CAR T cells outperform CAR NK cells in CAR-mediated effector functions in head-to-head comparison.
Adoptive cell therapy
Allogeneic
Autologous
Chimeric antigen receptor
Cytotoxicity
Human NK cells
Human T cells
IFN-γ
Journal
Experimental hematology & oncology
ISSN: 2162-3619
Titre abrégé: Exp Hematol Oncol
Pays: England
ID NLM: 101590676
Informations de publication
Date de publication:
14 May 2024
14 May 2024
Historique:
received:
29
10
2023
accepted:
08
05
2024
medline:
15
5
2024
pubmed:
15
5
2024
entrez:
14
5
2024
Statut:
epublish
Résumé
CAR NK cells as vehicles for engineered "off-the-shelf" cellular cancer immunotherapy have attracted significant interest. Nonetheless, a comprehensive comparative assessment of the anticancer activity of CAR T cells and CAR NK cells carrying approved benchmark anti-CD19 CAR constructs is missing. Here, we report a direct head-to-head comparison of CD19-directed human T and NK cells. We generated CAR T and CAR NK cells derived from healthy donor PBMC by retroviral transduction with the same benchmark second-generation anti-CD19 CAR construct, FMC63.28z. We investigated IFN-γ secretion and direct cytotoxicity in vitro against various CD19 Our main findings are a drastically reduced capacity for CAR-mediated IFN-γ production and lower CAR-mediated cytotoxicity of CAR NK cells relative to CAR T cells in vitro. Consistent with these in vitro findings, we report superior anticancer activity of autologous CAR T cells compared with allogeneic CAR NK cells in vivo. CAR T cells had significantly higher CAR-mediated effector functions than CAR NK cells in vitro against several cancer cell lines and autologous CAR T cells outperformed allogeneic CAR NK cells both in vitro and in vivo. CAR NK cells will likely benefit from further engineering to enhance anticancer activity to ultimately fulfill the promise of an effective off-the-shelf product.
Sections du résumé
BACKGROUND
BACKGROUND
CAR NK cells as vehicles for engineered "off-the-shelf" cellular cancer immunotherapy have attracted significant interest. Nonetheless, a comprehensive comparative assessment of the anticancer activity of CAR T cells and CAR NK cells carrying approved benchmark anti-CD19 CAR constructs is missing. Here, we report a direct head-to-head comparison of CD19-directed human T and NK cells.
METHODS
METHODS
We generated CAR T and CAR NK cells derived from healthy donor PBMC by retroviral transduction with the same benchmark second-generation anti-CD19 CAR construct, FMC63.28z. We investigated IFN-γ secretion and direct cytotoxicity in vitro against various CD19
RESULTS
RESULTS
Our main findings are a drastically reduced capacity for CAR-mediated IFN-γ production and lower CAR-mediated cytotoxicity of CAR NK cells relative to CAR T cells in vitro. Consistent with these in vitro findings, we report superior anticancer activity of autologous CAR T cells compared with allogeneic CAR NK cells in vivo.
CONCLUSIONS
CONCLUSIONS
CAR T cells had significantly higher CAR-mediated effector functions than CAR NK cells in vitro against several cancer cell lines and autologous CAR T cells outperformed allogeneic CAR NK cells both in vitro and in vivo. CAR NK cells will likely benefit from further engineering to enhance anticancer activity to ultimately fulfill the promise of an effective off-the-shelf product.
Identifiants
pubmed: 38745250
doi: 10.1186/s40164-024-00522-6
pii: 10.1186/s40164-024-00522-6
doi:
Types de publication
Journal Article
Langues
eng
Pagination
51Subventions
Organisme : Deutsche Forschungsgemeinschaft
ID : 415801544
Organisme : Krebsliga Schweiz
ID : KFS-4371-02-2018
Informations de copyright
© 2024. The Author(s).
Références
Elsallab M, Levine BL, Wayne AS, Abou-El-Enein M. CAR T-cell product performance in haematological malignancies before and after marketing authorisation. Lancet Oncol. 2020;21:e104–16.
pubmed: 32007196
pmcid: 7841982
doi: 10.1016/S1470-2045(19)30729-6
Westin JR, et al. Efficacy and safety of CD19-directed CAR-T cell therapies in patients with relapsed/refractory aggressive B-cell lymphomas: observations from the JULIET, ZUMA-1, and transcend trials. Am J Hematol. 2021;96:1295–312.
pubmed: 34310745
pmcid: 9290945
doi: 10.1002/ajh.26301
Cappell KM, Kochenderfer JN. Long-term outcomes following CAR T cell therapy: what we know so far. Nat Rev Clin Oncol. 2023;20:359–71.
pubmed: 37055515
pmcid: 10100620
doi: 10.1038/s41571-023-00754-1
Bach PB. National coverage analysis of CAR-T therapies—policy, evidence, and Payment. N Engl J Med. 2018;379:1396–8.
