iPS cell therapy / University of Minnesota - LARVOL DELTA

[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

iPSC-Derived NK Cells Synergize with T Cells and Anti-PD-1 Antibody to Mediate Durable Anti-Tumor Responses In Vivo (ASH 2019) - P1; "Thus, we developed a robust manufacturing system for the differentiation and expansion of high-quality NK cells derived from induced pluripotent stem cells (iPSCs) that can be combined with ICI antibodies for multiple tumor types...Collectively, these data demonstrate that iNK cells can serve as an off-the-shelf source of high-quality NK cells and synergize with anti-PD-1 ICI therapy to enhance anti-tumor T cell responses in vitro and in vivo, providing a novel immunotherapeutic platform for tumors in which iNK cells, activated CD3+ T cells or anti-PD-1 mAb therapy alone is not sufficiently effective. The current program is under clinical investigation and can be found at clinicaltrials.gov NCT03841110."

Preclinical • CCL3 • CCL4 • IFNG • IL2

VPS4A: A Novel Candidate Gene for Congenital Dyserythropoietic Anemia (ASH 2017) - P=N/A; "...Induced pluripotent stem cells (iPSCs) were generated from the patient’s peripheral blood mononuclear cells after the family’s consent...A) Binucleated erythroblasts and cytoplasmic bridges (arrows) were noted on the patient’s bone marrow aspirate smears. B) VPS4A localizes at the spindle poles (upper image) and midbody (lower image) in normal human erythroblasts."

Next-Generation Sequencing • Biosimilar • Hematological Malignancies • Oncology

The First Registry for Patients with Congenital Dyserythropoietic Anemia in North America: Design and Preliminary Results (ASH 2017) - P=N/A; "...The patients may elect to consent to donation of blood, DNA, and bone marrow specimens to the CDAR biorepository and to the generation of induced pluripotent stem cells and/or immortalized B-cells...CDAR will provide a longitudinal database and a biorepository to facilitate natural history studies and molecular pathways research in Congenital Dyserythropoietic Anemias. Such research is necessary to build-up knowledge for these rare diseases in order to guide diagnostic and therapeutic decisions and be a collaborative resource for patients, treating physicians, and investigators."

Biomarker • Retrospective data • Biosimilar • Hematological Malignancies

[VIRTUAL] Initial Clinical Activity of FT596, a First-in-Class, Multi-Antigen Targeted, Off-the-Shelf, iPSC‑Derived CD19 CAR NK Cell Therapy in Relapsed/Refractory B-Cell Lymphoma (ASH 2020) - P1 | "Induced pluripotent stem cell (iPSC)-derived immune effector cells offer distinct advantages over existing patient- and donor-derived therapeutic approaches, including the use of a clonal master engineered iPSC line as a renewable source for the mass production of immune cells, which are available off-the-shelf for broad patient access...FT596 is currently being investigated as a monotherapy and in combination with the anti-CD20 mAbs rituximab and obinutuzumab in a multicenter, Phase I clinical trial for the treatment of relapsed/refractory B-cell lymphoma and chronic lymphocytic leukemia...The patient received fludarabine and cyclophosphamide lympho-conditioning followed by a single administration of 30 million cells of FT596 as monotherapy...Additional clinical, pharmacokinetic, and pharmacodynamic data from this patient will be provided at the time of the meeting. The Phase I trial is ongoing and is registered on clinicaltrials.gov: NCT04245722."

Clinical • Chronic Lymphocytic Leukemia • CNS Disorders • Diffuse Large B Cell Lymphoma • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Hypertension • Immunology • Infectious Disease • Leukemia • Lymphoma • Nephrology • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Transplantation • CD19 • IL15 • IL2

Myogenic Cell Transplantation in Genetic and Acquired Diseases of Skeletal Muscle. (PubMed, Front Genet) - "As for any cell transplantation procedure, the choice between autologous and heterologous cells is dictated by a number of criteria, such as cell availability, possibility of in vitro expansion to reach the number required, need for genetic correction for many but not necessarily all muscular dystrophies, and immune reaction, mainly to a heterologous, even if HLA-matched cells and, to a minor extent, to the therapeutic gene product, a possible antigen for the patient. Finally, induced pluripotent stem cell derivatives, that have entered clinical experimentation for other diseases, may in the future offer a bank of immune-privileged cells, available for all patients and after a genetic correction for muscular dystrophies and other myopathies."

