in CD8+ T-cell immune responses. This effect is amplified with the addition of N-803 and haNK cells.

With encouraging preclinical and clinical responses already demonstrated for aNK as a single agent therapy or in combination, we believe this existing dataset provides validation for our novel, triple combination clinical trial design.

MCC is a rare and aggressive skin cancer that arises from uncontrolled growth of cells in the skin. Increasing in incidence, approximately 2,500 new cases are reported in the U.S. each year. Patients with metastatic or locally advanced MCC have an extremely poor prognosis, with less than 20% of patients surviving longer than five years. Typically these patients are treated with a range of drugs, including chemotherapy, which can result in significant side effects. Although new immune therapies have the potential to improve survival, MCC is still fatal for a majority patients who have progressed on or after treatment with a checkpoint inhibitor and represents an unmet medical need.

Study Design

The Phase II clinical study will evaluate a combination therapy with our off-the-shelf CD16-targeted natural killer cells (haNK), the IL-15 superagonist (N-803), and avelumab, without the use of cytotoxic chemotherapy, in subjects with MCC that have progressed on or after treatment with a checkpoint inhibitor. The combination of these agents have been safely studied in our previous clinical trials for other solid cancer indications. The goal of combining these therapies is to synergistically maximize the killing of cancer cells while attempting to spare patients from chemotherapy and its associated adverse side effects.

haNK Cell Therapy Platform

NantKwest’s haNK cell therapy platform is a natural killer cell therapy that was developed to optimize the key role of natural killer cells in mediating innate immunity, enhancing adaptive immune responses, and, specifically in the case of haNK, improve anti-tumor responses via antibody-dependent cell-mediated cytotoxicity (ADCC). ADCC is an important component of the human immune system associated with the synergistic interaction of natural killer cells with antibodies to directly kill a target cell that has been identified by an antigen-specific antibody. ADCC represents one of the key mechanisms that antibodies utilize to target and kill cancer cells. Engineered to express the high-affinity variant of the CD16, high affinity Fc receptor (V158 FcγRIIIa), in preclinical studies, the combination of haNK cells with a number of different therapeutic antibodies led to enhanced tumor cell killing when compared to the use of the antibody as a single therapeutic agent, providing strong support for this novel combination immunotherapeutic approach.

N-803 Superagonist IL-15 Cytokine Therapy

Interleukin-15 (IL-15) is a critical factor controlling the development, proliferation and activation of effector natural killer (NK) cells and CD8+ memory T cells. In preclinical and clinical studies, this cytokine has exhibited potent antitumor activities against well-established tumors. N-803, developed by NantCell, an affiliate company, is a novel IL-15 superagonist complex consisting of an IL-15 mutant (IL-15N72D) bound to an IL-15 receptor α/IgG1 Fc fusion protein. In preclinical and clinical studies, N-803 has shown improved biological activity, longer persistence in lymphoid tissues and enhanced anti-tumor activity by simultaneously mobilizing both the innate and adaptive arms of the immune system. This robust immunostimulatory capacity is believe to elicit rapid and durable responses against cancer cells compared to native, non-complexed IL-15 in vivo.

For additional information regarding this MCC clinical trial please visit, www.clinicaltrials.gov and for additional information on NantKwest, please visit www.nantkwest.com