Case report: CD19-directed CAR-T cell therapy combined with BTK inhibitor and PD-1 antibody against secondary central nervous system lymphoma

Wenqi Zhang, Chen Huang, Ruixia Liu, Huichao Zhang, Weijing Li, Shaoning Yin, Lianjing Wang, Wei Liu, Lihong Liu, Wenqi Zhang, Chen Huang, Ruixia Liu, Huichao Zhang, Weijing Li, Shaoning Yin, Lianjing Wang, Wei Liu, Lihong Liu

Abstract

Current therapeutic strategies for central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) are extremely limited. Secondary central nervous system lymphoma (SCNSL) also shows a grave prognosis and high mortality. This report describes a young female patient with DLBCL and CNS relapse who received low-dose CD19-directed chimeric antigen receptor T (CAR-T) cell therapy followed with Bruton's tyrosine kinase inhibitor and programmed cell death protein 1 antibody after several lines of chemotherapy. However, limited reports on CAR-T cell therapy are applied for SCNSL, particularly those in combination with targeted agents. The current treatment combination for this case provides a new regimen for CNS relapse from DLBCL.

Clinical trial registration: ClinicalTrials.gov number, NCT04666168.

Keywords: BTK inhibitor; CD19 CAR-T cell therapy; PD-1 antibody; scnsl; tislelizumab; zanubrutinib.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Zhang, Huang, Liu, Zhang, Li, Yin, Wang, Liu and Liu.

Figures

Figure 1
Figure 1
Flow chart of the disease process and therapeutic modalities.
Figure 2
Figure 2
(A) The pathological section of mediastinum lymphatic tissue (upper panel: hematoxylin and eosin stain; lower panel: immunohistochemistry, CD30 negative). (B) Positron emission tomography assessment of patient first diagnosed (left) and after CAR-T cells infusion (right). The white arrow indicates the invasion of DLBCL on the mediastinum, which is the primary site. (C) Brain MRI images before and after CAR-T cell therapy. (a) Brain MRI on March 2020, after the second cycle of chemotherapy of R2-ICE*5 and evaluated as CR2. (b) Brain MRI on May 2020, when the patient showed CNS relapse. The size of the right temporal lobe and occipital lobe masses are 3.19 cm×4.03 cm and1.75 cm×2.4 cm, respectively. (c) The same region on October 2020, more than 4 months after CAR-T cells infusion. The mass almost disappeared and was evaluated as CR for 2 months. (d) The follow-up image on December 2020 with continuous CR.
Figure 3
Figure 3
CAR19 DNA copies, CART cell expansion levels detected by flow cytometry and the proportion of CAR-T cell to CD3+ cell during treatment. The peak levels appeared on day 14 after CAR-T cell infusion, indicating CAR19 DNA copies were 2.79×103 copies/μg, CAR-T cells expansion detected by flow cytometry was 3.64×107/L and CD3+CAR19+/CD3+ T-cell was 8.55%.

