On June 24, 2019 NantKwest Inc. (Nasdaq:NK), a pioneering, next generation, clinical-stage immunotherapy company focused on harnessing the unique power of our immune system using natural killer (NK) cells to treat cancer, infectious diseases and other diseases, reported that the company’s PD-L1 t-haNK investigational new drug application (IND) has cleared FDA review and the program has now transitioned to a first-in-human clinical trial in patients with locally advanced or metastatic solid cancers (Press release, NantKwest, JUN 24, 2019, https://ir.nantkwest.com/news-releases/news-release-details/nantkwest-launches-first-class-first-human-phase-i-clinical?field_nir_news_date_value[min]=2019 [SID1234537231]).

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Programmed death-ligand 1 (PD-L1) is a transmembrane protein that plays a major role in suppressing the immune system in many cancer patients. The binding of PD-L1 to the inhibitory checkpoint molecule PD-1 establishes an inhibitory signal that reduces the proliferation of antigen-specific T-cells while also reducing apoptosis in suppressive regulatory T cells (Tregs) that further inhibits immune responses.

NantKwest’s PD-L1 t-haNK cell therapy is a novel, NK cell-based immuno-oncology therapy that includes a PD-L1 based Chimeric Antigen Receptor (CAR) engineered into the company’s proprietary haNK NK cell, which also includes the high affinity variant of the CD16 receptor (V158 FcγRIIIa) to mediate antibody dependent cellular cytotoxicity (ADCC). Together, the use of this targeted, bi-specific, next generation PD-L1 t-haNK therapy has been shown in preclinical studies to significantly enhance cancer cell killing and improve overall response rates.

"In just a few short weeks since announcing the FDA clearance of our first bi-specific, engineered NK cell therapy clinical trial using a CD19 t-haNK targeting patients in lymphoma, we are now pleased to announce that the FDA has authorized the company to go forward with our second bi-specific NK cell therapy clinical trial using a PD-L1 t-haNK targeting patients with solid tumors," commented Dr. Patrick Soon-Shiong, Chairman and CEO of NantKwest. Dr. Soon-Shiong continued, "We plan to synergistically combine a wide range of immunotherapy molecules with our proprietary, multi-targeted, off-the-shelf NK cell therapy, in this case, a PD-L1 t-haNK to explore the unique therapeutic potential of integrating both the innate and adaptive immune systems to achieve durable complete remissions. Based on the FDA clearance, we look to rapidly transition this program to a Phase I human clinical trial designed to assess the safety, tolerability and efficacy of PD-L1 t-haNK cell therapy in patients with solid tumors. Upon completion of this safety phase, NantKwest intends to combine this PD-L1 t-haNK cell therapy with other immunomodulatory agents including NabFc-N803, a IL15 cytokine super agonist and Adenovirus/ yeast vectors delivering tumor associated and neoantigens, as part of an integrative, combination therapy designed to further enhance the therapeutic effectiveness of this novel NK cell-based therapeutic intervention, which we describe as our NANT Cancer Memory Vaccine."

PD-L1 t-haNK

NantKwest’s PD-L1 t-haNK cell therapy is designed to provide precise tumor-cell specificity through the use of a CAR construct that utilizes a PD-L1-specific scFv (single chain antibody fragment) engineered into the company’s proprietary haNK NK cell that includes the high affinity variant of the CD16 receptor (V158 FcγRIIIa) to mediate antibody dependent cellular cytotoxicity (ADCC). In preclinical studies, cytotoxicity of these GMP-grade, cryopreserved PD-L1 t-haNK cells were comprehensively evaluated against a panel of cancer cell lines with different levels of PD-L1 expression in vitro and in vivo, with these studies showing increased activity and selective cytotoxicity toward a wide range of PD-L1-expressing tumor cells.

To better inform routine patient care, these clinical trials will incorporate a state-of-the-art, biomarker analysis, including GPS Cancer, which is an integrated, multi-omics, whole genome, transcriptomic platform, provided by NantHealth, an affiliated company. These comprehensive molecular analysis tools are designed to provide critical information to the clinical study team regarding the unique molecular alterations associated with the patient’s cancer and response rates, potentially enhancing patient management.

Additional information regarding the PD-L1 t-haNK clinical study can be found at www.nantkwest.com or www.clinicaltrials.gov/.