Background Transforming growth factor beta (TGFβ) is an immuno-suppressive cytokine commonly present in the tumor microenvironment (TME) that creates considerable challenges for the treatment of solid tumors. Here we describe a unique strategy where induced pluripotent stem cell (iPSC)-derived NK (iNK) and T (iT) cells engineered to express a chimeric TGFβ signal redirector receptor (TGFβ-SRR) block the TGFβ-mediated repressive signaling and redirect the signal to potentiate effector cell function and improve cell fitness. Methods To identify iNK cell-specific pathways for TGFβ signal redirection, candidate cytokines were tested for their ability to mitigate suppression of iNK cell anti-tumor activity in the presence of recombinant TGFβ. Next, we developed TGFβ-SRR constructs where selected cytokine endodomains were fused to TGFBR2 ectodomain. TGFβ-SRR constructs were then engineered into iPSCs and differentiated into iNK cells. Phospho-flow for pSMAD2/3 was used to test for blockade of TGFβ signaling in recombinant TGFβ-treated cells. Antibody-dependent cellular cytotoxicity (ADCC) from TGFβ-SRR iNK cells was tested in co-cultures with SKOV-3, PC3, and MDA-MB-231 targets, then measured using xCELLigence readout. Innate killing mechanism was tested via serial restimulation assay with Raji targets and measured by flow cytometry. Co-cultures were performed in the presence of recombinant TGFβ. Results Engineered iPSCs expressing candidate TGFβ-SRR constructs were successfully differentiated into iNK cells (>95% CD56+), uniformly expressing TGFβ-SRR transgene (TGFβ-SRR; >95% positive). Analysis for pSMAD2/3 in recombinant TGFβ-treated cells showed 95% reduction of SMAD2/3 phosphorylation in top performing TGFβ-SRR motif, indicating successful blockade of TGFβ signaling. Evaluation of ADCC toward multiple solid tumor lines and using various monoclonal antibodies (Herceptin, Cetuximab, and Avelumab) showed superiority of TGFβ-SRR iNK cells (>80% cytolysis) over parental iNK cell control (<40% cytolysis) in the presence of recombinant TGFβ. Innate killing mechanism was tested in the serial restimulation assay, where TGFβ-SRR iNK cells expanded 3.5-fold over parental iNK cells after the first round of co-culture. Notably, the TGFβ-SRR iNK cells exhibited enhanced functional persistence, completely controlling tumor growth through three rounds of co-culture despite the addition of suppressive quantities of recombinant TGFβ, unlike parental iNK cells which failed to control tumor growth after the first round. Conclusions Collectively, the data illustrate that a customized TGFβ-SRR construct can redirect TGFβ-mediated suppression and potentiate effector cell function to enhance the anti-tumor activity of iNK cells. This novel synthetic receptor represents an innovative strategy to enable adoptively-transferred cell therapy to overcome the immunosuppressive TME for the successful treatment of bulky tumors.

Immune cell therapies derived from induced pluripotent stem cells (iPSC) provide a novel opportunity for the treatment of multiple cancer types. Assessment of the persistence and biodistribution of these product candidates requires specific and sensitive methods to detect engineered cells in both liquid and solid biopsies. Here, we present the development and validation of two complimentary nucleic acid-based detection assays for iPSC-derived natural killer (iNK) cell product candidates containing Fate’s proprietary high-affinity, non-cleavable CD16 transgene (hnCD16). The first assay is a droplet digital PCR (ddPCR) method to detect and quantify hnCD16 transgene copies present in a pool of genomic DNA (gDNA). The primers and probe were designed to recognize the optimized codons of hnCD16. Assay linearity and accuracy were assessed through titration studies using 0.024 to 1 ng of hnCD16-containing DNA spiked into different amounts of hnCD16-negative gDNA. Precision was determined through multiple assay runs by different operators on two instruments. The second assay is an in situ hybridization based method utilizing RNAscope࣪ technology to detect cells expressing hnCD16 in fixed tissue. Probes targeting hnCD16 were used to optimize signal specificity. Cells expressing hnCD16 and tissues from in vivo studies treated with iNK products served as positive controls. For the ddPCR assay, absolute limit of detection (aLoD) was determined to be 4.9 copies of hnCD16 per 20 µL reaction, regardless of total genomic mass input. Absolute limit of quantification (aLoQ) was 12 copies per 20 µL reaction with a %CV ≤30. Relative limit of quantification (rLoQ), assessing transgene to total DNA ratio, is affected by the background gDNA input and is less sensitive with lower input mass. rLoQ for total mass of 70 - 250 ng was 97 - 22 copies/µg gDNA (0.064% - 0.015%) with a %CV ≤30. The sensitivity of this input range allows evaluation of clinical samples with low cellularity. While ddPCR provides robust quantification of the hnCD16 transcript, the RNAscope࣪ assay informs localization of the iNK product. Specificity of the probe was established by confirming its lack of affinity for endogenous CD16 using a variety of human normal and tumor tissues and by staining hnCD16-positive fixed cell pellets and tissues from in vivo studies. In cell pellets, positive RNAscope࣪ signal correlated with the known ratio of transgene positive cells. In murine tissues previously confirmed to contain iNK cell product, the RNAscope࣪ positive staining correlated with NKG2A immunohistochemistry staining, confirming the presence of product NK cells. The combined use of both the ddPCR and RNAscope࣪ assays targeted to hnCD16 allows for detection and quantification of transgene-bearing iNK cells in a wide variety of patient samples including tumor biopsies. Both assays are being utilized for cell detection and quantification in our ongoing clinical trials. Citation Format: Cara E. Bickers, Judy L. Martin, Steven Castro, Jason Zhang, Thomas Dailey, Eric Sung, Suzanna Gasparian, Jason O'Rourke, Moyar Ge, Tom T. Lee, Janel Huffman, Jode Goodridge, Ryan Bjordahl, Bahram Valamehr, Peter M. Szabo, Lilly Wong, Sarah Cooley. Detection of genetically engineered iPSC-derived natural killer cells in blood and tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1138.

Chimeric antigen receptor (CAR) T cells have shown remarkable clinical success in the treatment of many malignancies. However, certain challenges remain, including broad patient access and durability of response. We have shown that a scalable manufacturing platform, where genetically edited induced pluripotent stem cell (iPSC) master cell lines are created to serve as a renewable starting material for the derivation of uniformly engineered CAR T or NK cells, can facilitate broad patient access in an off-the-shelf manner. To improve durability of response, often plagued by antigen heterogeneity found in cancer, we are pursuing several combination strategies, merging cell therapy with therapeutic agents such as checkpoint blockade therapy and monoclonal antibodies to increase anti-tumor activity and multi-antigen targeting of cancer. T cell engagers have also shown remarkable advancements in the treatment of various cancer types, but they are also afflicted by their own challenges and would equally benefit from combination strategies. Unfortunately, T cell engagers are not compatible with allogeneic adoptive cell therapy, as the cells used in the allogenic setting do not express the CD3 molecule used for interaction with the engagers, as the T cell receptor (TCR) that supports CD3 surface expression, is either not expressed in NK cells or has been ablated in T cells to prevent graft-versus-host disease. To investigate the anti-tumor synergy between off-the-shelf cell therapy and T cell engagers, we developed a novel CD3ε fusion receptor (CD3-FR) to uniquely support the expression of a functional CD3 on TCR-less allogeneic T and NK cells and to enable compatibility between allogeneic cell therapy and T cell engagers. Initially, CD3-FR constructs with various co-stimulating endodomains were confirmed to elicit T cell engager-dependent NFAT activity in TCR alpha chain (TRAC) knockout (T-KO) Jurkat cells. Next, iPSCs already containing a CAR inserted into the TRAC locus were engineered to contain CD3-FR. CAR+ CD3-FR+ iPSCs were differentiated into CAR-iT cells, uniformly expressing both modalities (>95% CAR+, >90% CD3ε+, TCR not detected). To demonstrate that CD3-FR+ CAR-iT cells can elicit T cell engager-dependent antitumor activity, CAR antigen (1° Ag) negative but T cell engager (2° Ag) positive target cells were used in