References

    1. Zhang J, Chen B and Xu X. Impact of rituximab on incidence of and risk factors for central nervous system relapse in patients with diffuse large b-cell lymphoma: A systematic review and meta-analysis. Leuk. Lymphoma (2013) 55:509–14. doi: 10.3109/10428194.2013.811239
    1. El-Galaly TC, Cheah CY, Bendtsen MD, Nowakowski GS, Kansara R, Savage KJ, et al. . Treatment strategies, outcomes and prognostic factors in 291 patients with secondary CNS involvement by diffuse large b-cell lymphoma. Eur J Cancer (2018) 93:57–68. doi: 10.1016/j.ejca.2018.01.073
    1. Ayed AO, Chiappella A, Pederson L, Laplant BR, Congiu AG, Gaidano G, et al. . CNS relapse in patients with DLBCL treated with lenalidomide plus r-CHOP (R2CHOP): Analysis from two phase 2 studies. Blood Cancer J (2018) 8 (7) :63. doi: 10.1038/s41408-018-0097-0
    1. Ahmed G, Hamadani M and Shah NN. CAR T-cell therapy for secondary CNS DLBCL. Blood Adv (2021) 5:5626–30. doi: 10.1182/bloodadvances.2021005292
    1. Abramson JS, McGree B, Noyes S. Anti-CD19 CAR T cells in CNS diffuse Large-B-Cell lymphoma. N Engl J Med (2017) 377(8):783–4. doi: 10.1056/NEJMc1704610
    1. Niu Z, Sun L, Wen S, Song Z, Xing L, Wang Y, et al. . Programmed cell death protein-1 inhibitor combined with chimeric antigen receptor T cells in the treatment of relapsed refractory non-Hodgkin lymphoma: A case report. World J Clin cases. (2021) 9:2394–9. doi: 10.12998/wjcc.v9.i10.2394
    1. Zhu W, Tao S, Miao W, Liu H, Yuan X. Case report: Dual inhibition of HDAC and BTK for diffuse Large b-cell lymphoma after failure to CD19-targeted CAR-T therapy. Front Immunol (2022) 13:894787. doi: 10.3389/fimmu.2022.894787
    1. Liu M, Wang X, Li Z, Zhang R, Mu J, Jiang Y, et al. . Synergistic effect of ibrutinib and CD19 CAR-T cells on raji cells in vivo and in vitro . Cancer Sci (2020) 111(11):4051–60. doi: 10.1111/cas.14638
    1. Mhibik M, Wiestner A and Sun C. Harnessing the effects of BTKi on T cells for effective immunotherapy against CLL. Int J Mol Sci (2020) 21:68. doi: 10.3390/ijms21010068
    1. Xinfeng Chen XLYL, Huang HLFL, Sun HYZZ, Ying Zeng XWYH. A phase I clinical trial of chimeric antigen receptor-modified T cells in patients with relapsed and refractory lymphoma. Immunotherapy-uk (2020) 12(10):681–96. doi: 10.2217/imt-2020-0022
    1. Bernard E, Nannya Y, Hasserjian RP, Devlin SM, Tuechler H, Juan S, Medina-Martinez JS, et al. . Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes. Nat Med (2020) 26:1549–56. doi: 10.1038/s41591-020-1008-z
    1. Porpaczy E, Wohlfarth P, Königsbrügge O, Rabitsch W, Skrabs C, Staber P, et al. . Influence of TP53 mutation on survival of diffuse Large b-cell lymphoma in the CAR T-cell era. Cancers (2021) 13:5592. doi: 10.3390/cancers13225592
    1. Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. . Revised response criteria for malignant lymphoma. J Clin Oncol (2007) 25:579–86. doi: 10.1200/JCO.2006.09.2403
    1. Spiegel JY, Dahiya S, Jain MD, Tamaresis J, Nastoupil LJ, Jacobs MT, et al. . Outcomes of patients with Large b-cell lymphoma progressing after axicabtagene ciloleucel therapy. Blood (2021) 137(13):1832–5. doi: 10.1182/blood.2020006245
    1. Chong EA, Ruella M, Schuster SJ. Five-year outcomes for refractory b-cell lymphomas with CAR T-cell therapy. N Engl J Med (2021) 384:673–4. doi: 10.1056/NEJMc2030164
    1. Maude SLFN. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med (2014) 371 (16), 1507–17. doi: 10.1056/NEJMoa1407222
    1. Li X, Chen W. Mechanisms of failure of chimeric antigen receptor T-cell therapy. Curr Opin Hematol (2019) 26:427–33. doi: 10.1097/MOH.0000000000000548
    1. Ying Z, He T, Wang X, Zheng W, Lin N, Tu M, et al. . Parallel comparison of4-1BB or CD28 co-stimulated CD19-targeted CARTcells for b cell non-hodgkin’s lymphoma. Mol Ther Oncolytics (2019) 15:60–8. doi: 10.1016/j.omto.2019.08.002
