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Browsing by Author "Crooks, Gay M."
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Item Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency(Massachusetts Medical Society, 2021-05-27) Kohn, Donald B.; Booth, Claire; Shaw, Kit L.; Xu-Bayford, Jinhua; Garabedian, Elizabeth; Trevisan, Valentina; Carbonaro-Sarracino, Denise A.; Soni, Kajal; Terrazas, Dayna; Snell, Katie; Ikeda, Alan; Leon-Rico, Diego; Moore, Theodore B.; Buckland, Karen F.; Shah, Ami J.; Gilmour, Kimberly C.; De Oliveira, Satiro; Rivat, Christine; Crooks, Gay M.; Izotova, Natalia; Tse, John; Adams, Stuart; Shupien, Sally; Ricketts, Hilory; Davila, Alejandra; Uzowuru, Chilenwa; Icreverzi, Amalia; Barman, Provaboti; Fernandez, Beatriz Campo; Hollis, Roger P.; Coronel, Maritess; Yu, Allen; Chun, Krista M.; Casas, Christian E.; Zhang, Ruixue; Arduini, Serena; Lynn, Frances; Kudari, Mahesh; Spezzi, Andrea; Zahn, Marco; Heimke, Rene; Labik, Ivan; Parrott, Roberta; Buckley, Rebecca H.; Reeves, Lilith; Cornetta, Kenneth; Sokolic, Robert; Hershfield, Michael; Schmidt, Manfred; Candotti, Fabio; Malech, Harry L.; Thrasher, Adrian J.; Gaspar, H. Bobby; Medicine, School of MedicineBackground: Severe combined immunodeficiency due to adenosine deaminase (ADA) deficiency (ADA-SCID) is a rare and life-threatening primary immunodeficiency. Methods: We treated 50 patients with ADA-SCID (30 in the United States and 20 in the United Kingdom) with an investigational gene therapy composed of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with a self-inactivating lentiviral vector encoding human ADA. Data from the two U.S. studies (in which fresh and cryopreserved formulations were used) at 24 months of follow-up were analyzed alongside data from the U.K. study (in which a fresh formulation was used) at 36 months of follow-up. Results: Overall survival was 100% in all studies up to 24 and 36 months. Event-free survival (in the absence of reinitiation of enzyme-replacement therapy or rescue allogeneic hematopoietic stem-cell transplantation) was 97% (U.S. studies) and 100% (U.K. study) at 12 months; 97% and 95%, respectively, at 24 months; and 95% (U.K. study) at 36 months. Engraftment of genetically modified HSPCs persisted in 29 of 30 patients in the U.S. studies and in 19 of 20 patients in the U.K. study. Patients had sustained metabolic detoxification and normalization of ADA activity levels. Immune reconstitution was robust, with 90% of the patients in the U.S. studies and 100% of those in the U.K. study discontinuing immunoglobulin-replacement therapy by 24 months and 36 months, respectively. No evidence of monoclonal expansion, leukoproliferative complications, or emergence of replication-competent lentivirus was noted, and no events of autoimmunity or graft-versus-host disease occurred. Most adverse events were of low grade. Conclusions: Treatment of ADA-SCID with ex vivo lentiviral HSPC gene therapy resulted in high overall and event-free survival with sustained ADA expression, metabolic correction, and functional immune reconstitution.Item IND-Enabling Studies for a Clinical Trial to Genetically Program a Persistent Cancer-Targeted Immune System(American Association for Cancer Research, 2019-02-01) Puig-Saus, Cristina; Parisi, Giulia; Garcia-Diaz, Angel; Krystofinski, Paige E.; Sandoval, Salemiz; Zhang, Ruixue; Champhekar, Ameya S.; McCabe, James; Cheung-Lau, Gardenia C.; Truong, Nhat A.; Vega-Crespo, Agustin; Komenan, Marie Desiles S.; Pang, Jia; Macabali, Mignonette H.; Saco, Justin D.; Goodwin, Jeffrey L.; Bolon, Brad; Seet, Christopher S.; Montel-Hagen, Amelie; Crooks, Gay M.; Hollis, Roger P.; Campo-Fernandez, Beatriz; Bischof, Daniela; Cornetta, Kenneth; Gschweng, Eric H.; Adelson, Celia; Nguyen, Alexander; Yang, Lili; Witte, Owen N.; Baltimore, David; Comin-Anduix, Begonya; Kohn, Donald B.; Wang, Xiaoyan; Cabrera, Paula; Kaplan-Lefko, Paula J.; Berent-Maoz, Beata; Ribas, Antoni; Medical and Molecular Genetics, School of MedicinePURPOSE: To improve persistence