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On the 13th of May, the company filed a six-count complaint in San Diego Superior Court against Shoreline Bio and its two founders, Dr. Dan S. Kaufman and Dr. Kleanthis G. Xanthopoulos. These claims stem from Dr. Kaufman's founding of and participation in Shoreline's business, in breach of his exclusivity obligations pursuant to a Scientific Advisor Agreement between Dr. Kaufman and role as a scientific advisor to Fate. Fate claims include actions for breach of contract, breach of implied covenant of good faith and fair dealing, fraud and deceit, tortious interference, restitution for unfair business practices and unjust enrichment. Fate is seeking monetary damages.
Also, on the 13th of May, Fate and Whitehead Institute for Biomedical Research filed a second lawsuit in the U.S. District Court for the Southern District of California against Shoreline Bio and Dr. Kaufman seeking damages for the defendants' infringement of U.S. Patents. 8,071,369, 8,932,856, 8,951,797, 8,940,536, 9,169,490, and 10,457,917. The patents, which Fate exclusively license from Whitehead, relate to key compositions and methods for reprogramming human somatic cells to a pluripotent state in the generation of iPSCs. Shoreline Bio and Dr. Kaufman have each filed answers to the Fate complaint denying infringement and alleging invalidity of the patents. Both lawsuits are in their early stages and remain pending.
(OT): From this, ''One approach that’s gaining traction involves induced pluripotent stem cells, or IPSCs. These cells can reproduce indefinitely and be developed into any other cell type. Though researchers have struggled to transform them into the adult T cells capable of fighting cancers, recent progress has led biotech companies like Century Therapeutics and Fate Therapeutics to try.
The new startup from ElevateBio and Boston Children’s will be next in line. Daley says that, after about a decade of research, his lab “learned how to coax [IPSCs] into making more mature T cells that are comparable to the T cells that we would harvest from a patient's circulating blood.”
The research published Thursday describes a method by which scientists suppress an enzyme, dubbed EZH1, that hampers IPSCs’ ability to become mature T cells. Boston Children’s scientists also tried a different approach to growing the cells, leading to T cells with tumor-fighting power comparable to ones derived from currently used methods, the paper said. The cells were better able to clear cancer in mice than cells made with other IPSC approaches, researchers claimed.'' https://www.biopharmadive.com/news/elevatebio-boston-childrens-startup-cell-therapy-ipsc-daley/628874/
A look at some early stage CAR-NK biotech's who might be candidates for an IPO down the road… (sub req'd) https://biotechstrategyblog.com/2022/07/shoreline-rides-the-car-nk-wave-at-aacr22.html/
Jefferies Healthcare Conference webcast https://wsw.com/webcast/jeff240/fate/1824000
From AACR 2021: ''In this study, we evaluated the function of multiplexed engineered MICA/B CAR iNK cells (termed FT536) in combination with monoclonal antibodies (mAbs), to elicit multi-antigen targeting, and radiation therapy, to augment surface MICA/B expression. FT536 showed superior in vitro cytotoxicity and in vivo tumor control against an array of MICA/B expressing tumor lines.
Furthermore, ADCC, induced in combination with cetuximab or trastuzumab, enhanced the potency of FT536 against various solid tumor lines (p <0.05). To demonstrate the capability of FT536 to synergize with irradiation therapy, we utilized a panel of tumor lines, divergent in tissue origin and MICA/B expression profiles. This approach highlighted that irradiation of the SK-BR-3 tumor line, a breast adenocarcinoma that expresses low levels of surface MICA/B and high levels of EGFR, induced the upregulation of MICA/B expression (p <0.05). As anticipated, FT536 exhibited enhanced, CAR-dependent cytotoxicity against irradiated SK-BR-3 cells.
Ongoing work is focused on the development of in vivo models that combine FT536 with in situ tumor irradiation and mAbs in order to promote durable responses and the elimination of resistant and heterogenous cancer cells. These data demonstrate successful targeting of MICA/B positive tumors by FT536 can be augmented by mAb and radiation therapies as first-of-kind combinatorial strategies to broadly target escape-prone tumors.'' https://aacrjournals.org/cancerres/article/81/13_Supplement/1591/667388/Abstract-1591-FT536-Preclinical-development-of-a
FT536 is now listed and the first patient should be dosed soon https://clinicaltrials.gov/ct2/show/NCT05395052
The posters
Long-term Stability Assessment of Cryopreserved iPSC-derived T and NK Cells Supports Mass Production and Off-the-shelf Therapeutic Applications https://fatetherapeutics.com/wp-content/uploads/2022/05/1-2022-ASGCT-iNK-and-iT-DP-stability-Draft-2-VFINAL.pdf
Long-term Stability of iPSC-Derived CD34+ Cell Banks Supports the Sustainable Manufacture of Off-the-shelf Immunotherapies https://fatetherapeutics.com/wp-content/uploads/2022/05/2-2022-ASGCT-iCD34-to-iNK-and-iT-stability_vFINAL.pdf
Development of Next-Generation, Off-the-Shelf CAR T-cell Immunotherapies for Solid Tumors https://fatetherapeutics.com/wp-content/uploads/2022/05/3-ASGCT2022_Multiplexed-CAR-iT_Pan_VFINAL.pdf
Development of Master Multiplexed-Engineered iPSC Bank for Off-the-Shelf Cell-Based Cancer Immunotherapy with Reduced Conditioning Chemotherapy https://fatetherapeutics.com/wp-content/uploads/2022/05/4-2022_ASGCT_Stealth_MJ_VFINAL_09May2022.pdf
10-year Stability Assessment of Cryopreserved, Engineered iPSC Banks: Genetic and Phenotypic Characterization https://fatetherapeutics.com/wp-content/uploads/2022/05/5-ASGCT-2022-iPSC-Stability-Poster-NDB-Final_.pdf
Robust T-cell Cellular Reprogramming and Single-cell Engineering Platform Overcomes Inconsistencies and Heterogeneity Associated with Engineering Primary T cells https://fatetherapeutics.com/wp-content/uploads/2022/05/6-AGGCT-2022_Robust-T-cell-Cellular-Reprogramming-and-Single-cell-Engineering-Platform_VFinal.pdf
iPSC-derived CD38-null NK cells in Combination with CD38-targeted Antibody Represent a Novel Therapeutic Strategy to Reduce the Requirement of Conditioning Chemotherapy for Off-the-Shelf Cell-based Cancer Immunotherapy https://fatetherapeutics.com/wp-content/uploads/2022/05/7-2022_ASGCT_CD38-conditioning_Final.pdf
FT536: A First-of-Kind, Off-the-Shelf CAR-iNK Cell Product Candidate for Solid Tumors Designed to Specifically Target MICA/B Stress Proteins and Overcome Mechanisms of Tumor Evasion https://fatetherapeutics.com/wp-content/uploads/2022/05/2-2022_ASGCT_FT536_vFinal.pdf
This has just been published https://www.nejm.org/doi/full/10.1056/NEJMoa2119662
The editorial https://www.nejm.org/doi/full/10.1056/NEJMe2204283
I'm not aware of antigen spreading from other TCR-T's off the top of my head, but do know ADAP will add IL-7 and CCL19 to their MAGE-A4 TCR-T, which could result in that (clinical data next year) https://d1io3yog0oux5.cloudfront.net/adaptimmune/files/pages/adaptimmune/db/336/description/preclinical/DP008-22A_Pope_ADP-A2M4N7X19Poster_ASGCT_2022_Final_Print.pdf
No mention of the primary tumor or antigen spreading which is a must for solid cancers.