    1. Zhao X, Yang J, Zhang X, Lu X, Xiong M, Zhang J, et al. . Efficacy and safety of CD28- or 4-1BB-based CD19 CAR-T cells in b cellacute lymphoblastic leukemia. Mol Ther Oncolytics (2020) 18:272–81. doi: 10.1016/j.omto.2020.06.016
    1. Locke FL, Neelapu SS, Bartlett NL, Siddiqi T, Chavez JC, Hosing CM, et al. . Phase 1results of ZUMA-1: A multicenter study of KTE-C19anti-CD19 CAR T cell therapy in refractoryaggressive lymphoma. Mol Ther (2017) 25:285–95. doi: 10.1016/j.ymthe.2016.10.020
    1. Westin JR, Kersten MJ, Salles G, Abramson JS, Schuster SJ, Locke FL, et al. . Efficacy andsafety of CD19-directed CAR-T cell therapies inpatients with relapsed/refractory aggressive b-celllymphomas: Observations from the JULIET, ZUMA1,and TRANSCEND trials. Am J Hematol (2021) 96:1295–312. doi: 10.1002/ajh.26301
    1. Ying Z, He T, Jin S, Wang X, Zheng W, Lin N, et al. . A durable 4-1BB-based CD19 CAR-T cell for treatment of relapsed or refractory non-Hodgkin lymphoma. Chin J Cancer Res (2022) 34(1):53–62. doi: 10.21147/j.issn.1000-9604.2022.01.05
    1. Parihar R, Rivas C, Huynh M, Rooney CM, Omer B, Lapteva N, et al. . NK cells expressing a chimeric activating receptor eliminate MDSCs and rescue impaired CAR-T cell activity against solid tumors. Cancer Immunol Res (2019) 7:363–75. doi: 10.1158/2326-6066.CIR-18-0572
    1. Shi X, Zhang D, Li F, Zhang Z, Wang S, Xuan Y, et al. . Targeting glycosylation of PD-1 to enhance CAR-T cell cytotoxicity. J Hematol Oncol (2019) 12(1):127. doi: 10.1186/s13045-019-0831-5
    1. McGowan. E, Lin. Q, Ma. G, Lin. Y, Yin H, Chen S, et al. . PD-1 disrupted CAR-T cells in the treatment of solid tumors: Promises and challenges. BioMed Pharmacother (2020) 121:109625. doi: 10.1016/j.biopha.2019.109625
    1. Hu. W, Zi. Z, Jin. Y, Li G, Shao K, Wei. F, et al. . CRISPR/Cas9-mediated PD-1 disruption enhances human mesothelin-targeted CAR T cell effector functions. Cancer Immunol Immunother (2019) 68:365–77. doi: 10.1007/s00262-018-2281-2
    1. Simon. B, Harrer. DC, Schuler-Thurner. B, Schaft N, Schuler G, Dorrie J, et al. . The siRNA mediated down-regulation of PD-1 alone or simultaneously with CTLA-4 shows enhanced in vitro CAR-t-cell functionality for further clinical development towards the potential use in immunotherapy of melanoma. Exp Dermatol (2018) 27:769–78. doi: 10.1111/exd.13678
    1. Heczey. A, Louis. CU, Savoldo. B, Dakhova O, Durett A, Grilley B, et al. . CAR T cells administered in combination with lymphodepletion and PD-1 inhibition to patients with neuroblastoma. Mol Ther (2017) 25:2214–24. doi: 10.1016/j.ymthe.2017.05.012
    1. Cherkassky L, Morello A, Villena-Vargas J, Feng Y, Dimitrov DS, Jones DR, et al. . Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J Clin Invest (2016) 126:3130–44. doi: 10.1172/JCI83092
    1. Wen T, Wang J, Shi Y, Qian H and Liu P. Inhibitors targeting bruton’s tyrosine kinase in cancers: drug development advances. Leukemia (2021) 35:312–32. doi: 10.1038/s41375-020-01072-6
    1. Zhou K, Zou D, Zhou J, Hu J, Yang H, Zhang H, et al. . Zanubrutinib monotherapy in relapsed/refractory mantle cell lymphoma: A pooled analysis of two clinical trials. J Hematol Oncol (2021) 14:167. doi: 10.1186/s13045-021-01174-3
    1. Cheng Q, Wang J, Lv C, Xu. J. Successful management of a patient with refractory primary central nervous system lymphoma by zanubrutinib. Onco Targets Ther (2021) 14:3367–72. doi: 10.2147/OTT.S309408
    1. Wong J, Cher L, Grifffths J, Cohen A, Huang J, Wang L, et al. . Efffcacy of zanubrutinib in the treatment of bing-neel syndrome. Hemasphere (2018) 2(6):e155. doi: 10.1097/HS9.0000000000000155

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner