Neukoplast (CST-101)

P1/2, N=3, Terminated, ImmunityBio, Inc. | Unknown status --> Terminated; Study halted prematurely and will not resume; participants are no longer being examined or receiving intervention

P2, N=7, Terminated, ImmunityBio, Inc. | N=24 --> 7 | Unknown status --> Terminated

For that, we developed a procedure for the transduction and ex vivo expansion of NK cells from three different sources: NK-92 lineage, peripheral blood (NK-PB) and cord blood (NK-CB)... We developed two new functional CAR vectors. In addition, we generated CAR-NKs from three different sources with their anti-tumor activity increased against CD19 + cells. Next, we intend to use cytokines to improve ex vivo CAR-NK cell expansion, and to test their in vivo therapeutic potential.

Finally, the use of primary CD56 cells in ADCC experiments comparing glycoengineered variants of trastuzumab was conclusive to test the limits of this type of ex vivo system. Although the effector functions of CD56 cells reflected to some extent the in vitro receptor binding properties and cytolytic activity data using NK92 cells, as previously published, reaching a functional avidity plateau could limit their use in a quality control framework.

Induced pluripotent stem cell (iPSC)-derived natural killer (iNK) cells offer a promising platform for off-the-shelf immunotherapy against cancer...Knockdown of NKG2A led to a general reduction in functional capacity of NK92 cells (Figure 1E-F) and CAR19-iNK cells (Figure 1H), supporting a critical role for NKG2A-driven education in iNK cells...Specifically, our results point to a crucial role for NKG2A-driven acquisition of a mature effector cell phenotype in combination with functional education through cognate ligands. Importantly, iNK cell education is operational during iNK cell differentiation and expansion without interfering with recognition of tumor targets expressing HLA-E.

The engineered NK cells used in our study were derived from genetically edited and clonally derived induced pluripotent stem cells (iPSCs) through a series of stepwise differentiation stages (figure 2)...In Figure 3, using an in vitro Delfia® ADCC assay, we show that iNK-CD64/16A cells mediated ADCC against SKOV3 cells, an ovarian adenocarcinoma cell line, in the presence of the anti-HER2 therapeutic mAb trastuzumab (Herceptin) or anti-EGFR1 therapeutic mAb cetuximab (Erbitux), when either added to the assay or pre-adsorbed to the iNK cells (figure 3)...iNK-CD64/16A cells were added with or without pre-adsorbed Rituxan and the assay was performed in 10% AB serum...The various recombinant CD64 constructs were initially expressed in NK92 cells (lacks expression of endogenous FcγRs) (figure 7)...Our goal is to utilize this docking approach to pre-absorb mAbs to iNK cells for adoptive cell therapy. The mAbs would thus provide tumor-targeting elements that could be exchanged as a means of preventing tumor cell escape by selectively and easily altering NK cell specificity for tumor antigens.

GT19077 was also much less active at degrading c-Myc in GM-CSF-stimulated TF-1 or IL-2-stimulated lymphoid progenitor NK-92 cells assayed by WB. These results can help develop biomarkers for patient tailoring strategy. Finally, GT19077 demonstrates PK-dependent target engagement in vivo and is currently being evaluated in in vivo efficacy studies.

Further investigation showed that NK92 treatment with VEGF165b augments its killing ability against human K562 leukemia cells by upregulating perforin and granzyme B through the VEGFR1-PLC pathway, whereas VEGF165b had no impact on the proliferation of NK92 cells in vitro. The results of this study improve our understanding of the immunomodulatory function of VEGF165b, which may help in enhancing the efficacy of NK92-based cancer immunotherapy.

Furthermore, MSLN-CAR NK cells effectively eliminated ovarian cancer cells in both subcutaneous and intraperitoneal tumor models; these cells also significantly prolonged the survival of intraperitoneally tumor-bearing mice. These results demonstrate that MSLN-CAR NK cells have robust specific antitumor activity, both in vitro and in vivo, suggesting that mesothelin could be a potential target for CAR NK cells and could be applied in the treatment of ovarian cancer.

Further investigations unveiled that STAT3 was a target of miR-130a and STAT3 overexpression abrogated miR-130a-induced improvement in killing activity of NK cells against NSCLC cells. In conclusion, MiR-130a improved the killing capacity of NK cells against NSCLC cells by targeting STAT3, laying a foundation for future studies on the roles and molecular basis of miR-130a in NK cell-based immunotherapy against various cancers.

More importantly, DTCR-NK92 cells had considerable antitumor activity in the solid tumor cell SGC-7901-bearing mice model. Collectively, we demonstrated that expression of DTCR markedly augmented the cytotoxic potential of NK92 cells against solid tumor cells, and this potentially promising treatment modality will facilitate clinical translation of potent NK-tailored chimeric receptor strategy for a generalized cellular therapy that may be conducive to treat a wide range of solid tumors.

Furthermore, SSB NMs sustained release of SeC and TGF-β inhibitor and synergized with NK92 cells to induce significant anticancer effects in vivo. Together, this study not only demonstrates a simple strategy for the design of a nanoemulsion to co-deliver synergistic drugs but also sheds light on the application and action mechanisms in NK cell adaptive therapy against breast cancer, especially TNBCs.