Some data from a single patient with metastatic pancreatic treated with TCR-T therapy plus (systemic) anti-PD-1 and CD40
10-Year Stability Assessment of Cryopreserved, Engineered iPSC Banks: Genetic and Phenotypic Characterization
Induced pluripotent stem cells (iPSCs) represent a promising renewable source of starting material for the mass production of uniform and consistent multiplexed-engineered cellular therapies for off-the-shelf therapeutic use, including for cancer, autoimmune disease and regenerative medicine. Over the past decade, we have developed a robust proprietary iPSC platform, where cellular reprogramming, maintenance of pluripotency in the naïve state, and single-cell culture in a feeder-free environment is enabled by stage-specific, small molecule combinations to block differentiation, enhance survival, and support self-renewal of iPSCs (Valamehr et al., Stem Cell Reports 2014). We have applied our iPSC product platform to generate clonal master iPSC banks, and have used these banks for cGMP manufacture of multiplexed-engineered, off-the-shelf natural killer and T-cell product candidates now in clinical studies. Establishing a cell banking paradigm, including a bank stability program, to ensure the long-term availability and viability of clonal master iPSC banks for drug product manufacturing is critical to ensure safety, efficacy, regulatory compliance, and manufacturing demands throughout a product’s life cycle. To this end, we have performed long-term stability studies of cryopreserved iPSC banks, including at 2, 5 and 10 years from formation. Our data show that different somatic cells can be efficiently reprogrammed to the pluripotent state, frozen in a controlled environment, and maintained for at least 10 years. Cryopreserved iPSC banks were thawed and tested for critical quality attributes including viability, recovery, purity, and potency. In addition, the stability of cryopreserved, multiplexed-engineered iPSC lines was examined following thaw and stress-inducing manipulations, including further rounds of genetic engineering, single-cell subcloning and expansion in feeder-free culture, and cryopreservation to establish secondary iPSC banks. The data to be presented will collectively show that cryopreserved iPSC banks maintain viability (>90%), purity (>90%), potency (tri-lineage differentiation), phenotypic and genetic stability (genome integrity and transgene expression stability) over a long period of time without significant deterioration. Therefore, clonal master iPSC banks created using our proprietary iPSC platform and maintained under our proprietary banking paradigm can serve as a renewable source of starting material over the long term for the mass production of off-the-shelf cell therapies.
Robust T-Cell Cellular Reprogramming and Single-Cell Engineering Platform Overcomes Inconsistencies and Heterogeneity Associated with Engineering Primary T Cells
Adoptive transfer of primary T cells expressing chimeric antigen receptors (CARs) has shown great promise in treating hematologic malignancies. However, application of CAR T-cell therapy is limited by several challenges, including cell product inconsistencies and heterogeneity resulting from engineering primary T-cell populations as part of drug product manufacture. The use of clonally-derived, master induced pluripotent stem cell (iPSC) lines is an attractive source for the renewable manufacture of precisely-engineered, homogenous CAR T-cell products that can be fully characterized, stored, and administered on-demand for broad patient access. Furthermore, generation of such master iPSC lines from donor T cells (TiPSCs) allows for the unique opportunity to use the pre-rearranged TCR locus as an ideal approach to facilitate T-cell receptor alpha constant (TRAC) locus-targeted genetic editing to enhance CAR-mediated activity. Reprogramming of donor T cells has historically been inefficient though and iPSC-derived T cells often exhibit poor functional attributes. Here we evaluate our non-integrating proprietary T-cell cellular reprogramming platform for the efficient generation of high-quality naïve TiPSCs using current good manufacturing practice (cGMP)-grade processes, procedures, and materials. Donor T cells were sourced from leukapheresis blood collections following consent and screening for infectious disease markers. The aß T-cell population was isolated and banked in animal component-free cryopreservation medium. These parental banks were characterized for purity, safety, identity, viability, and recovery. cGMP parental cell banks from nine independent donors were assessed for reprogramming efficiency and naïve iPSC generation using our proprietary reprogramming platform (Valamehr et al., 2014). TiPSCs were efficiently generated from all nine cGMP parental cell banks regardless of donor background or attributes. The fraction of TiPSCs reached >80% by day 28 for most donors (n=7), whereas two donors exhibited lower TiPSC fraction (24 and 58%). In each case, this output of TiPSCs represented a significant increase over other donor T-cell reprogramming methods. To test the potential to precisely engineer and single-cell select TiPSCs for the generation of clonally-derived, master iPSC lines, TiPSCs from four cGMP parental cell banks were engineered by CRISPR-mediated CAR insertion into the TCR alpha constant locus. TiPSCs from all four cGMP banks showed robust knock-in efficiency (20-60%) and maintained uniform pluripotent phenotypes and genomic stability post genetic engineering. We next isolated and sorted single-cell TiPSCs into 96-well plates, and extensively characterized each clonal TiPSC population following expansion. Hundreds of TiPSC clones were successfully generated and cryopreserved for characterization and assessment. Cryopreserved TiPSC clones showed robust recovery upon thaw (viability >75%) and maintained normal karyotype (100% of clones tested). In contrast to engineering cell populations as part of each manufacturing campaign for primary CAR T-cell production, this study highlights the potential to use clonally-derived, master engineered TiPSC lines as a renewable source for the consistent and uniform manufacture of off-the-shelf CAR T cells for therapeutic applications.
Development of Next-Generation, Off-the-Shelf CAR T-Cell Immunotherapies for Solid Tumors
Despite inducing promising clinical outcomes in patients with relapsed / refractory hematologic malignancies, the adoptive transfer of engineered T cells armed with a chimeric antigen receptor (CAR) has been less effective against advanced solid tumors. Specific challenges that have emerged include lack of tumor-exclusive antigen targets, antigen heterogeneity, and functional suppression resulting from the tumor microenvironment. In addition, inherent limitations associated with patient- and donor-derived T-cell therapies limit the breadth of their therapeutic application, including the potential to reach patients earlier in care. Induced pluripotent stem cells (iPSCs) can serve as renewable starting material for the mass production of off-the-shelf, cell-based cancer immunotherapies. We have previously developed FT819, a first-of-kind off-the-shelf CAR T-cell therapy derived from a clonal master iPSC line engineered to uniformly express a novel CD19 1XX-CAR driven by the endogenous T-cell receptor (TCR) a promoter at the T-cell receptor a constant (TRAC) locus. FT819 was designed to promote antigen specificity, improved safety by knocking out the TCR to eliminate the possibility of graft versus host disease (GVHD), and enable off-shelf availability. Here, we describe a novel multiplexed-engineered, off-the-shelf CAR T-cell therapy derived from a clonal master iPSC line for the treatment of solid tumors. The master iPSC line incorporates seven functional modalities: 1) a CAR for direct targeting of tumor antigen; 2) a cytokine receptor fusion protein for enhanced T-cell activity; 3) a high-affinity, non-cleavable CD16 (hnCD16) for enhanced antibody-dependent cellular cytotoxicity (ADCC) in combination with tumor-targeting monoclonal antibodies; 4) an engineered modality for enhanced trafficking; 5) a novel chimeric protein for enhanced functionality in response to tumor microenvironment resistance signaling; 6) CD38 deletion for enhanced metabolic fitness; and 7) TRAC-targeted TCR deletion for eliminating the risk of GVHD. Utilizing our proprietary iPSC product platform, a clonal master iPSC line was derived by CRISPR-mediated knock-in of functional modalities into the TRAC and CD38 loci. Single iPSCs were assessed and selected for specific targeted integration at the desired loci without random donor template integration; transgene copy numbers were confirmed by droplet digital PCR as well as genome stability by karyotyping and microarray analysis. We next demonstrated that T cells derived from the clonal master iPSC line exhibited improved expansion during differentiation, including without the need for cytokine support. In vitro functional studies including antigen-specific cytokine release assays, cytotoxic T lymphocytes assays, mixed lymphocyte reaction, and serial restimulation assays demonstrated enhanced efficacy. Our data validate the potential of multi-loci engineering of iPSCs to create master multiplexed-engineered iPSC lines and produce next-generation, iPSC-derived CAR-T therapies against solid tumor.
FT536: A First-of-Kind, Off-the-Shelf CAR-iNK Cell Product Candidate for Solid Tumors Designed to Specifically Target MICA/B Stress Proteins and Overcome Mechanisms of Tumor Evasion
The advent of chimeric antigen receptor (CAR)-T cell therapies has revolutionized the treatment of hematological malignancies; however, broader therapeutic success has been challenged by observed toxicities, including on-target, off-tumor engagement of non-cancerous cells, limited tumor antigen expression and availability, and the ineffectiveness of single-antigen targeted CAR T cells to eradicate heterogeneous tumors. In addition, the inherent variability that arises from the use of patient- and donor-sourced T cells and the engineering of these T-cell populations as part of each manufacturing campaign results in significant drug product inconsistencies, which can impact safety, efficacy, and therapeutic reach. We have developed FT536, a first-of-kind, induced pluripotent stem cell (iPSC)-derived NK (iNK) cell product candidate that expresses a novel CAR and ubiquitously targets cancer cells through canonical stress ligand recognition (Figure 1A). FT536 recognizes the conserved a3 domain of the pan-tumor associated MICA and MICB (MICA/B) stress proteins, a novel targeting strategy that mitigates a key tumor immune evasion mechanism. In addition to the CAR, FT536 is derived from a clonal master iPSC line that incorporates multiple genetic edits to enhance NK cell effector function, persistence, and multi-antigen targeting. Starting with a clonal master iPSC line, the cGMP manufacturing process of FT536 is analogous to pharmaceutical drug product development, and consistently and uniformly delivers greater than 4x107 cellular fold expansion per manufacturing campaign. FT536 drug product can be cryopreserved, stored, and delivered to clinical sites for thaw-and-infusion to patients in the out-patient setting. Preclinical assessment of the product candidate’s unique CAR modality demonstrated potent antigen-specific cytolytic activity against an array of solid and hematological tumor cell lines. FT536 is also armed with a high-affinity, non-cleavable CD16 (hnCD16) Fc receptor, which provides the potential to target additional tumor antigens in combination with tumor-targeting antibodies. In addition, FT536 demonstrated significant tumor growth inhibition in multiple solid and liquid in vivo xenograft models (Figure 1B). An Investigational New Drug (IND) application for FT536 was allowed by the U.S. Food and Drug Administration (FDA) in December 2021, and a first-in-human clinical study of FT536 as monotherapy and in combination with tumor-targeting monoclonal antibody therapy for the treatment of multiple solid tumor indications is expected to commence in mid-2022.
(A) MICA/B CAR containing primary T cells demonstrated pan-tumor reactivity and superior IFN? cytokine responses compared to control and NKG2D CAR containing primary T cells. (B) FT536 significantly reduced the number of lung and liver (not shown) metastases compared to CAR negative iNK control cells in a murine metastatic melanoma model using B16/F10 cells engineered to overexpress human MICA.
For some reason the links don't work, so I will add the abstracts below.
