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Because PI3K inhibitor therapy is associated with the development of T-cell\u2013mediated autoimmunity, we studied the effects of inhibiting the PI3K\u03b4 and PI3K\u03b3 isoforms during the manufacture of CART cells prepared from patients with CLL. Dual PI3K\u03b4\/\u03b3 inhibition normalized CD4\/CD8 ratios and maximized the number of CD8+ T-stem cell memory, naive, and central memory T-cells with dose-dependent decreases in expression of the TIM-3 exhaustion marker. CART cells manufactured with duvelisib (Duv-CART cells) showed significantly increased in\u00a0vitro cytotoxicity against CD19+ CLL targets caused by increased frequencies of CD8+ CART cells. Duv-CART cells had increased expression of the mitochondrial fusion protein MFN2, with an associated increase in the relative content of mitochondria. Duv-CART cells exhibited increased SIRT1 and TCF1\/7 expression, which correlated with epigenetic reprograming of Duv-CART cells toward stem-like properties. After transfer to NOG mice engrafted with a human CLL cell line, Duv-CART cells expressing either a CD28 or 41BB costimulatory domain demonstrated significantly increased in\u00a0vivo expansion of CD8+ CART cells, faster elimination of CLL, and longer persistence. Duv-CART cells significantly enhanced survival of CLL-bearing mice compared with conventionally manufactured CART cells. In summary, exposure of CART to a PI3K\u03b4\/\u03b3 inhibitor during manufacturing enriched the CART product for CD8+ CART cells with stem-like qualities and enhanced efficacy in eliminating CLL in\u00a0vivo.<\/jats:p>","DOI":"10.1182\/blood.2021011597","type":"journal-article","created":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T11:33:23Z","timestamp":1643283203000},"page":"523-537","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":139,"title":["PI3K\u03b4\/\u03b3 inhibition promotes human CART cell epigenetic and metabolic reprogramming to enhance antitumor cytotoxicity"],"prefix":"10.1182","volume":"139","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4113-5038","authenticated-orcid":false,"given":"Christopher Ronald","family":"Funk","sequence":"first","affiliation":[{"name":"1Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuhua","family":"Wang","sequence":"additional","affiliation":[{"name":"1Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4250-8518","authenticated-orcid":false,"given":"Kevin Z.","family":"Chen","sequence":"additional","affiliation":[{"name":"1Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Waller","sequence":"additional","affiliation":[{"name":"1Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aditi","family":"Sharma","sequence":"additional","affiliation":[{"name":"1Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia L.","family":"Edgar","sequence":"additional","affiliation":[{"name":"1Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikas A.","family":"Gupta","sequence":"additional","affiliation":[{"name":"1Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanmuganathan","family":"Chandrakasan","sequence":"additional","affiliation":[{"name":"2Division of Bone Marrow Transplant and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7914-4610","authenticated-orcid":false,"given":"Jaquelyn T.","family":"Zoine","sequence":"additional","affiliation":[{"name":"3Cell and Gene Therapy Program, Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, GA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Fedanov","sequence":"additional","affiliation":[{"name":"3Cell and Gene Therapy Program, Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, GA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2903-9542","authenticated-orcid":false,"given":"Sunil S.","family":"Raikar","sequence":"additional","affiliation":[{"name":"3Cell and Gene Therapy Program, Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, GA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4414-0489","authenticated-orcid":false,"given":"Jean L.","family":"Koff","sequence":"additional","affiliation":[{"name":"1Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher R.","family":"Flowers","sequence":"additional","affiliation":[{"name":"3Cell and Gene Therapy Program, Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, GA;"},{"name":"4Department of Lymphoma\/Myeloma, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX; 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