Challenges in the Development of NK-92 Cells as an Effective Universal Off-the-Shelf Cellular Therapeutic.

The human-derived NK-92 cell-based CAR-NK therapy exhibits inconsistency with overall suboptimal efficacy and rapid in vivo clearance of CAR-NK92 cells in cancer patients. Analysis indicates that although pre-existing IgM in healthy individuals (n = 10) strongly recognizes both NK-92 and CAR-NK92 cells, IgG and IgE do not. However, only a subset of cancer patients (3/8) exhibit strong IgM recognition of these cells, with some (2/8) showing pre-existing IgG recognition.

A novel MICA/B-targeted chimeric antigen receptor augments the cytotoxicity of NK cells against tumor cells.

Chimeric antigen receptor (CAR)-modified immune cells have emerged as a promising approach for cancer treatment, but single-target CAR therapy in solid tumors is limited by immune escape caused by tumor antigen heterogeneity and shedding. Natural killer group 2D (NKG2D) is an activating receptor expressed in human NK cells, and its ligands, such as MICA and MICB (MICA/B), are widely expressed in malignant cells and typically absent from healthy tissue. NKG2D plays an important role in anti-tumor immunity, recognizing tumor cells and initiating an anti-tumor response.

The SpyCatcher-SpyTag interaction mediates tunable anti-tumor cytotoxicity of NK cells.

Chimeric antigen receptor (CAR)-modified T and NK cell immunotherapy is a promising approach for cancer treatment. Due to the lack of tunability in anti-tumor activity, conventional CAR therapies have limited efficacy at low tumor antigen densities. To tune the CAR response to tumor cell surface antigens, we have developed a split CAR using the SpyCatcher-SpyTag system.

Intrinsic and extrinsic factors determining natural killer cell fate: Phenotype and function.

Natural killer (NK) cells are derived from hematopoietic stem cells. They belong to the innate lymphoid cell family, which is an important part of innate immunity. This family plays a role in the body mainly through the release of perforin, granzyme, and various cytokines and is involved in cytotoxicity and cytokine-mediated immune regulation.

Engagement of an optimized lentiviral vector enhances the expression and cytotoxicity of CAR in human NK cells.

Adoptive chimeric antigen receptor (CAR)-modified T or NK cells (CAR-T/NK) have emerged as a novel form of disease treatment. Lentiviral vectors (LVs) are commonly employed to engineer NK cells for the efficient expression of CARs. This study reported the influence of single-promoter and dual-promoter LVs on the CAR expression and cytotoxicity of engineered NK cells.

Nanobody Library Construction by Using Gene Designated-Region Pan-Editing Technology.

Camelid single-domain antibody fragments (nanobodies) are an emerging force in therapeutic biopharmaceuticals and clinical diagnostic reagents in recent years. Nearly all nanobodies available to date have been obtained by animal immunization, a bottleneck restricting the large-scale application of nanobodies. In this study, we developed three kinds of gene designated-region pan-editing (GDP) technologies to introduce multiple mutations in complementarity-determining regions (CDRs) of nanobodies .

Cytokine Release Syndrome After Modified CAR-NK Therapy in an Advanced Non-small Cell Lung Cancer Patient: A Case Report.

Use of chimeric antigen receptors (CARs), as an immune cell therapy, has generated excellent clinical outcomes against hematologic tumors in recent years. Among them, the CAR-NK (natural killer) therapy has shown better efficacy, and less toxicity, than chimeric antigen receptor T-cell (CAR-T) therapy. In our phase II clinical trials, administering chimeric costimulatory converting receptor (CCCR)-NK92 cells on advanced non-small cell lung cancer patients proved efficacious in cell and animal experiments.

A chimeric switch-receptor PD1-DAP10-41BB augments NK92-cell activation and killing for human lung Cancer H1299 Cell.

Engineered natural killer (NK) cell-based therapies have been potentially broadly applicable and exhibited promising results in clinical trials, particularly in the fight against cancers. NK cell immunotherapy however always remains variable. One major obstacle is the inhibitory pathway including PD1/PDL1, providing tumor cells an escape mechanism from immunosurveillance.