Development of Master Multiplexed-Engineered iPSC Bank for Off-the-Shelf Cell-Based Cancer Immunotherapy with Reduced Conditioning Chemotherapy
Induced pluripotent stem cells (iPSCs) are a unique renewable starting material for the manufacture of off-the-shelf immune cells and offer the advantages such as enhanced product uniformity, reduced cost, and on-demand availability. Current practice of both autologous and allogeneic cell-based cancer immunotherapy requires administration of systemic conditioning chemotherapy, which suppresses the patient’s immune system in order to potentiate the adoptively-transferred immune cells. However, the intensity and frequency of immune suppression can also lead to increased risk of life-threatening complications, such as severe infections. New therapeutic strategies that enable potentiation of adoptively-transferred immune cells without substantially ablating the patient’s immune system may significantly improve the therapeutic paradigm of cell-based cancer immunotherapy. Here, we describe a novel off-the-shelf, iPSC-derived CAR NK (CAR-iNK) cell derived from a master multiplexed-engineered iPSC line with the potential to maintain functional persistence in the background of an intact host immune system. The multiplexed-engineered iPSC line incorporates six unique functional elements: 1) a CAR for targeting of plasma cells; 2) IL-15/IL-15 receptor fusion protein (IL-15RF) for enhanced NK cell activity; 3) a high-affinity, non-cleavable CD16 (hnCD16) for enhanced antibody-dependent cellular cytotoxicity (ADCC); 4) beta 2 microglobulin (B2M) deletion for resistance to host CD8 T cell-mediated rejection; 5) Class II transactivator (CIITA) deletion for resistance to host CD4 T cell-mediated rejection; and 6) CD38 deletion for resistance to fratricide when combined with anti-CD38 monoclonal antibody (mAb) to eliminate host allo-reactive immune cells. The multiplexed-engineered iPSC line was derived using our proprietary iPSC product platform. In the first stage, a clonal master iPSC line was established incorporating IL-15RF and hnCD16 at the CD38 locus. In the second stage, iPSCs from the clonal master iPSC line were further engineered to knock-out B2M and CIITA and knock-in the CAR. Single-cell selection was performed at each stage to assess for specific targeted integration, biallelic disruption of desired loci, and the lack of random donor template integration. Transgene copy numbers were further confirmed by droplet digital PCR. Importantly, karyotype analysis ensured genome stability of these clonal master iPSC lines, a testament to the robustness of the platform in enabling staged multiplexed engineering and single-cell selection. The master multiplexed-engineered iPSC line incorporating six functional elements was used to produce CAR-iNK cells, which were assessed for persistence and anti-tumor functionality. The successful production of these CAR-iNK cells supported the notion that the engineered modalities did not impact CAR-iNK cell differentiation and expansion (>95% CD56, >95% CAR, >95% CD16). In vitro functional studies including antigen-specific cytokine release assays, mixed lymphocyte reaction, and NK cell cytotoxicity assays in the presence of peripheral blood mononuclear cells demonstrated functional persistence from allo-reactive immune cells. In vivo studies with xenograft mouse model are ongoing. Collectively, the data provide evidence of the robust capability of our proprietary iPSC product platform to support multi-loci engineering of iPSCs at the single-cell level, the creation of master multiplexed-engineered iPSC lines, and the production of next-generation, off-the-shelf CAR-iNK cell therapies for use in minimally-conditioned patients.
Long-Term Stability of iPSC-Derived CD34+ Cell Banks Supports the Sustainable Manufacture of Off-the-Shelf Immunotherapies
Human induced pluripotent stem cells (hiPSC) have the unique dual properties of unlimited self-renewal and differentiation capacity into all three somatic cell lineages. To further leverage these attributes, we have established a versatile iPSC product platform that enables multiplexed engineering of hiPSCs at the single-cell level and have developed a proprietary differentiation protocol to support definitive hematopoiesis for the derivation of CD34+ hematopoietic progenitor (iCD34) cells. We have shown that these iCD34 cells exhibit multilineage differentiation to diverse subsets of immune cells, including Natural Killer (NK) and aß T cells. The highly efficient and scalable differentiation platform is chemically-defined and cGMP-compatible, and iCD34 cells can be cryopreserved, banked and stored. Here we show the successful cryopreservation and long-term cryogenic storage (2, 4, and 6 years) of iCD34 cells, as well as the ability of these long-term stored iCD34 cells to serve as an intermediate feedstock for mass production of iPSC-derived NK and T (iNK and iT, respectively) cell therapies.
A diverse set of iCD34 cells, including those engineered with a high-affinity, non-cleavable CD16 (hnCD16) and/or with an anti-CD19 chimeric antigen receptor (CAR19), were manufactured, cryopreserved, and stored in the vapor phase of liquid nitrogen at ≤ -150°C for up to 6 years. To determine the impact of long-term cryopreservation on cell quality, long-term stored iCD34 lots were thawed and assessed for viability, recovery, phenotype, differentiation potential and iNK / iT cell functional potency. Post-thaw viability and enumeration was determined by trypan blue dye exclusion or acridine orange/propidium iodide staining in conjunction with Annexin V staining by flow cytometry, which was found to be similar to recently cryopreserved batches. Phenotypic flow analysis showed consistent identity and purity with pre-cryopreservation trends. To evaluate their differentiation potential, iCD34 cells were subsequently differentiated and expanded into iNK and iT cells. Flow cytometry analysis confirmed iNK and iT cell identity and purity, and differentiation yields were comparable with recently cryopreserved batches. Lastly, functionality was assessed via antibody dependent cellular cytotoxicity (ADCC) and antigen-specific cytotoxicity. In combination with monoclonal antibodies, hnCD16-iNK cells continued to show enhanced ADCC and production of the pro-inflammatory cytokines against antigen-bearing tumor cell lines. Similarly, CAR19-expressing iNK and iT cells maintained antigen-specific activity CD19+ tumor cell lines in various cytotoxicity assays.
This study demonstrates that manufactured, cryopreserved, and stored iCD34 cells are stable for a minimum of 6 years in the vapor phase of liquid nitrogen and shows that cryopreserved iCD34 cells can serve as a robust starting material for mass production of iPSC-derived cell-based immunotherapies. We observed no changes in vitality, phenotype, differentiation potential or iNK and iT cell potency. Taken together, our studies show that long-term stored iCD34 cells can serve as an intermediate feedstock for rapid mass production of multiplexed engineered iNK and iT cell therapies.