pubmed: 30110578
doi: 10.1056/NEJMp1807382
Jain T, et al. Use of chimeric antigen receptor T cell therapy in clinical practice for relapsed/refractory aggressive B cell non-hodgkin lymphoma: an expert panel opinion from the american society for transplantation and cellular therapy. Biol Blood Marrow Transplant. 2019;25:2305–21.
pubmed: 31446199
doi: 10.1016/j.bbmt.2019.08.015
Morris EC, Neelapu SS, Giavridis T, Sadelain M. Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy. Nat Rev Immunol. 2022;22:85–96.
pubmed: 34002066
doi: 10.1038/s41577-021-00547-6
Qasim W. Genome-edited allogeneic donor ‘universal’ chimeric antigen receptor T cells. Blood. 2023;141:835–45.
pubmed: 36223560
doi: 10.1182/blood.2022016204
Berrien-Elliott MM, Jacobs MT, Fehniger TA. Allogeneic natural killer cell therapy. Blood. 2023;141:856–68.
pubmed: 36416736
doi: 10.1182/blood.2022016200
Zhang Y, Zhou W, Yang J, Yang J, Wang W. Chimeric antigen receptor engineered natural killer cells for cancer therapy. Exp Hematol Oncol. 2023;12:70.
pubmed: 37563648
pmcid: 10413722
doi: 10.1186/s40164-023-00431-0
Liu E, et al. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N Engl J Med. 2020;382:545–53.
pubmed: 32023374
pmcid: 7101242
doi: 10.1056/NEJMoa1910607
Marin D, et al. Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19+ B cell tumors: a phase 1/2 trial. Nat Med. 2024;30:772–84.
pubmed: 38238616
pmcid: 10957466
doi: 10.1038/s41591-023-02785-8
Portillo AL, et al. Expanded human NK cells armed with CAR uncouple potent anti-tumor activity from off-tumor toxicity against solid tumors. Iscience. 2021;24:102619.
pubmed: 34159300
pmcid: 8193615
doi: 10.1016/j.isci.2021.102619
Neelapu SS, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377:2531–44.
pubmed: 29226797
pmcid: 5882485
doi: 10.1056/NEJMoa1707447
Westin JR, et al. Survival with axicabtagene ciloleucel in large B-cell lymphoma. N Engl J Med. 2023;389:148–57.
pubmed: 37272527
doi: 10.1056/NEJMoa2301665
Kaulfuss M, et al. The NK cell checkpoint NKG2A maintains expansion capacity of human NK cells. Sci Rep. 2023;13:10555.
pubmed: 37386090
pmcid: 10310841
doi: 10.1038/s41598-023-37779-6
Chijioke O, et al. Human natural killer cells prevent infectious mononucleosis features by targeting lytic epstein-barr virus infection. Cell Rep. 2013;5:1489–98.
pubmed: 24360958
pmcid: 3895765
doi: 10.1016/j.celrep.2013.11.041
Concordet J-P, Haeussler M. CRISPOR: intuitive guide selection for CRISPR/Cas9 genome editing experiments and screens. Nucleic Acids Res. 2018;46:W242–5.
pubmed: 29762716
pmcid: 6030908
doi: 10.1093/nar/gky354
Roth TL, et al. Reprogramming human T cell function and specificity with non-viral genome targeting. Nature. 2018;559:405–9.
pubmed: 29995861
pmcid: 6239417
doi: 10.1038/s41586-018-0326-5
Ferlazzo G. Isolation and analysis of human natural killer cell subsets. Methods Mol Biol. 2008;415:197–213.
pubmed: 18370156
Denman CJ, et al. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. PLoS ONE. 2012;7: e30264.
pubmed: 22279576
pmcid: 3261192
doi: 10.1371/journal.pone.0030264
Ciurea SO, et al. Phase 1 clinical trial using mbIL21 ex vivo-expanded donor-derived NK cells after haploidentical transplantation. Blood. 2017;130:1857–68.
pubmed: 28835441
pmcid: 5649552
doi: 10.1182/blood-2017-05-785659
Ciurea SO, et al. Decrease post-transplant relapse using donor-derived expanded NK-cells. Leukemia. 2022;36:155–64.
pubmed: 34312462
doi: 10.1038/s41375-021-01349-4
Girard-Gagnepain A, et al. Baboon envelope pseudotyped LVs outperform VSV-G-LVs for gene transfer into early-cytokine-stimulated and resting HSCs. Blood. 2014;124:1221–31.
pubmed: 24951430
doi: 10.1182/blood-2014-02-558163
Kochenderfer JN, et al. Construction and preclinical evaluation of an anti-CD19 chimeric antigen receptor. J Immunother. 2009;32:689–702.
pubmed: 19561539
pmcid: 2747302
doi: 10.1097/CJI.0b013e3181ac6138
Sekine T, et al. TOX is expressed by exhausted and polyfunctional human effector memory CD8+ T cells. Sci Immunol. 2020. https://doi.org/10.1126/sciimmunol.aba7918 .
