PI3Kδ/γ inhibition promotes human CART cell epigenetic and metabolic reprogramming to enhance antitumor cytotoxicity
Current limitations in using chimeric antigen receptor T(CART) cells to treat patients with hematological cancers include limited expansion and persistence in vivo that contribute to cancer relapse. Patients with chronic lymphocytic leukemia (CLL) have terminally differentiated T cells with an exhau...
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| Veröffentlicht in: | Blood Jg. 139; H. 4; S. 523 |
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| Sprache: | Englisch |
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27.01.2022
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| Abstract | Current limitations in using chimeric antigen receptor T(CART) cells to treat patients with hematological cancers include limited expansion and persistence in vivo that contribute to cancer relapse. Patients with chronic lymphocytic leukemia (CLL) have terminally differentiated T cells with an exhausted phenotype and experience low complete response rates after autologous CART therapy. Because PI3K inhibitor therapy is associated with the development of T-cell-mediated autoimmunity, we studied the effects of inhibiting the PI3Kδ and PI3Kγ isoforms during the manufacture of CART cells prepared from patients with CLL. Dual PI3Kδ/γ 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 vitro 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 vivo 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 PI3Kδ/γ inhibitor during manufacturing enriched the CART product for CD8+ CART cells with stem-like qualities and enhanced efficacy in eliminating CLL in vivo. |
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| AbstractList | Current limitations in using chimeric antigen receptor T(CART) cells to treat patients with hematological cancers include limited expansion and persistence in vivo that contribute to cancer relapse. Patients with chronic lymphocytic leukemia (CLL) have terminally differentiated T cells with an exhausted phenotype and experience low complete response rates after autologous CART therapy. Because PI3K inhibitor therapy is associated with the development of T-cell-mediated autoimmunity, we studied the effects of inhibiting the PI3Kδ and PI3Kγ isoforms during the manufacture of CART cells prepared from patients with CLL. Dual PI3Kδ/γ 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 vitro 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 vivo 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 PI3Kδ/γ inhibitor during manufacturing enriched the CART product for CD8+ CART cells with stem-like qualities and enhanced efficacy in eliminating CLL in vivo.Current limitations in using chimeric antigen receptor T(CART) cells to treat patients with hematological cancers include limited expansion and persistence in vivo that contribute to cancer relapse. Patients with chronic lymphocytic leukemia (CLL) have terminally differentiated T cells with an exhausted phenotype and experience low complete response rates after autologous CART therapy. Because PI3K inhibitor therapy is associated with the development of T-cell-mediated autoimmunity, we studied the effects of inhibiting the PI3Kδ and PI3Kγ isoforms during the manufacture of CART cells prepared from patients with CLL. Dual PI3Kδ/γ 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 vitro 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 vivo 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 PI3Kδ/γ inhibitor during manufacturing enriched the CART product for CD8+ CART cells with stem-like qualities and enhanced efficacy in eliminating CLL in vivo. Current limitations in using chimeric antigen receptor T(CART) cells to treat patients with hematological cancers include limited expansion and persistence in vivo that contribute to cancer relapse. Patients with chronic lymphocytic leukemia (CLL) have terminally differentiated T cells with an exhausted phenotype and experience low complete response rates after autologous CART therapy. Because PI3K inhibitor therapy is associated with the development of T-cell-mediated autoimmunity, we studied the effects of inhibiting the PI3Kδ and PI3Kγ isoforms during the manufacture of CART cells prepared from patients with CLL. Dual PI3Kδ/γ 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 vitro 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 vivo 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 PI3Kδ/γ inhibitor during manufacturing enriched the CART product for CD8+ CART cells with stem-like qualities and enhanced efficacy in eliminating CLL in vivo. |
| Author | Wang, Shuhua Edgar, Claudia L Shanmugam, Mala Funk, Christopher Ronald Pachter, Jonathan A Spencer, H Trent Sharma, Aditi Chandrakasan, Shanmuganathan Waller, Alexandra Flowers, Christopher R Fedanov, Andrew Raikar, Sunil S Koff, Jean L Zoine, Jaquelyn T Gupta, Vikas A Ravindranathan, Sruthi Chen, Kevin Z Coma, Silvia Waller, Edmund K |
| Author_xml | – sequence: 1 givenname: Christopher Ronald orcidid: 0000-0002-4113-5038 surname: Funk fullname: Funk, Christopher Ronald organization: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA – sequence: 2 givenname: Shuhua surname: Wang fullname: Wang, Shuhua organization: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA – sequence: 3 givenname: Kevin Z orcidid: 0000-0003-4250-8518 surname: Chen fullname: Chen, Kevin Z organization: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA – sequence: 4 givenname: Alexandra surname: Waller fullname: Waller, Alexandra organization: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA – sequence: 5 givenname: Aditi surname: Sharma fullname: Sharma, Aditi organization: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA – sequence: 6 givenname: Claudia L surname: Edgar fullname: Edgar, Claudia L organization: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA – sequence: 7 givenname: Vikas A surname: Gupta fullname: Gupta, Vikas A organization: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA – sequence: 8 givenname: Shanmuganathan surname: Chandrakasan fullname: Chandrakasan, Shanmuganathan organization: Division of Bone Marrow Transplant and – sequence: 9 givenname: Jaquelyn T orcidid: 0000-0001-7914-4610 surname: Zoine fullname: Zoine, Jaquelyn T organization: Cell 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 – sequence: 10 givenname: Andrew surname: Fedanov fullname: Fedanov, Andrew organization: Cell 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 – sequence: 11 givenname: Sunil S orcidid: 0000-0003-2903-9542 surname: Raikar fullname: Raikar, Sunil S organization: Cell 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 – sequence: 12 givenname: Jean L orcidid: 0000-0003-4414-0489 surname: Koff fullname: Koff, Jean L organization: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA – sequence: 13 givenname: Christopher R surname: Flowers fullname: Flowers, Christopher R organization: Department of Lymphoma/Myeloma, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX; and – sequence: 14 givenname: Silvia surname: Coma fullname: Coma, Silvia organization: Verastem Oncology Inc, Needham, MA – sequence: 15 givenname: Jonathan A orcidid: 0000-0002-0263-474X surname: Pachter fullname: Pachter, Jonathan A organization: Verastem Oncology Inc, Needham, MA – sequence: 16 givenname: Sruthi orcidid: 0000-0003-0451-7931 surname: Ravindranathan fullname: Ravindranathan, Sruthi organization: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA – sequence: 17 givenname: H Trent surname: Spencer fullname: Spencer, H Trent organization: Cell 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 – sequence: 18 givenname: Mala surname: Shanmugam fullname: Shanmugam, Mala organization: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA – sequence: 19 givenname: Edmund K orcidid: 0000-0003-0816-6729 surname: Waller fullname: Waller, Edmund K organization: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/35084470$$D View this record in MEDLINE/PubMed |
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| References | 36136355 - Blood. 2022 Sep 22;140(12):1449-1451. doi: 10.1182/blood.2022017516 35084472 - Blood. 2022 Jan 27;139(4):473-474. doi: 10.1182/blood.2021013895 |
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| Snippet | Current limitations in using chimeric antigen receptor T(CART) cells to treat patients with hematological cancers include limited expansion and persistence... Current limitations in using chimeric antigen receptor T(CART) cells to treat patients with hematological cancers include limited expansion and persistence in... |
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| SubjectTerms | Animals Cells, Cultured Cellular Reprogramming Techniques - methods Class I Phosphatidylinositol 3-Kinases - antagonists & inhibitors Class I Phosphatidylinositol 3-Kinases - metabolism Class Ib Phosphatidylinositol 3-Kinase - metabolism Epigenesis, Genetic Humans Immunotherapy, Adoptive - methods Isoquinolines - therapeutic use Leukemia, Lymphocytic, Chronic, B-Cell - genetics Leukemia, Lymphocytic, Chronic, B-Cell - therapy Mice Phosphoinositide-3 Kinase Inhibitors - therapeutic use Purines - therapeutic use |
| Title | PI3Kδ/γ inhibition promotes human CART cell epigenetic and metabolic reprogramming to enhance antitumor cytotoxicity |
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