Generation of Human Myeloid Derived Suppressor Cells from Induced Pluripotent Stem Cells (IPSC) for Graft versus Host Disease Therapy
Allogeneic hematopoietic stem cells transplantation (aHSCT) is a widely used treatment for hematological disorders. Graft versus host disease (GVHD), a donor anti-host cell tissue destructive response, is a life-threatening aHSCT complication. Front line pharmaceutical treatment is not uniformly effective and has toxic side-effects. Myeloid derived suppressor cells (MDSC) are a heterogenous population of immature myeloid cells which are immunosuppressive. Their potential in GVHD therapy has been proven in different rodent models. However, a high MDSC to T cell ratio and multiple doses of MDSC are needed for GVHD therapy. But in vitro generation of MDSC limits its clinical usage by low yield and the need for personalized patient products. To remove the barriers that limit its application, we developed a method to generate MDSC in vitro from human iPSC derived CD34+ cells. We achieved a large-scale of cell expansion using OP9-DLL4 mouse stromal cells, cytokines to support CD34 differentiation followed those for myeloid lineage. In 19 days, 205-1085 iMDSC were derived from one CD34 of which 98% of iPSC derived MDSC (iMDSC) were CD45+CD33+, typical for a myeloid lineage phenotype. As with peripheral blood (PB) MDSC human iMDSC generated in our culture system are composed of two major populations: monocytic MDSC (51% CD45+CD33+ CD14+) and granulocytic MDSC (11% CD45+CD33+CD66b+). In contrast, PB MDSC expansion was < 5-fold. MDSC possess immunosuppressive function, key for a successful GVHD therapy. To investigate this property of iMDSC, we applied our iMDSC in a T cell proliferation assay and compared the potency of the immune suppressive effect to PB MDSC. iMDSC inhibited anti-CD3/28 bead driven proliferation of CD4 and CD8 T cells by 56% and 57%, respectively, at 1:2 (iMDSC:PBMC) while a correspondently lower % suppression was seen for CD4 (39%) and CD8 (30%) cells . Suppression was contact-dependent and associated with increased inhibitory receptor, resulting in decreased Teffector cell proinflammatory cytokine expression. We next investigated the suppressive capability of monocytic CD14+ vs granulocytic CD14- iMDSC subsets. We found that the %proliferation of CD4 (57%) and CD8 (55%) T cells suppressed by CD14+ iMDSC compared favorably to CD14- iMDSC for CD4 (19%) and CD8 (9%) at the same ratio. Previous studies have shown that LPS and ATP which are released due to tissue injury in the GVHD environment will induce inflammasome activation that we reported subverted in vivo suppression of murine GVHD lethality by bone marrow derived MDSC. To our surprise, iMDSC still retained 95% of their suppressive function after the LPS and ATP induced inflammasome activation while PB MDSC lost 77% of their suppressive function. Since MDSC have been reported to be sensitive to freeze-thaw that will be important for off-the-shelf clinical application, we investigated the function of iMDSC from frozen stock and found that iMDSC remained 86% of their function after the freeze thaw cycle. In summary, we developed a method for generating MDSC from human iPSC on a large scale. These iMDSC had potent immunosuppressive function and were resistant to inflammasome and freeze-thaw induced function loss facilitating the use of iMDSC as a potential alternative to or adjunct for GVHD therapy.
Long-Term Stability Assessment of IPSC-Derived T and NK Cells Support the Feasibility of Off-the-Shelf Therapeutic Applications
Cell-based immunotherapies have shown remarkable promise in the fight against various cancers. Induced pluripotent stem cell (iPSC)-derived natural killer (NK) and T (iNK and iT, respectively) cells can be mass produced and administered off-the-shelf to patients, and several iPSC-derived cell-based cancer immunotherapies are now undergoing human clinical testing. Our iPSC product platform leverages the use of clonal master iPSC lines that serve as the starting material for the manufacture of multiplexed-engineered, cell-based cancer immunotherapies that can be fully characterized, stored, and administered on-demand to patients. Here we demonstrate long-term stability (1, 3 and 6 years) of our engineered iNK and iT cell drug product candidates following long-term cryogenic storage. Multiple iNK and iT cell product candidates, including those engineered with a high-affinity, non-cleavable CD16 (hnCD16) and/or with an anti-CD19 chimeric antigen receptor (CAR19), were manufactured, cryopreserved and stored in the vapor phase of liquid nitrogen for up to 6 years. To assess the impact of cryogenic storage on these product candidates, cryopreserved lots were thawed and assessed for cell health, recovery, identity and functionality. Post-thaw recovery and viability was evaluated using acridine orange/propidium iodide staining and Annexin V staining by flow cytometry, and we found cell health was consistent with newly frozen cells suggesting that stability was maintained over years of cryogenic storage. Phenotypic analysis via flow cytometry was used to monitor product identity and purity and shown to be similar to pre-cryopreservation cells. Further, functionality was evaluated via pro-inflammatory cytokine production, antigen-specific cytotoxicity, and antibody-dependent cellular cytotoxicity (ADCC). Tumor necrosis factor-alpha and interferon-gamma production and secretion were examined in response to PMA/ionomycin or tumor cell lines via intracellular flow cytometry and electrochemiluminescence immunoassays and demonstrated consistent pro-inflammatory cytokine production. Notably, cryopreserved CAR-expressing iNK and iT cells maintained antigen-specific cytotoxicity against leukemia and lymphoma tumor cell lines in cytotoxicity assays, and hnCD16-expressing cells continued to show enhanced ADCC toward tumor cell lines when combined with tumor-targeting monoclonal antibodies. As there is no accelerated method established to model the shelf-life of cryopreserved cell therapies, periodic examination of stored drug product against release criteria provides the most thorough and accurate assessment of the feasibility of long-term storage. This study demonstrated that iNK and iT cells, including those that are genetically engineered, have a minimum shelf-life of 6 years when stored in the vapor phase of liquid nitrogen. No significant changes in viability, cell recovery, phenotype and tumor-killing potency were observed. Collectively, the data illustrate that engineered iNK and iT cell products can be mass produced, cryopreserved, and long-term stored for use as off-the-shelf cell-based cancer immunotherapy.
iPSC-Derived CD38-Null NK Cells in Combination with CD38-Targeted Antibody Represent a Novel Therapeutic Strategy to Avoid Host Immune Cell Rejection for Off-the-Shelf Cell-Based Cancer Immunotherapy
Conditioning chemotherapies that temporarily suppress a patient’s immune system are commonly used in both autologous and allogeneic cell-based cancer immunotherapy. However, the intensity and frequency of lympho-conditioning can impact immune reconstitution and increase a patient’s susceptibility to adverse outcomes, such as severe infections. Genetic deletion of cell-surface human leukocyte antigen (HLA) molecule expression has long been known to abrogate T-cell alloreactivity. Loss of class I HLA elicits NK cell-mediated recognition and attack though, and therefore additional immune-modulating strategies must be applied. To this end, mouse models using immune cells expressing certain inhibitory molecules, such as HLA-E and CD47, have been shown to abrogate NK cell alloreactivity. However, in the human system, HLA-E is the canonical activator of NKG2C, a dominant activating receptor found on human NK cells. Likewise, the expression of signal regulatory protein alpha (SIRPa), the major interactor for CD47, is mostly restricted to human macrophages and dendritic cells and not human NK cells. In this study, we provide details of a novel therapeutic strategy that combines engineered iPSC-derived NK (iNK) cells that uniformly lack CD38 surface expression with anti-CD38 antibodies to avoid host immune cell alloreactivity for off-the-shelf cell therapy. When testing iNK cells engineered with knockout of beta-2-microglobulin (B2M KO) to ablate HLA class I expression, B2M KO iNK cells were depleted over time in mixed lymphocyte reaction (MLR) assays containing peripheral blood mononuclear cells (PBMCs), suggesting activation of a “missing self” response by PBMC-containing NK cells. To overcome this mechanism of NK cell alloreactivity, we also genetically knocked-out CD38 (CD38 KO) to derive CD38 KO / B2M KO iNK cells having the potential to avoid anti-CD38 antibody-mediated fratricide. When combined with CD38-targeted antibody, the depletion of B2M KO CD38 KO iNK cells was abrogated as expected, and B2M KO CD38 KO iNK cell numbers were increased by 3.5-fold, comparable to the iNK cell numbers cultured without PBMCs. In contrast to these observations seen with B2M KO CD38 KO iNK cells, the combination of anti-CD38 antibody with B2M KO iNK cells resulted in fratricide and reduction of iNK cell counts. B2M KO iNK cells impaired expansion of PBMC-containing T cells over the duration of co-culture, resulting in 50% lower fold T-cell expansion at the peak of the control response, while B2M WT iNK cells stimulated T-cell activation and depleted iNK cells over time. However, parallel co-cultures maintained in the presence of anti-CD38 antibodies showed complete iNK cell resistance (both B2M KO and B2M WT iNK cells) to allogeneic PBMC attack, suggesting that anti-CD38 antibodies affords some control of allogeneic T-cell responses as well. Ongoing in vivo studies suggest that co-administration of anti-CD38 antibodies can significantly enhance the persistence of iNK cells in the presence of allogeneic PBMCs as seen in the blood, spleen and bone marrow. These data demonstrate the potential advantages of combining iPSC-derived CD38-null NK cells with anti-CD38 antibodies as a novel therapeutic strategy for reducing conditioning chemotherapy, depleting alloreactive lymphocytes, and promoting off-the-shelf cell therapy.
For (DTIL's) PBCAR19B (beginning at 2.7 × 108 with the ability to dose up to 8.1 × 108), it will be given following standard (not enhanced) LD chemo in R/R NHL. The first dose level of PBCAR19B is comparable to DL3 of the PBCAR0191A CAR-T therapy.
Also, they plan to test an ant-CD3 mAb https://www.businesswire.com/news/home/20210901006026/en/Precision-BioSciences-and-Tiziana-Life-Sciences-Announce-Exclusive-License-Agreement-to-Evaluate-Foralumab-a-Novel-Fully-Human-Anti-CD3-Monoclonal-Antibody-in-Conjunction-with-Allogeneic-CAR-T-Candidates-for-Cancer-Treatment
DTIC seems to be the only one increasing conditioning chemotherapy.
These data demonstrate the potential advantages of combining iPSC-derived CD38-null NK cells with anti-CD38 antibodies as a novel therapeutic strategy for reducing conditioning chemotherapy, depleting alloreactive lymphocytes, and promoting off-the-shelf cell therapy.
Development of Master Multiplexed-Engineered iPSC Bank for Off-the-Shelf Cell-Based Cancer Immunotherapy with Reduced Conditioning Chemotherapy https://annualmeeting.asgct.org/abstracts/abstract-details?abstractId=1327
Long-Term Stability of iPSC-Derived CD34+ Cell Banks Supports the Sustainable Manufacture of Off-the-Shelf Immunotherapies https://annualmeeting.asgct.org/abstracts/testing/abstract-details?abstractId=1326
Generation of Human Myeloid Derived Suppressor Cells from Induced Pluripotent Stem Cells (IPSC) for Graft versus Host Disease Therapy https://annualmeeting.asgct.org/abstracts/testing/abstract-details?abstractId=1669
Long-Term Stability Assessment of IPSC-Derived T and NK Cells Support the Feasibility of Off-the-Shelf Therapeutic Applications https://annualmeeting.asgct.org/abstracts/testing/abstract-details?abstractId=1655
iPSC-Derived CD38-Null NK Cells in Combination with CD38-Targeted Antibody Represent a Novel Therapeutic Strategy to Avoid Host Immune Cell Rejection for Off-the-Shelf Cell-Based Cancer Immunotherapy https://annualmeeting.asgct.org/abstracts/abstract-details?abstractId=1603
10-Year Stability Assessment of Cryopreserved, Engineered iPSC Banks: Genetic and Phenotypic Characterization https://annualmeeting.asgct.org/abstracts/abstract-details?abstractId=1323
Robust T-Cell Cellular Reprogramming and Single-Cell Engineering Platform Overcomes Inconsistencies and Heterogeneity Associated with Engineering Primary T Cells https://annualmeeting.asgct.org/abstracts/abstract-details?abstractId=1325
Development of Next-Generation, Off-the-Shelf CAR T-Cell Immunotherapies for Solid Tumors https://annualmeeting.asgct.org/abstracts/abstract-details?abstractId=1272
FT536: A First-of-Kind, Off-the-Shelf CAR-iNK Cell Product Candidate for Solid Tumors Designed to Specifically Target MICA/B Stress Proteins and Overcome Mechanisms of Tumor Evasion https://annualmeeting.asgct.org/abstracts/testing/abstract-details?abstractId=1765
This is testing systemic CDX-1140 (plus Keytruda) with neoantigen TCR-T's (targeting up to five) https://clinicaltrials.gov/ct2/show/NCT05349890
ASGCT titles:
Development of Master Multiplexed-Engineered iPSC Bank for Off-the-Shelf Cell-Based Cancer Immunotherapy with Reduced Conditioning Chemotherapy.
Long-Term Stability of iPSC-Derived CD34+ Cell Banks Supports the Sustainable Manufacture of Off-the-Shelf Immunotherapies.
Generation of Human Myeloid Derived Suppressor Cells from Induced Pluripotent Stem Cells (IPSC) for Graft versus Host Disease Therapy.
Long-Term Stability Assessment of IPSC-Derived T and NK Cells Support the Feasibility of Off-the-Shelf Therapeutic Applications.
iPSC-Derived CD38-Null NK Cells in Combination with CD38-Targeted Antibody Represent a Novel Therapeutic Strategy to Avoid Host Immune Cell Rejection for Off-the-Shelf Cell-Based Cancer Immunotherapy.
10-Year Stability Assessment of Cryopreserved, Engineered iPSC Banks: Genetic and Phenotypic Characterization.
