Pre-clinical toxicity evaluation of CAR-T cells for the treatment of non-Hodgkin's lymphoma

doi:10.19803/j.1672-8629.2022.08.04

Abstract

Abstract: Objective To evaluate the pre-clinical safety of chimeric antigen receptor T cells named U cells for non-Hodgkin's lymphoma in tumor-bearing immunodeficient mice. Methods The transplanted tumor model of Raji-Luc cells was established in NSG mice, and on this basis, U cells were given at a single dose and the mice were observed continuously until the 8^th week after administration. Then the fluorescence intensity of Raji-Luc cells, survival rate, clinical symptoms, changes of body weight, hematological indexes, classification of lymphocyte subsets, cytokines and histopathological changes in mice were investigated. Results U cells could significantly reduce the fluorescence intensity of Raji-Luc cells in vivo, inhibit the proliferation of Raji-Luc cells, effectively alleviate the clinical manifestations caused by Raji-Luc cells, slow down the weight loss caused by Raji-Luc cells to some extent in tumor-bearing mice, prolong the survival time of tumor-bearing mice, increase the level of human IFN- γ, decrease the level of human IL-10 in serum of tumor-bearing mice, and increase the levels of murine TNF and IL-6, and significantly decrease the production of Raji-Luc cells, which changes in the incidence of lymphoma in various tissues and organs of model animals were dose-related. Conclusion U cells have no obvious immunotoxicity and tumorigenicity risk, and show some pharmacodynamic effects in Raji-Luc NSG mice. Given the above, the data of this study can provide a reference for the non-clinical safety evaluation of related products.

Key words: chimeric antigen receptor T (CAR-T) cells, non-Hodgkin's lymphoma, immunodeficient tumor-bearing mice, toxicity evaluation, cytokines, Raji-Luc Cell

CLC Number:

R979.1

WEN Hairuo, HUANG Ying, QU Zhe, JIANG Hua, LAN Jie, LOU Xiaoyan, GENG Xingchao, WANG Sanlong, YU Lei. Pre-clinical toxicity evaluation of CAR-T cells for the treatment of non-Hodgkin's lymphoma[J]. Chinese Journal of Pharmacovigilance, 2022, 19(8): 828-835.

References

[1] SUNG H, FERLAY J, SIEGEL RL, et al.Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J].CA Cancer J Clin, 2021, 71(3): 209-249.
[2] TILLY H, MORSCHHAUSER F, SEHN LH, et al. The POLARIX study: polatuzumab vedotin with rituximab, cyclophosphamide, doxorubicin,prednisone (pola-R-CHP) versus rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) therapy in patients with previously untreated diffuse large B-cell lymphoma[J]. Blood, 2021, 138: LBA-1.
[3] HUTCHINGS M, MOUS R, CLAUSEN MR, et al.Subcutaneous epcoritmab in patients with relapsed/refractory B-cell non-Hodgkin lymphoma: safety profile and anti-tumor activity[J]. Hematol Oncol, 2021, 39(S2): 42-43.
[4] OLSZEWSKI AJ, AVIGDOR A, BABU S, et al.Mosunetuzumab monotherapy in elderly/unfit patients with first-line diffuse large B-cell lymphoma (DLBCL): safety and efficacy remain promising with durable complete responses[J]. Hematol Oncol, 2021, 39(S2): 328.
[5] CAIMI P, AI WZ, ALDERUCCIO JP, et al.Duration of response to loncastuximab tesirine in relapsed/refractory diffuse large B-cell lymphoma by demographic and clinical characteristics: subgroup analyses from LOTIS 2[J]. J Clin Oncol, 2021, 39(15): 7546.
[6] SONG Y, ZHOU K, JIN C, et al.A phase Ⅱ study of penpulimab, an anti-PD-1 antibody, in patients with relapsed or refractoryclassic Hodgkin lymphoma (cHL)[J]. J Clin Oncol, 2021, 39(15): 7529.
[7] KOCHENDERFER JN, DUDLEY ME, FELDMAN SA, et al.B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells[J]. Blood, 2012, 119(12): 2709-2720.
[8] PARDOLL DM.The blockade of immune checkpoints in cancer immunotherapy[J].Nat Rev Cancer, 2012,12(4): 252-264.
[9] BAO BY, TANG GG, WANG XW, et al.Research progress on new anti-tumor immunotherapy drugs[J]. Chinese Journal of Pharmacovigilance(中国药物警戒), 2021, 18(8): 719-724.
[10] China State Food And Drug Administration. Technical guidelines for non-clinical research and evaluation of gene modified cell therapy products (trial version) [EB/OL].(2021-12-03)[2022-04-27]. https://www.cde.org.cn/main/news/viewInfoCommon/41bc557bec23a6ebfb0e148cc989f041.
[11] ZHANG DS.Preclinical and clinical study of recombinant human CD22 monoclonal antibody SM03 in human B cell non-Hodgkin’s lymphomas[D]. Guangzhou: Sun Yat-Sen University, 2009.
[12] DONG ZX, WANG QQ, CHEN LH, et al.Comparative analysis of two novel quantitative methodologies for measuring recombiant-anti-CD20zumab based on RAJI cells and their application in pharmacokinetic study[J]. Chinese Journal of Analytical Chemistry(分析化学), 2009, 37(10): 1457-1462.
[13] WEN H, HUO G, HOU T, et al.Preclinical efficacy and safety evaluation of interleukin-6-knockdown CAR-T cells targeting at CD19[J]. Ann Transl Med, 2021, 9(23): 1713.
[14] PENSATO U, MUCCIOLI L, CANI I, et al.Brain dysfunction in COVID-19 and CAR-T therapy: cytokine storm-associated encephalopathy[J].Ann Clin Transl Neurol, 2021, 8(4): 968-979.
[15] WEN H, QU Z, YAN Y, et al.Preclinical safety evaluation of chimeric antigen receptor-modified T cells against CD19 in NSG mice[J]. Ann Transl Med, 2019, 7(23): 735.
[16] LANDRY K, THOMAS AA.Neurological complications of CAR T cell therapy[J].Curr Oncol Rep, 2020, 22(8): 83.
[17] HUNTER BD, JACOBSON CA.CAR T-cell associated neurotoxicity: mechanisms, clinicopathologic correlates, and future directions[J]. J Natl Cancer Inst, 2019, 111(7): 646-654.
[18] KOMOHARA Y, ANAMI T, KAMBA T, et al.Anti-cancer immune reaction and lymph node macrophage; a review from human and animal studies[J]. Biology Immuno, 2021, 1(3): 223-230.