various cytotoxicity assays. As expected, control CAR-iT cells failed to kill the 1° Ag negative tumors despite addition of T cell engager targeting 2° Ag. On the other hand, CD3-FR+ CAR-iT cells showed potent activity toward target cells but only in the presence of the T cell engager (>80% cytolysis). Furthermore, when comparing the expression of activation markers in CD3-FR+ CAR-iT cells in co-cultures with or without the T cell engager, we observed an increased proportion of CD69+ (61% vs. 28%) and CD25+ (37% vs. 2%) cells in the CD3-FR+ CAR-iT cell co-cultures containing the T cell engager. Cytokine production was also tested, with increased TNF (5-fold) and IFNγ (7-fold) measured in supernatants from CD3-FR+ co-cultures upon the addition of T cell engager, further demonstrating T cell engager-dependent functionality and specificity of the CD3-FR construct. To test the ability of CD3-FR CAR-iT cells to mitigate 1° Ag escape, we used a target cell population heterogenous for the CAR-specific target (1° Ag, 50% positive) but homogenous for EpCAM (2° Ag, 100% positive). After three days, the standard CAR-iT cells failed to control tumor cell growth due to antigen escape. In contrast, CD3-FR+ CAR-iT cells exhibited robust control (80% cytolysis) of the 1° Ag heterogenous targets in the presence of αEpCAM, indicating mitigation of 1° Ag escape. Lastly, CD3-FR was edited into iPSC-derived NK (iNK) cells to demonstrate compatibility of CD3-FR+ NK cells with T cell engagers. An xCelligence-based killing assay was performed in the presence of a T cell engager, where CD3-FR+ iNK cells showed superior target cell killing (~80% lysis) after 96 hours compared to parental iNK cells (~30% lysis), demonstrating the potential for synergy between T cell engagers and NK cells (Figure 1). Taken together, these studies present a novel opportunity to combine T cell engager technology with off-the-shelf CAR-iT or iNK cell products, uniquely merging two powerful therapeutics whose combination was previously underappreciated in improving cancer therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

FT819 is a first-of-kind, allogeneic, off-the-shelf CAR T-cell therapy derived from a clonal master induced pluripotent stem cell (iPSC) line precisely engineered to insert a novel 1XX anti-CD19 chimeric antigen receptor (CAR) under the regulation of the T-cell receptor alpha constant (TRAC) locus for optimized control of anti-tumor activity and to completely delete T-cell receptor (TCR) expression to eliminate the potential of graft-versus-host disease (GvHD). Unlike conventional allogeneic CAR T-cell therapies which require repeatedly sourcing of T cells from various donors as the starting material, the use of a clonal master engineered iPSC line serves as a renewable starting cell source and ensures routine mass production of a uniformly engineered, homogenous CAR T-cell product for broad patient access.

Despite the success of chimeric antigen receptor (CAR)-T cell therapy in various hematologic malignancies, obstacles to an effective therapeutic outcome are highly dependent on the tumor type being targeted and the immune microenvironment that the CAR-T cells encounter. For example, the presence of suppressive cells and soluble factors in the tumor microenvironment (TME) can prevent continued antitumor function of CAR-T cells. Toward this end, we explored multiple genetic editing options, including IL15-based edits, for improving the persistence and activation state of CAR-T cells in the TME. CAR-T cells engineered to express one of five different molecular barcoded constructs were developed and compared, including two versions of an IL-15 signaling complex (IL15RF), constitutively active IL-7 receptor (ca-IL7R), IL-21 signaling complex (IL21RF), and CD16 transgenes. The use of molecular tags allowed us to track CAR-T cell subpopulations in a complex pool with great resolution via next-generation sequencing (NGS) technology. Subsequent in vitro functional testing was performed to assess CAR-T expansion and function in response to serial stimulation with tumor cells bearing cognate antigen. Results showed that after four rounds of stimulation, cytotoxicity was enhanced in CAR-T cells engineered with the ca-IL7R and IL15RF transgene edits (1.5-fold increase in target cell lysis compared to control). Furthermore, an increased proportion of IL-2 producing cells was seen in CAR-T cells expressing the ca-IL7R and IL15RF-based edits (2-fold increase compared to control). In the initial proof of concept study, the best expansion after eight rounds of stimulation was seen in CAR-Ts engineered with IL15RF-based edits. Furthermore, using NGS to screen for the unique molecular barcodes in the CAR-T cell pool, we confirmed the enrichment of CAR-T cells with IL15RF-based edits over multiple rounds of stimulation. Single cell RNAseq was also performed after four and eight rounds of stimulation, where multiple clusters of CAR-T cells were identified and traced back to performance in vitro. Analysis of single cell clusters without IL15RF-based edits exhibited an increase in expression of the checkpoint receptor CTLA4 (p = 4.2E-2) and transcription factor GATA3 (p = 6.9E-5), while clusters with IL15RF-based edits had increased expression of effector molecules GZMB (p = 3.6E-2) and GZMH (p = 2.9E-8), T cell memory related markers CD62L (p = 5.2E-3) and CD27 (p = 2.2E-6), as well as increased expression of the cell proliferation marker Ki-67 (p = 3.3E-12). Because the presence and expansion of T cells in the tumor can be a good prognostic indicator for response to therapy, we used the pool of barcoded CAR-T cells and tested for enrichment/infiltration in a subcutaneous solid tumor implanted in NSG mice. Importantly, enrichment for CAR-T cells with IL15RF-based edits was observed using an NGS readout for the molecular barcodes present in the tumors. Analysis of the data from spatial transcriptomics on tumor sections, and single cell RNAseq of dissociated tumor samples, further informed our understanding of how CAR-T cells with IL15-based edits performed better in the TME (4-fold increase compared to control). The strategy of using molecular barcoded constructs for evaluating clonal populations of engineered CAR-T cells in a pool is shown here to be feasible and that it can be applied as a precise method to concurrently screen many distinct engineered modalities to improve effector cell function, homing and residence in various solid tumor settings. Disclosures Peralta: Fate Therapeutics, Inc.: Current Employment. Robbins:Fate Therapeutics, Inc.: Current Employment. Carron:Fate Therapeutics, Inc.: Current Employment. Denholtz:Fate Therapeutics, Inc: Current Employment. Navarrete:Fate Therapeutics, Inc.: Current Employment. Lu:Fate Therapeutics, Inc.: Current Employment. Yao:Fate Therapeutics, Inc.: Current Employment. Hanok:Fate Therapeutics, Inc.: Current Employment. Sui:Fate Therapeutics, Inc.: Current Employment. Gentile:Fate Therapeutics, Inc.: Current Employment. Sung:Fate Therapeutics, Inc.: Current Employment. ORourke:Fate Therapeutics, Inc.: Current Employment. Lee:Fate Therapeutics, Inc.: Current Employment. Shoemaker:Fate Therapeutics, Inc.: Current Employment. Nguyen:Fate Therapeutics, Inc.: Current Employment. Valamehr:Fate Therapeutics, Inc: Current Employment, Current equity holder in publicly-traded company.

Autologous chimeric antigen receptor (CAR)-T cell therapy has shown great promise in various hematologic malignancies. However, the complexities associated with immune cell evasion are prevalent causes of disease relapse in many cancers. With the advent of pluripotent stem cell (iPSC)-derived CAR-T cells, many factors that hamper therapeutic efficacy of CAR-T cells can be addressed through multiplexed engineering at the clonal level. This includes enhanced potency, increased capacity for multi-antigen targeting, and the consistency of a clonally derived engineered cellular product for off-the-shelf patient administration. In particular, strategies to mitigate antigen escape and address tumor heterogeneity may help promote durable responses. To combine the potent targeted therapy of the CAR with universal targeting of secondary and tertiary antigens, we expressed an MR1 clonal T cell receptor (TCR) and a high-affinity, non-cleavable CD16 Fc receptor (hnCD16) in our iPSC-derived CAR19 T cells (CAR19-iT cells) directed to leukemia and lymphoma and CAR-MICA/B T cells directed to solid tumors. The MR1-TCR allows highly specific recognition of tumor associated antigen presented by the MR1 protein. The non-polymorphic MHC class I-related