Robust T-Cell Cellular Reprogramming and Single-Cell Engineering Platform Overcomes Inconsistencies and Heterogeneity Associated with Engineering Primary T Cells.
Development of Next-Generation, Off-the-Shelf CAR T-Cell Immunotherapies for Solid Tumors.
FT536: A First-of-Kind, Off-the-Shelf CAR-iNK Cell Product Candidate for Solid Tumors Designed to Specifically Target MICA/B Stress Proteins and Overcome Mechanisms of Tumor Evasion.
Intratumoral CD40 or CD47 + ACT after HD lymphodepletion to treat solid cancers should be tried. Elevated MCP-1 is tied to higher ORR in CAR T trials.
Not that I'm aware. Some are planning trials without it. In 1H 2023, NKTX will file an IND amendment for NKX101 (an anti-NKG2DL CAR-NK). It will be tested in patients with HCC, intrahepatic cholangiocarcinoma, as well as surgically removed CRC where liver metastases remain. The cells will be delivered (no LD chemo before) by an injection into the hepatic artery, a standard technique for delivering certain anticancer agents to the liver and has been used for CAR-T cells in the past https://jitc.bmj.com/content/8/2/e001097.long
As for FATE, they plan on adding an ADR (alloimmune defence receptor, ALLO has assess to it as well)
Is HD lymphodepletion used in any NK cell therapy trial?
Some posters will be presented at https://www.nk2022.org/program/poster-sessions
AACR abstracts
A novel method to produce clinical scale induced pluripotent stem cell-derived natural killer (iPSC-NK) cells with improved anti-tumor activity for next-generation allogenic cell therapies https://www.abstractsonline.com/pp8/#!/10517/presentation/14665
Targeting hematological malignancies and solid tumors with switchable chimeric antigen receptor-engineered iPSC-derived natural killer cells https://www.abstractsonline.com/pp8/#!/10517/presentation/16686
Development of an iPSC-derived NK cell screening platform for discovery of NK cell optimized Chimeric Antigen Receptors (CARs) for next-generation CAR-NK cell immunotherapies https://www.abstractsonline.com/pp8/#!/10517/presentation/16679
Combined use of human iPSC-derived natural killer cells with macrophages and anti-CD47 blockade to improve killing of acute myeloid leukemia https://www.abstractsonline.com/pp8/#!/10517/presentation/16676
AACR abstracts
Detection of genetically engineered iPSC-derived natural killer cells in blood and tissue https://www.abstractsonline.com/pp8/#!/10517/presentation/13839
Combining dual CAR iPSC-derived immune cells with antibody for multi-antigen targeting to overcome clonal resistance in multiple myeloma https://www.abstractsonline.com/pp8/#!/10517/presentation/16806
A novel synthetic stealth receptor that redirects host immune cell alloreactivity and potentiates functional persistence of adoptively transferred off-the-shelf cell-based cancer therapy https://www.abstractsonline.com/pp8/#!/10517/presentation/16749
FT573: Preclinical development of multiplexed-engineered iPSC-derived NK cells expressing a novel camelid nanobody chimeric antigen receptor (CAR) targeting pan-cancer antigen B7-H3 https://www.abstractsonline.com/pp8/#!/10517/presentation/16570
Multiplexed-engineered, iPSC-derived T cells expressing three unique targeting modalities address tumor heterogeneity and antigen escape https://www.abstractsonline.com/pp8/#!/10517/presentation/16565
Chimeric CD3 fusion receptors expressed on iPSC-derived universal TCR-less CAR-T and -NK cells synergize with bispecific engagers to enhance antitumor activity and limit antigen escape https://www.abstractsonline.com/pp8/#!/10517/presentation/17732
The CSO and one of the scientific co-founders (Shoreline)
First patient has been enrolled in the FT538 trial. Multiple cycles each comprising Cy/Flu conditioning, three doses of FT538, and mAb therapy. Two 2 cycles; potential to administer additional cycles with clinical benefit and upon relapse. The dose ranges from 100M to 1.5B cells and each mAb combination enrolls independently. For anti-PD-1 and anti-PD-L1 it will be NSCLC, GE, HNSCC, TNBC and UC. With anti-HER2, gastric and breast, and anti-EGFR, it is NSCLC, CRC and HNSCC.
Milestones:
Launch registration study under RMAT for R/R aggressive BCL.
Initiate early-line aggressive BCL study for FT596 plus R-CHOP.
Generate clinical datasets with FT516/FT596, FT538, FT576 and FT819.
Generate dose-escalation datasets with FT538 plus mAb therapy.
Initiate dose-escalation study of FT536.
Complete IND-enabling studies of B7H3-targeted CAR program.
Nominate two novel multi-antigen targeted programs for solid tumours.
Complete preclinical development of ADR functionality to enable conditioning free cell therapy.
Complete preclinical development of TSR functionality to enhance TME persistence.
Submit IND to FDA for first iPSC-derived CAR-NK cell program under Janssen partnership.
Complete IND-enabling studies for iPSC-derived CAR-T cell program under Ono partnership.
Expand iPSC-derived product pipeline through additional collaborations.
A Novel Stealth Strategy That Activates Adoptively Transferred Allogeneic Immune Cells and Avoids Rejection for Off-the-Shelf Cell-Based Cancer Therapy https://ashpublications.org/blood/article/138/Supplement%201/4800/481796/A-Novel-Stealth-Strategy-That-Activates-Adoptively
ASH PR's https://www.biospace.com/article/releases/fate-therapeutics-highlights-positive-durability-of-response-data-from-ft516-phase-1-study-for-b-cell-lymphoma-and-announces-fda-regenerative-medicine-advanced-therapy-designation-granted-to-ft516-for-relapsed-refractory-dlbcl/
https://www.globenewswire.com/news-release/2021/12/13/2351194/0/en/Fate-Therapeutics-Showcases-Positive-Interim-Phase-1-Data-from-FT596-Off-the-shelf-iPSC-derived-CAR-NK-Cell-Program-for-Relapsed-Refractory-B-cell-Lymphoma-at-2021-ASH-Annual-Meeti.html
Also, a webcast tomorrow at 8:00 AM EST https://edge.media-server.com/mmc/p/9s697auf
On Monday, Nov 15, they intend to host a virtual investor event, to highlight their emerging pipeline of OTS multiplexed engineered iPSC derived NK and T-cell product candidates for solid tumours.