Journal • Review • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy • Myositis • Sarcopenia • Transplantation

Anti-NKG2C/IL-15/anti-CD33 Killer Engager Directs Primary and iPSC-derived NKG2C NK cells to Specifically Target Myeloid Leukemia. (PubMed, Mol Ther) - "The NKG2C-KE was also tested in a more homogeneous system using induced pluripotent stem cell derived NK cells (iNK) that have been engineered to express NKG2C at high levels. The NKG2C-KE triggered iNK cell-mediated cytotoxicity against CD33 cells and primary AML blasts. The NKG2C-KE specific interaction with adaptive NK and NKG2C iNK cells represents a new immunotherapeutic paradigm that uniquely engages highly active NK cells to induce cytotoxicity against AML through redirected targeting."

Journal • Acute Myelogenous Leukemia • Cytomegalovirus Infection • Hematological Malignancies • Infectious Disease • Leukemia • Oncology • Transplantation • IFNG • IL15

[VIRTUAL] Toggling of NKG2A expression drives adaptive reprogramming and functional specialization of iPSC-derived CD19 CAR NK cells (CIMT 2021) - "Induced pluripotent stem cell (iPSC)-derived natural killer (iNK) cells offer a promising platform for off-the-shelf immunotherapy against hematological malignancies...Our results shed light on the regulatory gene circuits and cellular programs that determine functional potential in iPSC-derived NK cells products. Specifically, our results point to a crucial role for NKG2A-driven acquisition of a mature effector cell phenotype and highlight the need to consider subset diversity and receptor interactions in the design of iNK cell therapy strategies."

IO biomarker • Hematological Disorders • Hematological Malignancies • Oncology • B2M • CD19 • GZMB • IFNG

Impaired Mitochondrial Function in iPSC-Retinal Pigment Epithelium with the Complement Factor H Polymorphism for Age-Related Macular Degeneration. (PubMed, Cells) - "This study used RPE generated from induced pluripotent stem cells (iPSC-RPE), which were derived from human donors with or without AMD and genotyped for the complement factor H (CFH) AMD high-risk allele (rs1061170, Y402H) to investigate whether donor disease state or genotype had a detrimental effect on mitochondrial function and inflammation...A more pronounced reduction in mitochondrial function and increased inflammatory markers was observed in CFH high-risk cells, irrespective of disease state. These results provide evidence for a previously unrecognized link between CFH and mitochondrial function that could contribute to RPE loss in AMD patients harboring the CFH high-risk genotype."

Journal • Age-related Macular Degeneration • Complement-mediated Rare Disorders • Immunology • Inflammation • Macular Degeneration • Ophthalmology • Retinal Disorders

[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] Targeting NK Cells to Treat Cancer: Individual to Off-the-Shelf Products (PEGS 2021) - "To enhance specificity, trispecific killer engagers can be used alone or with adoptive transfer. NK cell multi-dosing will be achieved with off-the-shelf, genetically modified, induced pluripotent stem cells overexpressing CD16 or CAR with an endogenous IL-15 signal to enhance persistence."

Clinical • Acute Myelogenous Leukemia • Oncology • IL15

Humanized skeletal muscle in MYF5/MYOD/MYF6-null pig embryos. (PubMed, Nat Biomed Eng) - "Human:pig chimaeras generated with TP53-null human induced pluripotent stem cells led to higher chimaerism efficiency, with embryos collected at embryonic days 20 and 27 containing humanized muscle, as confirmed by immunohistochemical and molecular analyses. Human:pig chimaeras may facilitate the production of exogenic organs for research and xenotransplantation."

Journal • Transplantation • TP53

[VIRTUAL] Triple Gene-Modified iPSC-Derived NK Cells Combined with Daratumumab for Targeted Immunotherapy Against AML (ASH 2020) - "To overcome these barriers, we developed a robust genetic editing and manufacturing platform for the uniform engineering and expansion of high-quality NK cells derived from induced pluripotent stem cells (iPSCs)...Previously, we reported on our ability to effectively target multiple myeloma with our FT538 program (the iNK defined below), now FDA approved for clinical trials...Collectively, our results show that utilizing the iNK cell platform to uniformly express hnCD16 and IL15RF combined with complete CD38 KO is an effective strategy to promote effective ADCC against CD38+ cells in the absence of fratricide, and that CD38 KO reprograms NK cells for higher oxidative metabolic fitness for improved persistence and anti-tumor function. Furthermore, we have generated proof-of-concept data supporting triple gene-modified iNK cells combined with dara as a novel AML immunotherapy."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology • CD38 • IL15