of adoptively transferred T-cell receptor (TCR)-engineered T cells and durable clinical responses, we designed a clinical trial to transplant genetically-modified hematopoietic stem cells (HSCs) together with adoptive cell transfer of T cells both engineered to express an NY-ESO-1 TCR. Here, we report the preclinical studies performed to enable an investigational new drug (IND) application. EXPERIMENTAL DESIGN: HSCs transduced with a lentiviral vector expressing NY-ESO-1 TCR and the PET reporter/suicide gene HSV1-sr39TK and T cells transduced with a retroviral vector expressing NY-ESO-1 TCR were coadministered to myelodepleted HLA-A2/Kb mice within a formal Good Laboratory Practice (GLP)-compliant study to demonstrate safety, persistence, and HSC differentiation into all blood lineages. Non-GLP experiments included assessment of transgene immunogenicity and in vitro viral insertion safety studies. Furthermore, Good Manufacturing Practice (GMP)-compliant cell production qualification runs were performed to establish the manufacturing protocols for clinical use. RESULTS: TCR genetically modified and ex vivo-cultured HSCs differentiated into all blood subsets in vivo after HSC transplantation, and coadministration of TCR-transduced T cells did not result in increased toxicity. The expression of NY-ESO-1 TCR and sr39TK transgenes did not have a detrimental effect on gene-modified HSC's differentiation to all blood cell lineages. There was no evidence of genotoxicity induced by the lentiviral vector. GMP batches of clinical-grade transgenic cells produced during qualification runs had adequate stability and functionality. CONCLUSIONS: Coadministration of HSCs and T cells expressing an NY-ESO-1 TCR is safe in preclinical models. The results presented in this article led to the FDA approval of IND 17471.Item Transcriptionally and Functionally Distinct Mesenchymal Subpopulations Are Generated from Human Pluripotent Stem Cells(Cell Press, 2018-01-04) Chin, Chee Jia; Li, Suwen; Corselli, Mirko; Casero, David; Zhu, Yuhua; He, Chong Bin; Hardy, Reef; Péault, Bruno; Crooks, Gay M.; Medicine, School of MedicineVarious mesenchymal cell types have been identified as critical components of the hematopoietic stem/progenitor cell (HSPC) niche. Although several groups have described the generation of mesenchyme from human pluripotent stem cells (hPSCs), the capacity of such cells to support hematopoiesis has not been reported. Here, we demonstrate that distinct mesenchymal subpopulations co-emerge from mesoderm during hPSC differentiation. Despite co-expression of common mesenchymal markers (CD73, CD105, CD90, and PDGFRβ), a subset of cells defined as CD146hiCD73hi expressed genes associated with the HSPC niche and supported the maintenance of functional HSPCs ex vivo, while CD146loCD73lo cells supported differentiation. Stromal support of HSPCs was contact dependent and mediated in part through high JAG1 expression and low WNT signaling. Molecular profiling revealed significant transcriptional similarity between hPSC-derived CD146++ and primary human CD146++ perivascular cells. The derivation of functionally diverse types of mesenchyme from hPSCs opens potential avenues to model the HSPC niche and develop PSC-based therapies., • hPSCs generated functionally and transcriptionally distinct mesenchymal populations • CD146hiCD73hi mesenchyme expressed HSC niche genes and supported human HSPCs ex vivo • CD146loCD73lo mesenchyme drove HSPC differentiation • CD146hiCD73hi mesenchyme shared a transcriptome profile with human pericytes , Crooks and colleagues demonstrated a previously underappreciated functional and molecular heterogeneity in mesenchyme generated from human pluripotent stem cells. Two mesenchymal subsets were distinguished by the reciprocal expression of CD146, CD73, and CD140a. CD146hiCD73hi mesenchyme supported self-renewing hematopoietic stem and progenitor cells (HSPCs), expressed markers of the HSPC niche, and shared a similar molecular signature with primary human adult pericytes.