protein MR1 is widely expressed with minimal variability among patients and enables the unique prospect to be a universal cancer immunotherapy by using the cognate MR1-TCR. The hnCD16 Fc receptor has been shown to improve antibody-dependent cellular cytotoxicity (ADCC) leveraging the broad range of available therapeutic monoclonal antibodies to target clinically validated tumor antigens. A preliminary assessment demonstrated that MR1-TCR overexpressed in T cells allowed for enhanced recognition of multiple hematological and solid tumor cell lines. Notably, prominent target specific killing was seen in A549 lung carcinoma cells (>75% reduction in total viable cells) with the directed cytotoxicity specifically inhibited by an MR1 blocking antibody. Next, in vitro functional testing was performed on the engineered CAR19-iT cells in co-culture assays where we measured killing of tumor cells via MR1-TCR engagement and via hnCD16 mediated ADCC. Specifically, we show that CAR19-iT cells expressing hnCD16 can be efficiently directed to lyse CD20+ Raji cells in the presence of rituximab or HER2+ SKOV3 cells in the presence of Herceptin, demonstrating the potential to target both hematological malignancies and solid tumors with one target modality in combination with various monoclonal antibodies. Moreover, CAR19-iT cells expressing either MR1-TCR or hnCD16 show the ability to control growth of CD19 KO lymphoma cells in the co-culture assays, further highlighting the unique ability to elicit multiple ways to target antigen escape. Further in vitro and in vivo combinatorial targeting studies focused on antigen escape and tumor heterogeneity are ongoing and will be discussed. In summary, the advances presented here demonstrate that both the MR1-TCR and hnCD16 modalities synergize with CAR-iT cells as an off-the-shelf therapeutic that can provide durable responses and enable broad applicability for targeting of additional tumor antigens where single-agent therapeutics fail to provide clinical benefit for patients. Disclosures Nguyen: Fate Therapeutics, Inc.: Current Employment. Peralta:Fate Therapeutics, Inc.: Current Employment. Lu:Fate Therapeutics, Inc.: Current Employment. Sung:Fate Therapeutics, Inc.: Current Employment. Lee:Fate Therapeutics, Inc.: Current Employment.

Background Although CAR T cells have been shown to be effective and potent in treating several hematologic malignancies, engineered T-cell therapies have had limited success in addressing solid tumors. Unlike liquid tumors where uniformly expressed antigens are accessible and can be effectively targeted, tumor access and antigen heterogeneity are a significant barrier to the successful development of CAR-T cells in solid tumors. Methods Here we demonstrate that the combination of a bi-specific T-cell engager (BiTE) targeting EpCAM with a CAR T cell targeting HER2 enhances the in vitro and in vivo anti-tumor activity against heterogenous solid tumors. Results We observed a dose-dependent enhancement of cytolytic activity when EpCAM-specific BiTEs were titrated alongside 4D5-based HER2-specific CAR T cells against HER2low tumors, enhancing maximal cytolysis by two-fold compared to CAR T cells alone (figure 1). Moreover, the escape of HER2low tumor cells in mixed heterogenous culture systems was circumvented by the combination of HER2-specific CAR T cells and EpCAM-specific BiTEs. The enhancement of efficacy was further demonstrated in an established HER2low MDA-MB-231 xenografts. HER2-specific CAR T cells were unable to contain Her2low tumors, whereas tumor growth was effectively controlled in mice receiving both EpCAM-specific BiTEs and HER2-specific CAR T cells. Conclusions Collectively, these data demonstrate that multi-antigen targeting mediated by BiTEs and CARs extends overall anti-tumor efficacy in preclinical models of heterogenous solid tumors. Fate Therapeutics is currently using its proprietary induced pluripotent stem cell (iPSC) product platform to generate iPSC-derived CAR T cells and iPSC-derived CAR NK cells that secrete BiTEs for the treatment of solid tumors. Ethics Approval These studies were approved by Fate Therapeutics Institutional Animal Care and Use Committee and were carried out in accordance with the National Institutes of Health’s Guide for the Care and Use of Laboratory Animals.