During the investor event they plan to discuss the following; the multiplexed engineered preclinical candidates for which they intend to submit IND applications during the next 18 months. This includes the unique mechanisms of action that the product candidates seek to exploit and attacking solid tumours, proprietary multiplex engineering and single iPSC selection platform as well as new innovative features and functionality that they are currently assessing for integration into the solid tumour product candidates or multi armed PhI study of FT538 in solid tumours, where they have initiated enrolment in combination with checkpoint inhibitor therapy, in patients with resistance to checkpoint inhibitor and in combination with tumour targeting monoclonal antibody therapy, including those that target the tumour associated antigens, EGFR, HER2 and PD-L1.
Also, they plan to disclose clinical data from our first generation product candidates for solid tumours in patients that have progressed or failed checkpoint inhibitor therapy. The PhI study of FT500 has enrolled approximately 10 patients in dose expansion at 300 million cells per dose, and includes heavily pre-treated patients with non-small cell lung cancer or classical Hodgkin lymphoma that have progressed or failed PD(L)-1 checkpoint inhibitor therapy.
The PhI study of FT516 has enrolled approximately 12 patients in dose escalation, ranging from 90 million cells per dose to 900 million cells per dose, and primarily includes heavily pre-treated patients with Stage IV melanoma that have progressed or failed PD(L)-1 checkpoint inhibitor therapy.
ASH abstracts
Safety and Efficacy 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 https://ash.confex.com/ash/2021/webprogram/Paper151185.html
Off-the-Shelf, Multiplexed-Engineered iPSC-Derived NK Cells Mediate Potent Multi-Antigen Targeting of B-Cell Malignancies with Reduced Cytotoxicity Against Healthy B Cells https://ash.confex.com/ash/2021/webprogram/Paper148654.html
Arming of iPSC-Derived NK Cells Expressing a Novel CD64 Fusion Receptor with Therapeutic Antibodies Represents a Novel Off-the-Shelf, Antigen-Targeting Strategy for Cancer https://ash.confex.com/ash/2021/webprogram/Paper148642.html
Phase I Study of FT516, an Off-the-Shelf, iPSC-Derived NK Cell Therapy, in Combination with Rituximab in Patients with Relapsed / Refractory B-Cell Lymphoma https://ash.confex.com/ash/2021/webprogram/Paper151520.html
Clinical Manufacture of FT819: Use of a Clonal Multiplexed-Engineered Master Induced Pluripotent Stem Cell Line to Mass Produce Off-the-Shelf CAR T-Cell Therapy https://ash.confex.com/ash/2021/webprogram/Paper152985.html
Combination of Three Unique Anti-Tumor Modalities Engineered into iPSC-Derived T Cells Demonstrate a Synergistic Effect in Overcoming Tumor Heterogeneity and Cancer Escape https://ash.confex.com/ash/2021/webprogram/Paper153268.html
Dual Chimeric Antigen Receptor Approach Combining Novel Tumor Targeting Strategies Circumvents Antigen Escape in Multiple Myeloma https://ash.confex.com/ash/2021/webprogram/Paper154025.html
Off-the-Shelf, iPSC-Derived CAR NK Cells Multiplexed-Engineered for the Avoidance of Allogeneic Host Immune Cell Rejection https://ash.confex.com/ash/2021/webprogram/Paper153484.html
SITC:
Oral Presentation
FT536 Path to IND: Ubiquitous targeting of solid tumors with an off-the-shelf, first-of-kind MICA/B-specific CAR-iNK cellular immunotherapy
Abstract #: 117
Session 212: Cellular Therapies; November 13, 3:40 pm - 4:55 pm EST
Poster Presentation
Synthetic re-direction of TGFß receptors as a novel strategy to enhance the anti-tumor activity of iPSC-derived CAR-T cells in solid tumors
Abstract #: 138
Chemokine receptor engineering enhances trafficking and homing of primary and iPSC-derived CAR-T cells to solid tumors
Abstract #: 120
Off-the-shelf, engineered iPSC-derived NK cells mediate potent cytotoxic activity against primary glioblastoma cells and promote durable long-term survival in vivo
Abstract #: 169
Novel FcyR recombinant fusion facilitates antibody arming of engineered iPSC-derived NK cells to enhance targeting and killing of ovarian cancer cells
Abstract #: 197
New preclinical data which show that its iPSC-derived NK cell product candidate FT538 exhibits "significantly enhanced" serial killing and functional persistence compared to peripheral blood NK cells https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(21)00350-7
The data showed that FT538 persists in vivo at high levels for more than six weeks in the absence of cytokine support, whereas peripheral blood NK cells required co-infusion of either IL-2 or IL-15 to achieve low-level persistence for up to two weeks. Additionally, in sequential killing assays, FT538 was shown to have robust serial killing and functional persistence, which were not observed with peripheral blood NK cells. The superior antitumour activity of FT538 was attributable to its novel engineered components, including the knockout of CD38 and the expression of IL-15/IL-15R fusion protein.
I don't view the data as negative, but I think they should focus on FT596. Also, look to move it forward to a registration-direct trial in either CAR-T refractory and/or ineligible patients.
Thanks for posting this link! Will be interesting to see market reaction. Recently it seems like a strong sell on the news reaction across multiple stocks in multiple sectors, regardless of how positive the news is. Will FATE buck the trend?
The company will host a virtual event to highlight interim PhI clinical data from its FT596 and FT516 programs for the treatment of R/R B-cell lymphomas on August 19, at 4:30 p.m. ET.
Another day, another company working on iPSC derived cell therapies https://www.sec.gov/Archives/edgar/data/1619856/000119312521206262/d145328ds1.htm
No, but NKTX (working with CRSP [1]) will combine CAR-T plus CAR-NK [2]. Each will be edited to overcome the immunosuppressive TME [3], possibly be edited to reduce rejection (they use healthy donors) and each likely target two different antigens.
Refs:
1 https://www.globenewswire.com/news-release/2021/05/06/2224961/0/en/CRISPR-Therapeutics-and-Nkarta-Announce-Global-Collaboration-to-Develop-Gene-Edited-Cell-Therapies-for-Cancer.html
2 https://www.nkartatx.com/file.cfm/75/docs/Nkarta_AACR_2020_NK_plus_T_4235_9.pdf
3 https://www.nkartatx.com/file.cfm/75/docs/Nkarta_AACR_2020_gene_editing_891_20.pdf
Has anyone tried low dose NK -> CAR T or NK + TIL after lymphodepletion?
It improves expansion and persistence. The CD38 and CISH KO products should improve upon that and should have better cytotoxicity as well https://ashpublications.org/blood/article-abstract/136/21/2416/461232/CD38-deletion-of-human-primary-NK-cells-eliminates https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30206-X
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