Genetical engineering for NK and T cell immunotherapy with CRISPR/Cas9 technology: Implications and challenges.

Immunotherapy has become one of the most promising strategies in cancer therapies. Among the therapeutic alternatives, genetically engineered NK/T cell therapies have emerged as powerful and innovative therapeutic modalities for cancer patients with precise targeting and impressive efficacy. Nonetheless, this approach still faces multiple challenges, such as immunosuppressive tumor microenvironment, exhaustion of immune effector cells in tumors, off-target effects manufacturing complexity, and poor infiltration of effector cells, all of which need to be overcome for further utilization to cancers.

Chimeric antigen receptor-modified macrophages trigger systemic anti-tumour immunity.

Preliminary results and emerging data have shown that lipid droplet high (LD ) immunosuppressive cells accumulate in tumour tissues. By tracking and phenotypic profiling of LD cells, we find that LD CD19 , LD CD11b , and LD Ly6G immune cell populations appear in the spleen, thymus, and tumour tissues in a syngeneic tumour model. Using a contact-dependent reporter system, we discover a LD CCR7 immunosuppressive cell population that migrates from tumour tissues to the spleen and thymus.

VEGF165b augments NK92 cytolytic activity against human K562 leukemia cells by upregulating the levels of perforin and granzyme B via the VEGR1-PLC pathway.

Pro-angiogenic Vascular endothelial growth factors (VEGFs) exert immunosuppressive functions on some immune cells by interacting with VEGF receptors. Blocking the VEGF/VEGFR pathway could reverse the tumor immunosuppressive microenvironment to some degree. We recently demonstrated that the anti-angiogenic VEGF isoform VEGF165b, similar to other anti-angiogenic agents, inhibit the accumulation immunosuppressive cells such as Tregs and MDSCs.

A novel chimeric PD1-NKG2D-41BB receptor enhances antitumor activity of NK92 cells against human lung cancer H1299 cells by triggering pyroptosis.

Chimeric antigen receptor (CAR)-modified adoptive natural killer (NK) cells represent a promising immunotherapeutic modality for cancer treatment but face many challenges in solid tumors. One major obstacle is the immune-suppressive effects induced by inhibitory receptors (IR) including PD1. To interfere with PD1 signaling to augment CAR-NK cells' activity against solid tumors, we rationally designed a novel chimeric costimulatory converting receptor (CCCR), comprising mainly the extracellular domain of PD1, transmembrane and cytoplasmic domains of NKG2D, and the cytoplasmic domain of 41BB.

VEGF165b and its mutant demonstrate immunomodulatory, not merely anti-angiogenic functions, in tumor-bearing mice.

A great deal of evidence has shown that anti-angiogenic molecules and antibodies targeting the VEGF-A/VEGFRs signal pathway can also reverse tumor-induced immunosuppression to an extent. VEGF165b, an anti-angiogenic VEGF-A isoform, has demonstrated capacity as an efficacious anti-tumor therapy in mice as an anti-angiogenic agent. However, whether VEGF165b also plays an immunomodulatory role in anti-tumor field remains unclear.

A novel bispecific chimeric PD1-DAP10/NKG2D receptor augments NK92-cell therapy efficacy for human gastric cancer SGC-7901 cell.

Cell-based immunotherapy continues to be a promising avenue for cancers that standard therapy has failed. Although the specificity, avidity, and efficacy of infused cells have improved, immunocytotherapy still faces substantial hurdles. To this end, we developed a structure-based rational design approach and constructed a novel Dual Targeting Chimeric Receptor (DTCR) PD1-DAP10/NKG2D comprising the truncated ectodomain of PD1 fused to a key co-stimulatory receptor DAP10, and subsequently harnessed the activating receptor NKG2D, which evaluated the capacity of solid tumor cell killing.

sp. nov., isolated from seawater.

A novel Gram-stain-negative, rod-shaped, non-spore-forming, non-flagellated, strictly aerobic strain, designated A6024, was isolated from coastal seawater near Rizhao, PR China (119.61° E 35.47° N).

sp. nov., isolated from a marine alga [ (L.) Gaillon].

A novel bacterial strain, C3212, was isolated from a marine alga collected from the sea shore of Yantai, China. The strain was Gram-stain-negative, rod-shaped, aerobic, non-motile, and oxidase- and catalase-positive. Growth was observed at 8-37 °C (optimum, 28 °C), at pH 6.

Structure-based rational design of a novel chimeric PD1-NKG2D receptor for natural killer cells.

Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells have the potential to provide the potential for the implementation of allogeneic "off-the-shelf" cellular therapy against cancers. Currently, most CARs are not optimized for NK cells, so new NK-tailored CARs are needed. Here, a major activating receptor of NK cells, NKG2D was harnessed to design different chimeric receptors that mediate strong NK cell signaling.

Utilizing VEGF165b mutant as an effective immunization adjunct to augment antitumor immune response.

Compelling evidence has shown that blocking VEGF via monoclonal antibodies may be beneficial in that it not only inhibits tumor angiogenesis but also reduces immune suppression and promotes T cell infiltration into tumors. Herein, we determined whether our recently generated VEGF165b mutant could be used as a co-immunization adjunct to augment the peptide cancer-vaccine- induced immune response in a mouse model of breast cancer. When co-immunized mVEGF165b with the peptide-based cancer vaccine (MUC1, a T-cell epitope dominant peptide vaccine from Mucin1), the VEGF antibody titers increased approximately 600,000-fold in mice.

VEGF165b mutant with a prolonged half-life and enhanced anti-tumor potency in a mouse model.

VEGF165b has been shown to be an effective anti-cancer agent; however, its short half-life limits further application in the clinical field. The development of a mutant VEGF165b with a prolonged half-life is urgently needed for its future application. A mutant VEGF165b was generated by inactivation of its plasmin cleavage site.

Thalassotalea atypica sp. nov., isolated from seawater, and emended description of Thalassotalea eurytherma.

A novel Gram-stain-negative, straight or slightly curved rod-shaped, non-spore-forming, non-flagellated, strictly aerobic strain, designated RZG4-3-1, was isolated from coastal seawater of Rizhao, China (119.625° E 35.517° N).

[Over-expressed HER2 enhances proliferation, migration and invasion of melanoma B16 cells].

Objective To establish a melanoma B16 cell line stably over-expressing the HER2 (ErbB2) gene and study its effect on the proliferation, migration and invasion of melanoma cells. Methods The recombinant plasmid pCMV3-ErbB2 was transfected into B16 melanoma cell line by cationic liposome. The positive clones were screened with hygromycin B.

Polaribacter marinaquae sp. nov., isolated from seawater.

A novel Gram-stain-negative, rod-shaped, non-spore-forming, non-flagellated, strictly aerobic strain, designated RZW3-2T, was isolated from seawater from near the Yellow Sea coast of PR China (35.475° N 119.613° E).

Overexpression of VEGF183 promotes murine breast cancer cell proliferation in vitro and induces dilated intratumoral microvessels.

Vascular endothelial growth factor (VEGF) was considered as a critical growth factor for tumor expansion. The roles of VEGF121, VEGF165, and VEGF189 in tumor growth have been intensely investigated; however, involvements of another extracellular matrix (ECM)-binding VEGF isoform, namely VEGF183 (six amino acids shorter than VEGF189 in exon 6a), in physiological or pathological processes are still unclear although the wide tissue distribution. To investigate the role of VEGF183 in carcinogenesis, we generated murine breast cancer cell (EMT-6) clones stably overexpressing VEGF183, VEGF121, VEGF165, and VEGF189 shortened as V183, V121, V165, and V189, respectively.

[Corrigendum] Overexpression of the chimeric plasmin-resistant VEGF165/VEGF183 (132-158) protein in murine breast cancer induces distinct vascular patterning adjacent to tumors and retarded tumor growth.

After the publication of the article, the authors noted that they had made an error regarding certain facts in their manuscript: In the abstract VEGF192 (132-158) should be changed to VEGF183 (132-158) (Page 1, Line 2). In addition, width should be changed to width2 (Page 3, Line 50). The authors regret these errors.