The development of chimeric antigen receptor (CAR) T cell therapeutics is widely recognized as a significant advancement for the treatment of cancer. However, several obstacles currently impede the broad use of CAR T cells, including the inherent process variability, cost of manufacturing, the absolute requirement for precise and uniform genetic editing in the allogeneic setting, and the challenge to keep pace with clonal heterogeneity and tumor growth. Utilizing our previously described induced pluripotent stem cell (iPSC)-derived T (iT) cell platform, we illustrate here the unique ability to address these challenges by creating a consistent CAR iT cell product that can be repeatedly manufactured in large quantities from a renewable iPSC master cell bank that has been engineered to mitigate the occurrence of graft versus host disease (GvHD), antigen escape and tumor relapse. Utilizing our proprietary cellular reprogramming and engineering platform and stage-specific T cell differentiation protocol, we demonstrate that iPSC can be engineered at the single cell level to generate a fully characterized clonal iPSC line, which can then be accessed routinely to yield CAR iT cells in a highly scalable manufacturing process (>100,000 fold expansion). Through bi-allelic targeting of a CAR into the T cell receptor alpha constant (TRAC) region, we generated CAR iT cells with uniform CAR expression (99.0 ± 0.5% CAR+) and complete elimination of T cell receptor (TCR) expression to avoid GvHD in the allogeneic setting. We elected to utilize the 1XX-CAR configuration, which has demonstrated superior anti-tumor performance relative to other CAR designs and when introduced into iT cells displayed enhanced antigen specificity (% specific cytotoxicity at E:T=10:1, antigen positive group: 86.4 ± 7.8; antigen null group: 8.9 ± 3.5). To enhance persistence without reliance on exogenous cytokine support, we engineered signaling-fusion complexes, including IL-7 receptor fusion (RF), into iPSC and studied its impact on iT phenotype, persistence, and efficacy. In vitro, IL-7RF clones demonstrated improved anti-tumor activity in a serial antigen dependent tumor challenge assay (Day 10, relative tumor counts, IL-7RF group: 1.95 ± 0.01; control group: 57.56 ± 4.55, P<0.000001). In a preclinical in vivo model of disseminated leukemia, IL-7RF clones demonstrate enhanced tumor growth inhibition (Day 34, Log [BLI], IL-7RF group: 6.68 ± 1.93; control group: 9.99 ± 0.23, P=0.0143). We next investigated a unique strategy to incorporate multi-antigen targeting potential into anti-CD19 1XX CAR iT cells with the addition of a high-affinity non-cleavable CD16 (hnCD16) Fc receptor. The combination of hnCD16 with anti-CD19 1XX CAR culminated in iT cells capable of multi-antigen specificity through combinatorial use with monoclonal antibodies to tackle antigen escape. Utilizing CD19 negative leukemia cells as targets, superior antibody-dependent cellular cytotoxicity (ADCC) was demonstrated by the combination of hnCD16 CAR iT and Rituximab (% specific cytotoxicity at E:T=1:1, hnCD16 group + Rituximab: 75.64 ± 2.12; control group + Rituximab: 16.98 ± 3.87, P<0.001). To address T cell fitness, the role of CD38 knockout (KO) in T cells was investigated, which we have previously shown to mediate NK cell resistance to oxidative stress induced apoptosis. CD38 gene was disrupted at the iPSC stage to generate 1XX-CAR T cells that lack CD38 expression (% CD38+ population, CD38WT group: 69.67 ± 24.34; CD38KO group: 0.12 ± 0.11) and upon antigen mediated stimulation, CD38KO CAR iT cells showed higher percentages of degranulation (2.3-fold increase in CD107a/b), and IFNγ (4.1-fold increase) and TNFα (2.5-fold increase) production. Antigen specific in vitro tumor killing also was enhanced in CD38KO CAR iT cells (EC50, 3.2-fold decrease). Lastly, to avoid the potential host-mediated rejection, the inclusion of allogeneic defense receptor (ADR) which has been shown to significantly reduce host-mediated rejection will be discussed. Collectively, the described studies demonstrate that iPSCs are an ideal cellular source to generate large-quantities of uniformly multi-edited off-the-shelf CAR T cell products that include a best-in-class CAR design, enhanced product modalities, and complete elimination of TCR expression to avoid the potential of GvHD while maintaining high anti-tumor efficacy in allogeneic setting. Disclosures Hsia: Fate Therapeutics Inc.: Current Employment. Clarke:Fate Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Lee:Fate Therapeutics, Inc.: Current Employment. Robbins:Fate Therapeutics, Inc.: Current Employment. Denholtz:Fate Therapeutics, Inc: Current Employment. Hanok:Fate Therapeutics, Inc.: Current Employment. Carron:Fate Therapeutics, Inc.: Current Employment. Navarrete:Fate Therapeutics, Inc.: Current Employment. ORourke:Fate Therapeutics, Inc.: Current Employment. Sung:Fate Therapeutics, Inc.: Current Employment. Gentile:Fate Therapeutics, Inc.: Current Employment. Nguyen:Fate Therapeutics, Inc.: Current Employment. Valamehr:Fate Therapeutics, Inc: Current Employment, Current equity holder in publicly-traded company.