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First-in-class PF-LI shows potential across multiple cancer cell lines
06-10-2020
by DDN Staff  |  Email the author
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EL SEGUNDO, Calif.—NantKwest Inc., a clinical-stage, natural killer cell-based therapeutics company, just announced the publication of two peer-reviewed manuscripts in the Journal of Immunotherapy of Cancer that reportedly support the mechanism and functionality of NantKwest’s engineered natural killer (NK) cell lines—haNK and first-in-class PD-L1 t-haNK—across multiple cancer types.
 
These in-vitro and  in-vivo studies, conducted in collaboration with the National Cancer Institute pursuant to a Cooperative Research and Development Agreement, demonstrated haNK and t-haNK as effecting antitumor activity in treatment-refractory cancer types even in the hypoxemic setting of the solid tumor microenvironment.
 
“These published studies provide important insight and validation for the mechanism and activity of our novel first-in-class engineered NK cells for use in notoriously difficult solid tumor types,” said Dr. Patrick Soon-Shiong, chairman and CEO of NantKwest. “NK cells have the potential to kill tumor cells; however, the hypoxic nature of the suppressive tumor environment has been shown to curb primary NK cell function.”
 
The published data in the papers, he added, indicate that the company’s engineered haNK cells remain active in hypoxic conditions, which may be an important new mechanism of its antitumor activity. In addition, these NK cells appear to be resistant even to acute hypoxia and apparently are capable of maintaining tumor-killing activity in conditions that are comparable to a suppressive tumor microenvironment.
 
“In addition, we are encouraged to observe antitumor activity in every cancer cell line tested by the investigators at NCI. The positive data in the in-vivo models of solid tumors with PD-L1 t-haNK, our engineered haNK cell line that also expresses a PD-L1 CAR, provides a novel approach to target tumors expressing PD-L1,” Soon-Shiong continued. “This highly targeted NK cell therapy has the potential to address the evolution of tumors as they become resistant to chemotherapy, antibody therapy and, ultimately, checkpoint immunotherapy.
 
“We have hypothesized that cancer undergoes a quantum change and adapts to the therapy administered, resulting in the selection of resistant, cancer stem-like cells. It is at this stage of evolution where intractable tumors such as in patients with metastatic pancreatic cancer and triple negative breast cancer, are deemed incurable. It is our belief that these cancer ‘stem’ cells, which do not divide and hence are untouchable by chemotherapy, become resistant and render checkpoint therapy futile by not expressing t-cell receptor ligands. In the face of this immunosuppressive milieu, our PD-L1 t-haNK cells can act to kill these otherwise highly resistant cancer cells, as demonstrated by these two important reports by our colleagues at the NCI.”
 
In addition, clinical results in the first patient with advanced metastatic pancreatic cancer to have received PD-L1 t-haNK demonstrated a durable complete response.
 
Study highlights from one of the papers, “Overcoming hypoxia-induced functional suppression of NK cells,” include:
  • NantKwest haNK cells engineered to express a high-affinity CD16 receptor as well as internal interleukin (IL)-2 for increased antibody-dependent cellular cytotoxicity (ADCC) and activation maintained killing activity under hypoxic conditions comparable to those of the suppressive tumor microenvironment, while healthy donor NK cell activity was significantly impaired
  • NK killing, serial killing and ADCC were maintained under hypoxia in haNK cells
  • haNK cells’ IL-2 is likely a driver of maintained killing capacity under hypoxic conditions
Study highlights from the article titled “PD-L1-targeting high-affinity NK cells (PD-L1 t-haNK) induce direct antitumor effects and target suppressive MDSC populations” include:
  • PD-L1.t-haNK cells engineered to express a high-affinity CD16 receptor, an internal interleukin (IL)-2 and PD-L1-specific chimeric antigen receptor (CAR) broke down all 15 human tumor cell lines tested, including those modeling historically treatment-refractory cancers (triple negative breast cancer, lung, and urogenital cancer)
  • In vitro, the cytotoxicity of PD-L1 t-haNK cells was correlated to the PD-L1 expression of the tumor targets
  • In mouse models of solid tumors, PD-L1 t-haNK inhibited the growth of engrafted TNBC, lung and bladder tumors in mice without toxicity
The articles may be found on the Publications section of the NantKwest corporate website here: https://nantkwest.com/peer-reviewed-publications/
 
NantKwest is a clinical-stage immunotherapy company focused on harnessing the power of the innate immune system to treat cancer and virally-induced infectious diseases. The safety of the company’s optimized activated NK cells—as well as their activity against a broad range of cancers—has been tested in Phase 1 clinical trials in Canada and Europe, as well as in multiple Phase 1 and 2 clinical trials in the United States.

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