doi: 10.1126/sciimmunol.aba7918
pubmed: 32989174
pmcid: 7857393
Zhao X, Shan Q, Xue H-H. TCF1 in T cell immunity: a broadened frontier. Nat Rev Immunol. 2022;22:147–57.
pubmed: 34127847
doi: 10.1038/s41577-021-00563-6
Abou-El-Enein M, et al. Scalable manufacturing of CAR T cells for cancer immunotherapy. Blood Cancer Discov. 2021;2:408–22.
pubmed: 34568831
pmcid: 8462122
doi: 10.1158/2643-3230.BCD-21-0084
Ayala Ceja M, Khericha M, Harris CM, Puig-Saus C, Chen YY. CAR-T cell manufacturing: major process parameters and next-generation strategies. J Exp Med. 2024;221: e20230903.
pubmed: 38226974
pmcid: 10791545
doi: 10.1084/jem.20230903
Van Acker HH, Capsomidis A, Smits EL, Van Tendeloo VF. CD56 in the immune system: more than a marker for cytotoxicity? Front Immunol. 2017;8:892.
pubmed: 28791027
pmcid: 5522883
doi: 10.3389/fimmu.2017.00892
Long EO, Kim HS, Liu D, Peterson ME, Rajagopalan S. Controlling natural killer cell responses: integration of signals for activation and inhibition. Annu Rev Immunol. 2013;31:227–58.
pubmed: 23516982
doi: 10.1146/annurev-immunol-020711-075005
Liu LL, et al. Critical role of CD2 Co-stimulation in adaptive natural killer cell responses revealed in NKG2C-deficient humans. Cell Rep. 2016;15:1088–99.
pubmed: 27117418
pmcid: 4858565
doi: 10.1016/j.celrep.2016.04.005
Wong P, et al. T-BET and EOMES sustain mature human NK cell identity and antitumor function. J Clin Invest. 2023;133: e162530.
pubmed: 37279078
pmcid: 10313375
doi: 10.1172/JCI162530
Abel AM, Yang C, Thakar MS, Malarkannan S. Natural killer cells: development, maturation, and clinical utilization. Front Immunol. 2018;9:1869.
pubmed: 30150991
pmcid: 6099181
doi: 10.3389/fimmu.2018.01869
Wolf NK, Kissiov DU, Raulet DH. Roles of natural killer cells in immunity to cancer, and applications to immunotherapy. Nat Rev Immunol. 2023;23:90–105.
pubmed: 35637393
doi: 10.1038/s41577-022-00732-1
Koehne G, et al. Serial in vivo imaging of the targeted migration of human HSV-TK-transduced antigen-specific lymphocytes. Nat Biotechnol. 2003;21:405–13.
pubmed: 12652311
doi: 10.1038/nbt805
Hiwarkar P, et al. Cord blood T cells mediate enhanced antitumor effects compared with adult peripheral blood T cells. Blood. 2015;126:2882–91.
pubmed: 26450984
doi: 10.1182/blood-2015-06-654780
Dasari V, et al. Lymph node targeted multi-epitope subunit vaccine promotes effective immunity to EBV in HLA-expressing mice. Nat Commun. 2023;14:4371.
pubmed: 37553346
pmcid: 10409721
doi: 10.1038/s41467-023-39770-1
Neelapu SS, et al. Five-year follow-up of ZUMA-1 supports the curative potential of axicabtagene ciloleucel in refractory large B-cell lymphoma. Blood. 2023;141:2307–15.
pubmed: 36821768
pmcid: 10646788
Kiekens L, et al. T-BET and EOMES accelerate and enhance functional differentiation of human natural killer cells. Front Immunol. 2021;12: 732511.
pubmed: 34630413
pmcid: 8497824
doi: 10.3389/fimmu.2021.732511
Brentjens RJ, et al. Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts. Clin Cancer Res. 2007;13:5426–35.
pubmed: 17855649
doi: 10.1158/1078-0432.CCR-07-0674
Zhao Z, et al. Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells. Cancer Cell. 2015;28:415–28.
pubmed: 26461090
pmcid: 5003056
doi: 10.1016/j.ccell.2015.09.004
Larson RC, et al. CAR T cell killing requires the IFNγR pathway in solid but not liquid tumours. Nature. 2022;604:563–70.
pubmed: 35418687
doi: 10.1038/s41586-022-04585-5
Alizadeh D, et al. IFNγ is critical for CAR T cell-mediated myeloid activation and induction of endogenous immunity. Cancer Discov. 2021;11:2248–65.
pubmed: 33837065
pmcid: 8561746
doi: 10.1158/2159-8290.CD-20-1661
Ma L, et al. Vaccine-boosted CAR T crosstalk with host immunity to reject tumors with antigen heterogeneity. Cell. 2023;186:3148-3165.e20.
pubmed: 37413990
pmcid: 10372881
doi: 10.1016/j.cell.2023.06.002