[VIRTUAL] FT576: Multi-Specific Off-the-Shelf CAR-NK Cell Therapy Engineered for Enhanced Persistence, Avoidance of Self-Fratricide and Optimized Mab Combination Therapy to Prevent Antigenic Escape and Elicit a Deep and Durable Response in Multiple Myeloma (ASH 2020) - "There are multiple advantages in expanding treatment options beyond autologous primary T and NK cells, including the use of induced pluripotent stem cells (iPSC) to derive effector cells that can be uniformly manufactured at scale from renewable starting cellular material and where precision genetic engineering can be achieved at the clonal level which can be applied sequentially in order to build multiple specificities and functional modalities...Utilizing hnCD16, BCMA-CAR was tested in combination with anti-CD38 (daratumumab), anti-SLAMF7 (elotuzumab), or anti-CD19, showing synergistic increase in tumor targeting through various tumor associated antigens (TAAs)...Combination with other monoclonal antibodies displayed a similar response demonstrating the unique ability of FT576 to be directed to target multiple TAAs. Together, these studies demonstrate the versatility of FT576 as a highly effective multi-antigen targeting and cost-effective off-the-shelf BCMA-CAR iNK..."

Combination therapy • IO Biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • CD38

[VIRTUAL] A Phase I Study of FT538, a First-of-Kind, Off-the-Shelf, Multiplexed Engineered, iPSC-Derived NK Cell Therapy As Monotherapy in Relapsed/Refractory Acute Myelogenous Leukemia and in Combination with Daratumumab or Elotuzumab in Relapsed/Refractory Multiple Myeloma (ASH 2020) - "FT538 is an investigational, first-of-kind, multiplexed engineered NK cell therapy generated from a clonal master engineered induced pluripotent stem cell (iPSC) line, which can be used as a renewable source for the mass production of off-the-shelf NK cells for broad patient access...Lympho-conditioning consisting of three consecutive days of fludarabine and cyclophosphamide will be administered prior to the first dose of FT538...Key exclusion criteria include active central nervous system disease, need for systemic immunosuppressive therapy, and prior allograft organ transplant. This trial is expected to begin patient enrollment in 2020."

Combination therapy • IO Biomarker • Monotherapy • P1 data • Acute Myelogenous Leukemia • Gene Therapies • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology • Transplantation • CD38 • IL15

[VIRTUAL] Human diffuse midline glioma avatars as a platform to search for novel therapeutic targets (SNO 2020) - "We have recently proposed glioblastoma models derived from human induced pluripotent stem cells (hiPSCs) genetically engineered with different combinations of glioblastoma-associated genetic alterations as a platform to search for therapeutic targets...Using these models faithfully recapitulating histology and pathobiology of the patient tumors, we have performed drug screening and confirmed that their sensitivity to known drugs, including an EZH2 inhibitor and histone deacetylase inhibitors. On these faithful human avatars of diffuse midline glioma with H3K27M, we have applied bioinformatics algorithms of drug sensitivity prediction aiming at developing novel therapeutics for this devastating pediatric glioma."

Diffuse Midline Glioma • Glioblastoma • Glioma • Oncology • Pediatrics • Solid Tumor • EZH2 • TP53

[VIRTUAL] KEYNOTE PRESENTATION: Targeting NK Cells to Treat Cancer: Individual to Off-the-Shelf Products (PEGS 2020) - "To enhance specificity, trispecific killer engagers can be used alone or with adoptive transfer. NK cell multi-dosing will be achieved with off-the-shelf, genetically modified, induced pluripotent stem cells overexpressing CD16 or CAR with an endogenous IL-15 signal to enhance persistence."

Clinical • Oncology • IL15

Novel strategies to activate NK cells and make them antigen-specific (EBMT 2018) - "In addition, we have exploredIL-15/IL-15Ra-Fc (ALT-803), an IL-15 superagonistcomplex, which may be more optimal to present IL-15 to the immune system. Our data suggeststhat adaptive NK cells can be enriched from CMV+ donors after culture withIL-15 and a GSK3b inhibitor, a novelNK cell product in phase I clinical trials. Lastly, new strategies usingoff-the-shelf NK cells from induced pluripotent stem cells (iPSC) are beingdeveloped and will be in the clinic by the end of the year. This will allowmultiple dosing of cryopreserved “living drugs” to treat patients with cancer."

