The differential effects of tumor burdens on predicting the net benefits of ssCART-19 cell treatment on r/r B-ALL patients

Minghao Li, Sheng-Li Xue, Xiaowen Tang, Jiayu Xu, Suning Chen, Yue Han, Huiying Qiu, Miao Miao, Nan Xu, Jingwen Tan, Liqing Kang, Zhou Yu, Xiaoyan Lou, Yang Xu, Jia Chen, Zhiqiang Yan, Weixing Feng, Depei Wu, Lei Yu, Minghao Li, Sheng-Li Xue, Xiaowen Tang, Jiayu Xu, Suning Chen, Yue Han, Huiying Qiu, Miao Miao, Nan Xu, Jingwen Tan, Liqing Kang, Zhou Yu, Xiaoyan Lou, Yang Xu, Jia Chen, Zhiqiang Yan, Weixing Feng, Depei Wu, Lei Yu

Abstract

The tumor burden (TB) is significantly related to the severity of cytokine release syndrome (CRS) caused by CAR-T cells, but its correlation with therapeutic efficacy has not been systematically studied. This study focused on the effects of the TB level on both the safety and efficacy of ssCART-19 as a treatment for r/r B-ALL. Taking the 5% tumor burden as the boundary, the study participants were divided into 2 groups, high and low tumor burden groups. Under this grouping strategy, the impacts of differential r/r B-ALL TBs on the clinical therapeutic efficacy (CR rate and long-term survival) and safety profiles after ssCART-19 cell treatment were analysed. 78 patients were reported in this study. The differential B-ALL TBs significantly affected the complete remission (CR) rates of patients treated with ssCART-19, with rates of 93.94% and 75.56% in the low and high TB groups, respectively (P = 0.0358). The effects of TBs on long-term therapeutic efficacy were further studied based on event-free survival (EFS) and overall survival (OS) profiles; both the OS and EFS of the low TB group were better than those of the high TB group, but the differences were not statistically significant. Importantly, the time points of TB measurement did not significantly affect the OS and EFS profiles regardless of whether the TBs were measured before or after fludarabine-cyclophosphamide (FC) preconditional chemotherapy. On the other hand, the severity of CRS was significantly correlated with the TB level (P = 0.0080), and the incidence of sCRS was significantly related to the TB level (the sCRS incidence increased as the TB level increased, P = 0.0224). Unexpectedly, the ssCART-19 cell expansion peaks were not significantly different (P = 0.2951) between the study groups. Patients with a low r/r B-ALL TB yield more net benefits from CAR-T treatment than those with a high TB in terms of safety and CR rate. These findings are critical and valuable for determining the optimal CAR-T cell treatment window for r/r B-ALL patients and will further the development of comprehensive and reasonable CAR-T cell treatment plans for r/r B-ALL patients with differential TBs.Trial registration: ClinicalTrials.gov identifier, NCT03919240.

Conflict of interest statement

The authors declare no competing interests.

© 2022. The Author(s).

Figures

Figure 1
Figure 1
Flow chart of the study participants. The diagram shows the courses all of the study participants from the time of consent to treatment. *In this study, only patients with an infusion dose of 5 × 106 cells/kg were included in the statistical analysis.
Figure 2
Figure 2
Response to ssCART-19 cells. (A) The rates of minimal residual disease (MRD)-positive complete remission, MRD-negative complete remission and no response. Patients with an unknown MRD status were included with those who achieved MRD-positive complete remission. (B) Correlation between the remission status and tumor burden (P = 0.0358; Fisher's exact test). (C, D) Kaplan–Meier analyses demonstrated better OS and EFS rates in patients who had a low tumor burden (blue line, n = 33) than in those who had a high tumor burden (red line, n = 45; P = 0.2 and P = 0.57, respectively; log-rank test).
Figure 3
Figure 3
Long-term survival based on the tumor burden evaluation time point. (A, B) The OS and EFS, respectively, of patients who underwent bone marrow evaluations before and after interim therapy. (C, D) Correlations between OS or EFS and the tumor burden evaluated before FC treatment. (E, F) Correlations between OS or EFS and the tumor burden evaluated after FC treatment.
Figure 4
Figure 4
Cytokine release syndrome and neurotoxic effects after infusion of ssCART-19 cells. (A) Correlation between the CRS level and tumor burden (P = 0.0080; t test). (B) Correlation between the occurrence of sCRS and the tumor burden (P = 0.0053; Fisher's exact test). (C) Correlation between the occurrence of sCRS and the tumor burden subgroup (P = 0.0224; one-way ANOVA); no CRS means CRS level 0, normal CRS means CRS levels 1 and 2, and sCRS means CRS level 3 or higher. (D) No correlation was observed between the occurrence of neurotoxic effects and the tumor burden (P > 0.9999; Fisher's exact test).
Figure 5
Figure 5
Cytokines and the tumor burden. (A, C, E, G) The peak concentration scatter plots of IL-2, IL-6, TNF-α and IFN-γ. (B, D, F, H) Plots of the dynamic levels of IL-2, IL-6, TNF-α and IFN-γ.
Figure 6
Figure 6
Post-infusion CAR-T cell expansion and the tumor burden. (A) Correlation between chimeric antigen receptor T (CAR-T) cell expansion after infusion and the tumor burden (P = 0.2951). (B) CAR-T cell counts in the blood over the first 44 days after CAR-T cell infusion in patients with a low tumor burden (blue line) compared with patients with a high tumor burden (red line).

