nach oben

10.05.2024 | Case Report

DNT cells mediate resistance to CAR-T cells therapy in a pediatric patient with relapsed and refractory B-ALL

verfasst von: Ruotong Chen, Qianshan Tao, Fan Wu, Zhimin Zhai, Yuchen Jiang, Caixian Xu, Huiping Wang

Einloggen, um Zugang zu erhalten

Abstract

Chimeric antigen receptor T (CAR-T) cells therapy is a milestone achievement in the immunotherapy of relapsed and refractory (R/R) B cell acute lymphoblastic leukemia (B-ALL). However, some patients treated with CAR-T cells do not achieve complete remission, the mechanisms of which have not been elucidated. In the present study, we report a 9-year-old pediatric patient with refractory B-ALL received a triple infusion of autologous CD19 CAR-T cells therapy after the second relapse. CAR-T cells expanded in the peripheral blood and bone marrow. However, the patient did not achieve complete remission, indicating a lack of response to CAR-T cells therapy. Analysis of etiological factors revealed that the number of CD4 and CD8 double-negative T (DNT) cells was significantly upregulated in the peripheral blood, bone marrow, and autologous CAR-T cells products. In conclusiont, these findings indicate that DNT cells mediated resistance to CAR-T cells therapy in this pediatric patient with R/R B-ALL.

Bulliard Y, Andersson BS, Baysal MA, Damiano J, Tsimberidou AM (2023) Reprogramming T cell differentiation and exhaustion in CAR-T cells therapy. Journal of Hematology & Oncology 16(1):108. doi:https://doi.org0.1186/s13045-023-01504-7

Gumber D, Wang LD (2022) Improving CAR-T immunotherapy: overcoming the challenges of T cell exhaustion. Ebiomedicine 77:103941. https://doi.org/10.1016/j.ebiom.2022.103941CrossRefPubMedPubMedCentral

Hay KA, Gauthier J, Hirayama AV, Voutsinas JM, Wu Q, Li D, Gooley TA, Cherian S, Chen X, Pender BS, Hawkins RM, Vakil A, Steinmetz RN, Schoch G, Chapuis AG, Till BG, Kiem H-P, Ramos JD, Shadman M, Cassaday RD, Acharya UH, Riddell SR, Maloney DG, Turtle CJ (2019) Factors associated with durable EFS in adult B-cell ALL patients achieving MRD-negative CR after CD19 CAR T-cell therapy. Blood 133(15):1652–1663. https://doi.org/10.1182/blood-2018-11-883710CrossRefPubMedPubMedCentral

Liu Y, Liu G, Wang J, Zheng Z-Y, Jia L, Rui W, Huang D, Zhou Z-X, Zhou L, Wu X, Lin S, Zhao X, Lin X (2021) Chimeric STAR receptors using TCR machinery mediate robust responses against solid tumors. Sci Transl Med 13(586):51–91. https://doi.org/10.1126/scitranslmed.abb5191CrossRef

Spiegel JY, Patel S, Muffly L, Hossain NM, Oak J, Baird JH, Frank MJ, Shiraz P, Sahaf B, Craig J, Iglesias M, Younes S, Natkunam Y, Ozawa MG, Yang E, Tamaresis J, Chinnasamy H, Ehlinger Z, Reynolds W, Lynn R, Rotiroti MC, Gkitsas N, Arai S, Johnston L, Lowsky R, Majzner RG, Meyer E, Negrin RS, Rezvani AR, Sidana S, Shizuru J, Weng W-K, Mullins C, Jacob A, Kirsch I, Bazzano M, Zhou J, Mackay S, Bornheimer SJ, Schultz L, Ramakrishna S, Davis KL, Kong KA, Shah NN, Qin H, Fry T, Feldman S, Mackall CL, Miklos DB (2021) CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial. Nat Med 27(8):1419–1431. https://doi.org/10.1038/s41591-021-01436-0CrossRefPubMedPubMedCentral

Kang H (2022) Enhancing therapeutic efficacy of double negative T cells against Acute myeloid leukemia using Idelalisib. Cancers 13(20):5039. https://doi.org/10.3390/cancers13205039CrossRef

Lee J, Minden MD, Chen WC, Streck E, Chen B, Kang H, Arruda A, Ly D, Der SD, Kang S, Achita P, D’Souza C, Li Y, Childs RW, Dick JE, Zhang L (2018) Allogeneic Human Double Negative T Cells as a Novel Immunotherapy for Acute myeloid leukemia and its underlying mechanisms. Clin Cancer Res 24(2):370–382. https://doi.org/10.1158/1078-0432.Ccr-17-2228CrossRefPubMed

Yao J, Ly D, Dervovic D, Fang L, Lee JB, Kang H, Wang Y-H, Nhu-An P, Pan H, Tsao M-S, Zhang L (2019) Human double negative T cells target lung cancer via ligand-dependent mechanisms that can be enhanced by IL-15. J Immunother Cancer 7:1–14. https://doi.org/10.1186/s40425-019-0507-2CrossRef

Flugel CL, Majzner RG, Krenciute G, Dotti G, Riddell SR, Wagner DL, Abou-el-Enein M (2023) Overcoming on-target, off-tumour toxicity of CAR T cell therapy for solid tumours. Nat Reviews Clin Oncol 20(1):49–62. https://doi.org/10.1038/s41571-022-00704-3CrossRef

10.

Fang KK-L, Lee J, Khatri I, Na Y, Zhang L (2023) Targeting T-cell malignancies using allogeneic double-negative CD4-CAR-T cellss. J Immunother Cancer 11(9). https://doi.org/10.1136/jitc-2023-007277

11.

Shen S, Cai J, Chen J, Xue H, Pan C, Gao Y, Tang Y, Wang J, Li B, Wang X, Chen J, Gu L, Tang J (2018) Long-term results of the risk-stratified treatment of childhood acute lymphoblastic leukemia in China. Hematol Oncol 36(4):679–688. https://doi.org/10.1002/hon.2541CrossRefPubMed

12.

Finney OC, Brakke H, Rawlings-Rhea S, Hicks R, Doolittle D, Lopez M, Futrell B, Orentas RJ, Li D, Gardner R, Jensen MC (2019) CD19 CAR T cell product and disease attributes predict leukemia remission durability. J Clin Invest 129(5):2123–2132. https://doi.org/10.1172/jci125423CrossRefPubMedPubMedCentral

13.

Merims S, Li X, Joe B, Dokouhaki P, Han M, Childs RW, Wang ZY, Gupta V, Minden MD, Zhang L (2011) Anti-leukemia effect of Ex vivo expanded DNT cells from AML patients: a potential novel autologous T-cell adoptive immunotherapy. Leukemia 25(9):1415–1422. https://doi.org/10.1038/leu.2011.99CrossRefPubMedPubMedCentral

14.

Chowdhary VR, Krogman A, Tilahun AY, Alexander MP, David CS, Rajagopalan G (2017) Concomitant disruption of CD4 and CD8 genes facilitates the development of double negative αβ TCR + peripheral T cells that respond robustly to Staphylococcal Superantigen. J Immunol 198(11):4413–4424. https://doi.org/10.4049/jimmunol.1601991CrossRefPubMed

15.

Maccari ME, Fuchs S, Kury P, Andrieux G, Volkl S, Bengsch B, Lorenz MR, Heeg M, Rohr J, Jagle S, Castro CN, Gross M, Warthorst U, Koenig C, Fuchs I, Speckmann C, Thalhammer J, Kapp FG, Seidel MG, Duckers G, Schoenberger S, Schuetz C, Fuhrer M, Kobbe R, Holzinger D, Klemann C, Smisek P, Owens S, Horneff G, Kolb R, Naumann-Bartsch N, Miano M, Staniek J, Rizzi M, Kalina T, Schneider P, Erxleben A, Backofen R, Ekici A, Niemeyer CM, Warnatz K, Grimbacher B, Eibel H, Mackensen A, Frei AP, Schwarz K, Boerries M, Ehl S, Rensing-Ehl A (2021) A distinct CD38 + CD45RA + population of CD4+, CD8+, and double-negative T cells is controlled by FAS. J Exp Med 218(2):2019–2191. https://doi.org/10.1084/jem.20192191CrossRef

16.

Graiqevci-Uka V, Behluli E, Spahiu L, Liehr T, Temaj G (2023) Targeted treatment and immunotherapy in high-risk and Relapsed/ refractory Pediatric Acute Lymphoblastic Leukemia. Curr Pediatr Reviews 19(2):150–156. https://doi.org/10.2174/1573396318666220901165247CrossRef

17.

Zhu R, Yan Q, Wang Y, Wang K (2023) Biological characteristics of γδT cells and application in tumor immunotherapy. Front Genet 13:1077419. https://doi.org/10.3389/fgene.2022.1077419CrossRefPubMedPubMedCentral

18.

Velikkakam T, Gollob KJ, Dutra WO (2022) Double-negative T cells: setting the stage for disease control or progression. Immunology 165(4):371–385. https://doi.org/10.1111/imm.13441CrossRefPubMed

19.

Zhao Y, Zhu R, Wang Y, Wang K (2023) Classification and function of γδT cells and its research progress in anti-glioblastoma. Discover Oncol 14(1):150. https://doi.org/10.1007/s12672-023-00770-8CrossRef

20.

Silva-Santos B, Mensurado S, Coffelt SB (2019) γδ T cells: pleiotropic immune effectors with therapeutic potential in cancer. Nat Rev Cancer 19(7):392–404. https://doi.org/10.1038/s41568-019-0153-5CrossRefPubMedPubMedCentral

Titel: DNT cells mediate resistance to CAR-T cells therapy in a pediatric patient with relapsed and refractory B-ALL
verfasst von: Ruotong Chen
Qianshan Tao
Fan Wu
Zhimin Zhai
Yuchen Jiang
Caixian Xu
Huiping Wang
Publikationsdatum: 10.05.2024
Verlag: Springer Berlin Heidelberg
Erschienen in: Annals of Hematology
Print ISSN: 0939-5555
Elektronische ISSN: 1432-0584
DOI: https://doi.org/10.1007/s00277-024-05790-0

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

DNT cells mediate resistance to CAR-T cells therapy in a pediatric patient with relapsed and refractory B-ALL

Abstract

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Costims – das nächste heiße Ding in der Krebstherapie?

Perioperative Checkpointhemmer-Therapie verbessert NSCLC-Prognose

Positiver FIT: Die Ursache liegt nicht immer im Dickdarm

GLP-1-Agonisten können Fortschreiten diabetischer Retinopathie begünstigen

Update Innere Medizin

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Costims – das nächste heiße Ding in der Krebstherapie?

Perioperative Checkpointhemmer-Therapie verbessert NSCLC-Prognose

Positiver FIT: Die Ursache liegt nicht immer im Dickdarm

GLP-1-Agonisten können Fortschreiten diabetischer Retinopathie begünstigen

Update Innere Medizin