Acute Myelogenous Leukemia • Biosimilar • Cytomegalovirus Infection • Myelodysplastic Syndrome

Insights into autosomal recessive bestrophinopathy from a disease in a dish model. (ARVO 2017) - P=N/A; "...Skin fibroblasts from these subjects were reprogramed to induced pluripotent stem cells (iPSCs)...Based on these data, we conclude that ARB in this patient results at least in part from absent or severely diminished expression of Best1 leading to a defect in OS phagocytosis."

Clinical • Biosimilar • Inherited Retinal Dystrophy • Ophthalmology

Enhancing ADCC by human natural killer cells to improve tumor cell killing (IMMUNOLOGY 2020) - "We expressed CD64/16A in human NK92 cells, which lack endogenous FcγRs but mediates ADCC upon expression of CD16A, and in induced pluripotent stem cells differentiated into NK (iNK) cells. We are currently exploring an in vivo xenograft model using NSG immunocompromised mice engrafted with a HER2+ ovarian cancer cells to further examine the ADCC potency of CD64/16A iNK cells. Our findings suggest that CD64/16A may be utilized by engineered NK cells, leading to the formation of an “off-the-shelf” cellular therapy that can be combined with therapeutic mAbs for the treatment of various tumor types."

FCGR3A • HER-2

Gene Editing and Base Editing for Cell Therapies (TRICON 2020) - "This course will highlight some of the new methods and strategies for efficient gene and base editing, targeted in vivo and ex vivo delivery and cell production for therapeutic use in various cells such as induced pluripotent stem cells, T cells, natural killer (NK) cells and hematopoietic cells. Clinical translation and safety concerns surrounding gene-edited cell therapies will also be discussed. The instructors will give short talks followed by open discussion with attendees, where they can elaborate on their experiences and expertise."

FT538: Preclinical Development of an Off-the-Shelf Adoptive NK Cell Immunotherapy with Targeted Disruption of CD38 to Prevent Anti-CD38 Antibody-Mediated Fratricide and Enhance ADCC in Multiple Myeloma When Combined with Daratumumab (ASH 2019) - "It is derived from induced pluripotent stem cells (iPSC) engineered to lack CD38 expression, which we have previously shown to eliminate daratumumab-induced fratricide among iPSC-derived NK cells, resulting in enhanced long-term daratumumab-mediated ADCC. Additionally, the combined survival benefit of IL-15RF expression and fratricide resistance mediated by the CD38 knockout as well as the enhanced hnCD16-mediated ADCC allowed for greater cytotoxicity of FT538 against MM tumor spheroids. Together, these preclinical data support the clinical translation of FT538, an off-the-shelf adoptive NK cell immunotherapy product engineered for uniform hnCD16 and IL-15RF expression with CD38 elimination for enhanced ADCC in combination with daratumumab and other anti-CD38 mAbs for the treatment of MM."

IO Biomarker • Preclinical • CD38 • IL15

Authentic human glioma modeling using genetically engineered induced pluripotent stem cells (SNO 2019) - "Brainstem tumors derived from NPCs introduced with TP53 R248Q and H3F3A K27M mutations presented features of glial tumors with global expression of histone H3 K27M accompanied by suppression of histone H3K27 trimethylation, compatible with H3 K27M-mutant pediatric diffuse midline glioma. Using these isogenic human brain tumor models, we aim to advance our understanding of the pathobiology associated with different driver mutations and further, to provide a platform for development of targeted therapy."

PTEN • TP53

MicroRNA-448 Regulates the Cardiac Sodium Channel During Ischemia (BCVS 2019) - "...The effect of miR-448 mimic on sodium current was determined in induced pluripotent stem cells-derived cardiomyocytes... These results indicated that miR-448 contributed to post-transcriptional modification of SCN5A. miR-448 is likely one cause of sodium channel downregulation during ischemia and may represent a target for antagomir therapy to reduce arrhythmic risk associated with cardiomyopathy..Keywords: SCN5A, miR-448, Cardiomyocyte, Hypoxia, NF-κB, HIF1α"

CRISPR/Cas9-Base Editing Mediated Correction for Recessive Dystrophic Epidermolysis Bullosa (ASGCT 2019) - "...We delivered ABEmax mRNA with minimal toxicity into primary fibroblasts or induced pluripotent stem cells from two patients with RDEB, and observed mutation correction rates of up to 50% in along with concomitant restoration of COL7A1 protein production (Fig 1c.d)...3D bioprinting was used to deposit base-edited fibroblasts in a biopolymer complex that allowed for significant fibroblast expansion in support of a scalable, ex vivo approach for skin graft generation. These findings suggest that an optimized base editing approach may provide an efficient and precise genome editing method for individualized autologous cell therapy for RDEB."