دورية أكاديمية
A novel lentiviral vector-based approach to generate chimeric antigen receptor T cells targeting Aspergillus fumigatus .
| العنوان: | A novel lentiviral vector-based approach to generate chimeric antigen receptor T cells targeting Aspergillus fumigatus . |
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| المؤلفون: | Kumaresan PR; Department of Hematopoietic Biology & Malignancy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.; Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Wurster S; Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Bavisi K; Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., da Silva TA; The International School of Pharmaceutical Sciences in Araraquara, Sao Paulo, Brazil., Hauser P; Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Kinnitt J; Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Albert ND; Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Bharadwaj U; Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Neelapu S; Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Kontoyiannis DP; Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. |
| المصدر: | MBio [mBio] 2024 Apr 10; Vol. 15 (4), pp. e0341323. Date of Electronic Publication: 2024 Feb 28. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Microbiology Country of Publication: United States NLM ID: 101519231 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2150-7511 (Electronic) NLM ISO Abbreviation: mBio Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, D.C. : American Society for Microbiology |
| مواضيع طبية MeSH: | Receptors, Chimeric Antigen*/genetics , Receptors, Chimeric Antigen*/therapeutic use , Aspergillosis*/drug therapy, Humans ; Mice ; Animals ; Aspergillus fumigatus/genetics ; Interleukin-2 ; Antifungal Agents/therapeutic use ; Lentivirus/genetics ; Leukocytes, Mononuclear ; Aspergillus ; T-Lymphocytes ; Cytokines |
| مستخلص: | Invasive aspergillosis (IA) is a common and deadly mold infection in immunocompromised patients. As morbidity and mortality of IA are primarily driven by poor immune defense, adjunct immunotherapies, such as chimeric antigen receptor (CAR) T cells, are direly needed. Here, we propose a novel approach to generate Aspergillus fumigatus (AF)-CAR T cells using the single-chain variable fragment domain of monoclonal antibody AF-269-5 and a lentiviral vector system. These cells successfully targeted mature hyphal filaments of representative clinical and reference AF isolates and elicited a potent release of cytotoxic effectors and type 1 T cell cytokines. Furthermore, AF-CAR T cells generated from peripheral blood mononuclear cells of four healthy human donors and expanded with either of three cytokine stimulation regimens (IL-2, IL-2 + IL-21, or IL-7 + IL-15) significantly suppressed mycelial growth of AF-293 after 18 hours of co-culture and synergized with the immunomodulatory antifungal agent caspofungin to control hyphal growth for 36 hours. Moreover, cyclophosphamide-immunosuppressed NSG mice with invasive pulmonary aspergillosis that received two doses of 5 million AF-CAR T cells (6 and 48 hours after AF infection) showed significantly reduced morbidity on day 4 post-infection ( P < 0.001) and significantly improved 7-day survival ( P = 0.049) compared with mice receiving non-targeting control T cells, even without concomitant antifungal chemotherapy. In conclusion, we developed a novel lentiviral strategy to obtain AF-CAR T cells with high targeting efficacy, yielding significant anti-AF activity in vitro and short-term protection in vivo . Our approach could serve as an important steppingstone for future clinical translation of antifungal CAR T-cell therapy after further refinement and thorough preclinical evaluation.IMPORTANCEInvasive aspergillosis (IA) remains a formidable cause of morbidity and mortality in patients with hematologic malignancies and those undergoing hematopoietic stem cell transplantation. Despite the introduction of several new Aspergillus -active antifungals over the last 30 years, the persisting high mortality of IA in the setting of continuous and profound immunosuppression is a painful reminder of the major unmet need of effective antifungal immune enhancement therapies. The success of chimeric antigen receptor (CAR) T-cell therapy in cancer medicine has inspired researchers to translate this approach to opportunistic infections, including IA. Aiming to refine anti- Aspergillus CAR T-cell therapy and improve its feasibility for future clinical translation, we herein developed and validated a novel antibody-based CAR construct and lentiviral transduction method to accelerate the production of CAR T cells with high targeting efficacy against Aspergillus fumigatus . Our unique approach could provide a promising platform for future clinical translation of CAR T-cell-based antifungal immunotherapy. Competing Interests: D.P.K. reports honoraria and research support from Gilead Sciences and Astellas Pharma. He received consultant fees from Astellas Pharma, Merck, and Gilead Sciences and is a member of the Data Re-view Committee of Cidara Therapeutics, AbbVie, Scynexis, and the Mycoses Study Group. |
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| معلومات مُعتمدة: | P30 CA016672 United States CA NCI NIH HHS |
| فهرسة مساهمة: | Keywords: CAR T cells; T lymphocytes; aspergillosis; cytokines; immunotherapy; mouse model |
| المشرفين على المادة: | 0 (Receptors, Chimeric Antigen) 0 (Interleukin-2) 0 (Antifungal Agents) 0 (Cytokines) |
| تواريخ الأحداث: | Date Created: 20240228 Date Completed: 20240411 Latest Revision: 20240412 |
| رمز التحديث: | 20240412 |
| مُعرف محوري في PubMed: | PMC11005356 |
| DOI: | 10.1128/mbio.03413-23 |
| PMID: | 38415653 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2150-7511 |
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| DOI: | 10.1128/mbio.03413-23 |