References

    1. Frey NV, et al. Optimizing chimeric antigen receptor T-cell therapy for adults with acute lymphoblastic leukemia. J. Clin. Oncol. 2020;38:415–422. doi: 10.1200/JCO.19.01892.
    1. Maude SL, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 2018;378:439–448. doi: 10.1056/NEJMoa1709866.
    1. Kenderian SS, Porter DL, Gill S. Chimeric antigen receptor T cells and hematopoietic cell transplantation: How not to put the CART before the horse. Biol. Blood Marrow Transpl. 2017;23:235–246. doi: 10.1016/j.bbmt.2016.09.002.
    1. Curran KJ, et al. Toxicity and response after CD19-specific CAR T-cell therapy in pediatric/young adult relapsed/refractory B-ALL. Blood. 2019;134:2361–2368. doi: 10.1182/blood.2019001641.
    1. Kotch C, Barrett D, Teachey DT. Tocilizumab for the treatment of chimeric antigen receptor T cell-induced cytokine release syndrome. Expert. Rev. Clin. Immunol. 2019;15:813–822. doi: 10.1080/1744666X.2019.1629904.
    1. Hay KA. Cytokine release syndrome and neurotoxicity after CD19 chimeric antigen receptor-modified (CAR-) T cell therapy. Br. J. Haematol. 2018;183:364–374. doi: 10.1111/bjh.15644.
    1. Teachey DT, et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov. 2016;6:664–679. doi: 10.1158/-16-0040.
    1. Giavridis T, et al. CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nat. Med. 2018;24:731–738. doi: 10.1038/s41591-018-0041-7.
    1. Turtle, C. J. et al. Immunotherapy of non-Hodgkin's lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Sci Transl Med8, 355ra116. 10.1126/scitranslmed.aaf8621 (2016).
    1. Porter, D. L. et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med7, 303ra139. 10.1126/scitranslmed.aac5415 (2015).
    1. Maude SL, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 2014;371:1507–1517. doi: 10.1056/NEJMoa1407222.
    1. Turtle CJ, et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J. Clin. Invest. 2016;126:2123–2138. doi: 10.1172/JCI85309.
    1. Kochenderfer JN, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J. Clin. Oncol. 2015;33:540–549. doi: 10.1200/JCO.2014.56.2025.
    1. Pan J, et al. High efficacy and safety of low-dose CD19-directed CAR-T cell therapy in 51 refractory or relapsed B acute lymphoblastic leukemia patients. Leukemia. 2017;31:2587–2593. doi: 10.1038/leu.2017.145.
    1. Fraietta JA, et al. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat. Med. 2018;24:563–571. doi: 10.1038/s41591-018-0010-1.
    1. Qin JS, et al. Antitumor potency of an anti-CD19 chimeric antigen receptor T-cell therapy, lisocabtagene maraleucel in combination with ibrutinib or acalabrutinib. J. Immunother. 2020;43:107–120. doi: 10.1097/CJI.0000000000000307.
    1. Park JH, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N. Engl. J. Med. 2018;378:449–459. doi: 10.1056/NEJMoa1709919.
    1. Lee DW, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: A phase 1 dose-escalation trial. Lancet. 2015;385:517–528. doi: 10.1016/S0140-6736(14)61403-3.
    1. Davila, M. L. et al. Efficacy and toxicity management of 19–28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med6, 224ra225. 10.1126/scitranslmed.3008226 (2014).
    1. Hay KA, et al. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy. Blood. 2017;130:2295–2306. doi: 10.1182/blood-2017-06-793141.
    1. Brentjens, R. J. et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci. Transl. Med.5, 177ra138. 10.1126/scitranslmed.3005930 (2013).
    1. Kang L, et al. Interleukin-6-knockdown of chimeric antigen receptor-modified T cells significantly reduces IL-6 release from monocytes. Exp. Hematol. Oncol. 2020;9:11. doi: 10.1186/s40164-020-00166-2.
    1. Ramos CA, et al. Clinical responses with T lymphocytes targeting malignancy-associated kappa light chains. J. Clin. Invest. 2016;126:2588–2596. doi: 10.1172/JCI86000.
    1. Kang L, et al. Characterization of novel dual tandem CD19/BCMA chimeric antigen receptor T cells to potentially treat multiple myeloma. Biomark. Res. 2020;8:14. doi: 10.1186/s40364-020-00192-6.
    1. Hoelzer D, et al. Acute lymphoblastic leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2016;27:v69–v82. doi: 10.1093/annonc/mdw025.
    1. Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: Recognition and management. Blood. 2016;127:3321–3330. doi: 10.1182/blood-2016-04-703751.
    1. Li L, et al. Treatment response, survival, safety, and predictive factors to chimeric antigen receptor T cell therapy in Chinese relapsed or refractory B cell acute lymphoblast leukemia patients. Cell Death Dis. 2020;11:207. doi: 10.1038/s41419-020-2388-1.
    1. Mueller KT, et al. Cellular kinetics of CTL019 in relapsed/refractory B-cell acute lymphoblastic leukemia and chronic lymphocytic leukemia. Blood. 2017;130:2317–2325. doi: 10.1182/blood-2017-06-786129.
    1. Neelapu SS, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N. Engl. J. Med. 2017;377:2531–2544. doi: 10.1056/NEJMoa1707447.
    1. Qu C, et al. Radiation priming chimeric antigen receptor T-cell therapy in relapsed/refractory diffuse large B-cell lymphoma with high tumor burden. J. Immunother. 2020;43:32–37. doi: 10.1097/CJI.0000000000000284.

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