Neukoplast (CST-101) / ImmunityBio - LARVOL DELTA

Characterization of lysate from NK-92 cells and its potential use as an immunotherapeutic modality. (PubMed, Cell Immunol) - "Here lysate from NK-92 (aNK™) cells, and its erIL-2 engineered variant haNK™ was obtained by repeat freeze/thawing...Intra-tumor injection of haNK lysate into intradermal tumors of immunocompetent C57BL/6 mice provided tumor control in 40 % of treated animals. When re-challenged with the same tumor line several weeks after primary tumor clearance, no growth occurred indicating that intra-tumor administration of haNK lysate can generate a vaccine-like effect."

IO biomarker • Journal • Oncology

NK-92® (aNK™) whole cell lysate exerts potent cytotoxic and anti-proliferative activity on tumor cells (AACR 2025) - "Strikingly, when re-challenged with the same tumor cells 6-8 weeks later, no tumor growth occurred suggesting a vaccine-like effect of the haNK lysate. In conclusion, we have developed a simple, scalable method to prepare bioactive cell lysates from NK-92 and haNK that show anti-tumor activity and a potential for immune modulation both in vitro and in vivo."

IO biomarker • Tumor cell • Oncology • CXCL8 • GZMB • IL10 • IL16 • IL2

Generation and characterization of NK-92®(aNK™) cells with hypoimmunogenic modifications (AACR 2025) - "We report here that abolishment of HLA class-I and re-expression of HLA-E on NK-92 cells effectively inhibited CD8+ T-cell recognition as well as provided significant protection against resting and IL-2 activated PBNKs. Our results also suggest that these modifications are likely sufficient to allow the engineered NK-92 cells to evade immune alloreactivity in a majority of patients after infusion."

Oncology • B2M • CD8 • HLA-E • KLRC1 • KLRD1 • LAMP1

QUILT-3.039: NANT Pancreatic Cancer Vaccine: Combination Immunotherapy in Subjects With Pancreatic Cancer Who Have Progressed on or After Standard-of-care Therapy (clinicaltrials.gov) - P1/2 | N=3 | Terminated | Sponsor: ImmunityBio, Inc. | Unknown status ➔ Terminated; Study halted prematurely and will not resume; participants are no longer being examined or receiving intervention

Trial termination • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor

QUILT-3.009: Patients With Stage III (IIIB) or Stage (IV) Merkel Cell Carcinoma (MCC) (clinicaltrials.gov) - P2 | N=7 | Terminated | Sponsor: ImmunityBio, Inc. | N=24 ➔ 7 | Unknown status ➔ Terminated

Combination therapy • Enrollment change • Metastases • Trial termination • Merkel Cell Carcinoma • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor

[VIRTUAL] Engineered iPSC-Derived NK Cells Expressing Recombinant CD64 for Enhanced ADCC (ASH 2020) - "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..."

IO Biomarker • Burkitt Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Ovarian Cancer • Solid Tumor • CD44 • FCGR3A • NKG2D

NANT cancer vaccine an orchestration of immunogenic cell death by overcoming immune suppression and activating NK and T cell therapy in patients with third line or greater metastatic pancreatic cancer. (ASCO-GI 2019) - P1b/2; "Treatment will occur in 3-week cycles of low-dose chemotherapy (aldoxorubicin, cyclophosphamide, oxaliplatin, nab-paclitaxel, 5-FU/L), antiangiogenic therapy (bevacizumab), SBRT, engineered allogeneic high affinity CD16 NK-92 cells (haNK), IL-15RαFc (N-803), adenoviral vector-based CEA vaccine (Ad-CEA), yeast vector-based RAS vaccine (Ye-RAS), and an IgG1 PD-L1 inhibitor, avelumab. Secondary endpoints include ORR, DCR, PFS, and OS. A maximum of 24 patients will be enrolled."

Clinical • Immunogenic cell death • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor

[VIRTUAL] The non-peptidomimetic cIAP1/2 and XIAP antagonist ASTX660 promotes an anti-tumour immune response in T-cell lymphoma (AACR-NCI-EORTC 2020) - P1/2 | "In co-culture models ASTX660 demonstrated enhanced killing of a human lymphoma cell line by anti-CD3 antibody-stimulated PBMCs or the IL-15-stimulated NK92 cells line. Conclusions In addition to its known role as an IAP antagonist in inducing apoptosis in cancer cells, we describe a novel role for ASTX660 as an immunomodulatory molecule capable of boosting an anti-tumour immune response as demonstrated in in vitro and in vivo pre-clinical models of T-cell lymphoma. These data add to our understanding of ASTX660’s mode of action behind the clinical activity that has been reported."

Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • T Cell Non-Hodgkin Lymphoma • IL15 • TNFA

[VIRTUAL] The non-peptidomimetic cIAP1/2 and XIAP antagonist ASTX660 promotes an anti-tumour immune response in T-cell lymphoma (AACR-NCI-EORTC 2020) - P1/2 | "In co-culture models ASTX660 demonstrated enhanced killing of a human lymphoma cell line by anti-CD3 antibody-stimulated PBMCs or the IL-15-stimulated NK92 cells line. Conclusions In addition to its known role as an IAP antagonist in inducing apoptosis in cancer cells, we describe a novel role for ASTX660 as an immunomodulatory molecule capable of boosting an anti-tumour immune response as demonstrated in in vitro and in vivo pre-clinical models of T-cell lymphoma. These data add to our understanding of ASTX660’s mode of action behind the clinical activity that has been reported."

Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • T Cell Non-Hodgkin Lymphoma • IL15 • TNFA

The NK-92 cell line-30 years later: its impact on natural killer cell research and treatment of cancer. (PubMed, Cytotherapy) - "Infusions of either unmodified or modified NK-92 cells have been reported to be safe and efficacious, leading in some cases to disease remission even in patients who had failed multiple previous lines of therapy. It is the purpose of this review to distill the plethora of scientific data on NK-92 cells and its genetic variants, highlighting relevant experimental findings that have contributed to a better understanding of NK cell biology and summarize the therapeutic potential of these cells for treatment of cancer and infections."

Journal • Preclinical • Review • Hematological Malignancies • Infectious Disease • Lymphoma • Oncology

ImmunityBio Awarded Seminal Patent on Natural Killer Cells (Businesswire) - "ImmunityBio, Inc...has been granted a U.S. patent (11,207,350 B2) for a novel natural killer (NK) cell therapy composition and method for treating cancer that combines the company’s genetically modified NK-92 cells with CD16 receptors to enhance binding and activity of monoclonal antibodies. The combination of these engineered NK-92 cells with current monoclonal antibody therapies has the potential to augment the overall cytotoxic effects of monoclonal antibody treatment alone and help to address relapse by bolstering the patient’s own natural immune system response....The patent, which protects this therapeutic approach for 20 years from its original filing, covers the use of these NK-92 cells in conjunction with the mAbs that are a standard of care in many cancer cases."

Patent • Breast Cancer • Gastrointestinal Cancer • Hematological Malignancies • Non-Hodgkin’s Lymphoma • Oncology • Pancreatic Cancer • Solid Tumor • Triple Negative Breast Cancer

Innate and adaptive immunotherapy: An orchestration of immunogenic cell death by overcoming immune suppression and activating NK and T-cell therapy in patients with third line or greater TNBC. (ASCO 2019) - P1/2; "Treatment occurred in 3-week cycles of low-dose chemotherapy (aldoxorubicin, cyclophosphamide, cisplatin, nab-paclitaxel, 5-FU/L), antiangiogenic therapy (bevacizumab), SBRT, engineered allogeneic CD16 NK-92 cells (haNK), IL-15RαFc (N-803), adenoviral vector-based CEA, MUC1, brachyury, and HER2 vaccines, yeast vector-based Ras, brachyury and CEA vaccines, and an IgG1 PD-L1 inhibitor, avelumab. These preliminary data suggest that low-dose chemo-radiation combined with innate and adaptive immunotherapy can be administered safely in an outpatient setting with a manageable safety profile. Clinical trial information: NCT03387085"

Clinical • Immunogenic cell death • Breast Cancer • HER2 Breast Cancer • Oncology • Triple Negative Breast Cancer

NANT cancer vaccine an orchestration of immunogenic cell death by overcoming immune suppression and activating NK and T cell therapy in patients with third line or greater metastatic pancreatic cancer. (ASCO-GI 2019) - P1b/2; "Treatment will occur in 3-week cycles of low-dose chemotherapy (aldoxorubicin, cyclophosphamide, oxaliplatin, nab-paclitaxel, 5-FU/L), antiangiogenic therapy (bevacizumab), SBRT, engineered allogeneic high affinity CD16 NK-92 cells (haNK), IL-15RαFc (N-803), adenoviral vector-based CEA vaccine (Ad-CEA), yeast vector-based RAS vaccine (Ye-RAS), and an IgG1 PD-L1 inhibitor, avelumab. Secondary endpoints include ORR, DCR, PFS, and OS. A maximum of 24 patients will be enrolled."

Clinical • Immunogenic cell death • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor

NANT Cancer Vaccine an orchestration of immunogenic cell death by overcoming immune suppression and activating NK and T cell therapy in patients with third line or greater TNBC and head & neck SCC (SITC 2018) - P1/2; "Treatment occurred in 3-week cycles of low-dose chemotherapy (aldoxorubicin, cyclophosphamide, cisplatin, nab-paclitaxel, 5-FU/L), antiangiogenic therapy (bevacizumab), SBRT, engineered allogeneic high affinity CD-16 NK-92 cells (haNK), IL-15RαFc (N803), adenoviral vector-based CEA, MUC1, Brachyury, HER2 vaccine (Ad), yeast vector-based RAS, Brachyury and CEA vaccine (Ye), and an IgG1 PD-L1 inhibitor, avelumab plus cetuximab. Conclusions This preliminary data suggests that the NANT Cancer Vaccine of low-dose chemoradiation combined with innate and adaptive immunotherapy can be administered safely in an outpatient setting without any observed increased irAE’s. Preliminary efficacy result of four out of five patients (80%) with confirmed overall responses, with one of these four patients demonstrating a complete response with 5th-line metastatic disease is encouraging."

Clinical • Immunogenic cell death • Head and Neck Cancer • HER2 Breast Cancer • Triple Negative Breast Cancer

NANT Cancer Vaccine an orchestration of immunogenic cell death by overcoming immune suppression and activating NK and T cell therapy in patients with third line or greater metastatic pancreatic cancer (SITC 2018) - P1/2; "Treatment occurred in 3-week cycles of low-dose chemotherapy (aldoxorubicin, cyclophosphamide, oxaliplatin, nabpaclitaxel, 5-FU/L), antiangiogenic therapy (bevacizumab), SBRT, engineered allogeneic high affinity CD-16 NK-92 cells (haNK), IL-15RαFc (N-803), adenoviral vector-based CEA vaccine (Ad-CEA), yeast vector-based RAS vaccine (Ye-RAS), and an IgG1 PDL1 inhibitor, avelumab. Conclusions This preliminary data suggests that the NANT Cancer Vaccine of low-dose chemo-radiation combined with innate and adaptive immunotherapy can be administered safely in an outpatient setting. Preliminary efficacy results are encouraging and the overall survival of 9.5 months currently exceeds all standards of care for patients at this advanced stage of disease."

Clinical • Immunogenic cell death • Late-breaking abstract • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor

Innate and adaptive immunotherapy: An orchestration of immunogenic cell death by overcoming immune suppression and activating NK and T cell therapy in patients with third line or greater metastatic pancreatic cancer. (ASCO 2019) - P1b/2; "Treatment occurred in 3-week cycles of low-dose chemotherapy (aldoxorubicin, cyclophosphamide, oxaliplatin, nab-paclitaxel, 5-FU/L), antiangiogenic therapy (bevacizumab), SBRT, allogeneic CD16 NK-92 cells (haNK), IL-15RαFc (N-803), adenoviral CEA vaccine, yeast Ras vaccine, and an IgG1 PD-L1 inhibitor, avelumab. These preliminary data suggest that low-dose chemo-radiation combined with innate and adaptive immunotherapy can be administered safely in an outpatient setting. Preliminary OS of 8.2 months is encouraging for this heavily-pretreated population. Clinical trial information: NCT03586869"

Clinical • Immunogenic cell death • Gastrointestinal Cancer • Oncology • Pancreatic Cancer

[VIRTUAL] Recurrent Mutations of the C-C Motif Chemokine Ligand 22 (CCL22) Define a Distinct Subgroup of Chronic Lymphoproliferative Disorder of NK Cells (CLPD-NK) (ASH 2020) - "To examine the in vivo effects of the mutations on proliferation and phenotype, GFP-tagged empty vector, wtCCL22, or mtCCL22-transduced NK-92 cells were engrafted into IL15-transgenic NOD.Cg-Prkdcscid Il2rgtm1Wjl Tg(IL15)1Sz/SzJ (NSG) mice...We show that mtCCL22 enhanced cellular chemotaxis by preventing CCR4 internalization and promoted expansion of CD56+ NK cells in vivo. We recommend to study mtCCL22 in cases suspected of CLPD-NK, in order to distinguish clonal NK neoplasms from polyclonal reactive expansion."

IO biomarker • Hematological Malignancies • Inflammation • Oncology • CCL2 • CCL22 • IL15 • NCAM1 • TET2 • TP53

[VIRTUAL] CAR19 iPSC-Derived NK Cells Utilize the Innate Functional Potential Mediated through NKG2A-Driven Education and Override the HLA-E Check Point to Effectively Target B Cell Lymphoma (ASH 2020) - "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."

IO biomarker • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD19

[VIRTUAL] Obinutuzumab-Retreatment in Combination with Bendamustine Is Effective for Obinutuzumab Resistant Models in Vitro and In Vivo (ASH 2020) - "It’s mode of action is mainly characterized by the induction of direct cell death and it shows stronger antibody-dependent cellular cytotoxicity (ADCC) than rituximab...Methods : OBI-induced ADCC resistant clones were established from an RL cell line by inducing ADCC three times with CD16-transfected NK-92 cells...It is possible that activation of NK cells by Benda might be involved in this combination mechanism. Although the mechanisms need to be examined in more detail, these results indicate the possible effectiveness of OBI-retreatment after prior OBI-containing therapy."

Combination therapy • Preclinical • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Transplantation

The neoantigen-targeting antibody NEO-201 enhances NK cell-dependent killing of tumor cells through blockade of the inhibitory CEACAM5/CEACAM1 immune checkpoint pathway (AACR 2018) - "Functionally, NEO-201 treatment augmented the cytolytic activity of NK-92 cells against NEO-201+ tumor cells in proportion to their level of CEACAM5 expression (average increase of 2-fold), but not against NEO-201+ cells that only expressed CEACAM6. This study demonstrates that NEO-201 is reactive against a tumor-associated variant of CEACAM5/6, and provides evidence that this antibody can block the interaction between tumor cell CEACAM5 and NK cell CEACAM1 to reverse CEACAM1-dependent inhibition of NK cytotoxicity. This study demonstrates that NEO-201 is reactive against a tumor-associated variant of CEACAM5/6, and provides evidence that this antibody can block the interaction between tumor cell CEACAM5 and NK cell CEACAM1 to reverse CEACAM1-dependent inhibition of NK cytotoxicity. Experiments are in progress to determine the involvement of NK cell CEACAM1 and/or other checkpoint pathways in this mechanism of action. These results suggest that NEO-

IO Biomarker • PD(L)-1 Biomarker • Tumor-specific neoantigens • Colorectal Cancer

In vitro and in vivo evaluation of the beta-emitting lutetium-177 labeled anti-CD37 antibody radionuclide conjugate 177Lu-NNV003 in DLBCL, CLL and MCL models (AACR 2018) - "The aim of this study was to evaluate the cytotoxic and anti-tumor efficacy of the beta-emitting lutetium labelled NNV003 antibody (177Lu-NNV003) in non-Hodgkin lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL) models.Antibody-Dependent Cellular Cytotoxicity (ADCC) and Complement-Dependent Cytotoxicity (CDC) were measured in REC-1 (MCL), MEC-2 (CLL) and DOHH-2 (DLBCL) cells using FcRIIIa immortalized NK92 cells as effector cells...177Lu-NNV003 has shown significant tumor uptake and therapeutic effect in vivo in all three models tested. The results warrant clinical testing in patients suffering from CD37-expressing B-cell malignancies."

Preclinical • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Indolent Lymphoma

Microvesicles Produced by Natural Killer Cells Regulate the Formation of Blood Vessels. (PubMed, Bull Exp Biol Med) - "It was found that microvesicles derived from NK-92 cells promoted elongation of tube-like structures formed by endothelial ЕА.Hy926 cells. Microvesicles produced by NK cells can modulate functional activity of endothelial cells by affecting their ability to form blood vessels."

Journal

[VIRTUAL] ENGINEERED CD19-CAR NK CELLS AS AN OFF-THE-SHELF ALTERNATIVE TO B CELL LEUKEMIA AND LYMPHOMA TREATMENT (HEMO 2020) - "The transduction efficiency was assessed 48h after transduction, and it was 28% for CAR.19-IL-15 and 39% for CAR.19-IL-27 in NK-92 cells and for NK-PB and NK-CB cells, the transduction efficiency was around 20% for CAR.19-IL-15... 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."

IO Biomarker • Graft versus Host Disease • Hematological Malignancies • Immunology • Leukemia • Lymphoma • Oncology • CD19 • IL15

The Molecular Mechanism of LncRNA-CASC2/miR-155-5p/APC Axis Regulating the Progression of Non-Hodgkin Lymphoma (PubMed, Zhongguo Shi Yan Xue Ye Xue Za Zhi) - "Overexpression of CASC2 suppresses the proliferation and invasion of NK-92 cells, promote the apoptosis of NK-92 cells via targeting miR-155-5p and upregulating APC expression."

Journal • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • MIR155

[VIRTUAL] Protein Phosphatase 2A Inhibition in NK Cell Therapy for Treatment of Medulloblastoma (SNO 2020) - "CD107a+ NK92 cells increased from 19% to 28% with 8uM of LB100. NK92 cells are cytotoxic against MB cells in vitro and inhibition of PP2A in NK cells can enhance their activity against MB cells."

IO Biomarker • Medulloblastoma • Oncology • Solid Tumor • GZMB • IFNG • TMB