CD19-directed CAR T-cell therapy for treatment of primary CNS lymphoma
Tanya Siddiqi, Xiuli Wang, M Suzette Blanchard, Jamie R Wagner, Leslie L Popplewell, L Elizabeth Budde, Tracey L Stiller, Mary C Clark, Laura Lim, Vibhuti Vyas, Christine E Brown, Stephen J Forman, Tanya Siddiqi, Xiuli Wang, M Suzette Blanchard, Jamie R Wagner, Leslie L Popplewell, L Elizabeth Budde, Tracey L Stiller, Mary C Clark, Laura Lim, Vibhuti Vyas, Christine E Brown, Stephen J Forman
Abstract
CD19-directed chimeric antigen receptor (CD19CAR) T-cell therapy has been successful in treating several B-cell lineage malignancies, including B-cell non-Hodgkin lymphoma (NHL). This modality has not yet been extended to NHL manifesting in the central nervous system (CNS), primarily as a result of concerns for potential toxicity. CD19CAR T cells administered IV are detectable in cerebrospinal fluid (CSF), suggesting that chimeric antigen receptor (CAR) T cells can migrate from the periphery into the CNS, where they can potentially mediate antilymphoma activity. Here, we report the outcome of a subset of patients with primary CNS lymphoma (PCNSL; n = 5) who were treated with CD19CAR T cells in our ongoing phase 1 clinical trial. All patients developed grade ≥ 1 cytokine release syndrome and neurotoxicity post-CAR T-cell infusion; toxicities were reversible and tolerable, and there were no treatment-related deaths. At initial disease response, 3 of 5 patients (60%; 90% confidence interval, 19-92%) seemed to achieve complete remission, as indicated by resolution of enhancing brain lesions; the remaining 2 patients had stable disease. Although the study cohort was small, we demonstrate that using CD19CAR T cells to treat PCNSL can be safe and feasible. This trial was registered at www.clinicaltrials.gov as #NCT02153580.
© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
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References
- Neelapu SS, Locke FL, Bartlett NL, et al. . Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531-2544.
- Schuster SJ, Bishop MR, Tam CS, et al. ; JULIET Investigators . Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45-56.
- Abramson JS, Palomba ML, Gordon LI, et al. . Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396(10254):839-852.
- Karschnia P, Jordan JT, Forst DA, et al. . Clinical presentation, management, and biomarkers of neurotoxicity after adoptive immunotherapy with CAR T cells. Blood. 2019;133(20):2212-2221.
- Gust J, Hay KA, Hanafi LA, et al. . Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov. 2017;7(12):1404-1419.
- Abramson JS, McGree B, Noyes S, et al. . Anti-CD19 CAR T cells in CNS diffuse large-B-cell lymphoma. N Engl J Med. 2017;377(8):783-784.
- Frigault MJ, Dietrich J, Martinez-Lage M, et al. . Tisagenlecleucel CAR T-cell therapy in secondary CNS lymphoma. Blood. 2019;134(11):860-866.
- Abbasi A, Peeke S, Shah N, et al. . Axicabtagene ciloleucel CD19 CAR-T cell therapy results in high rates of systemic and neurologic remissions in ten patients with refractory large B cell lymphoma including two with HIV and viral hepatitis. J Hematol Oncol. 2020;13(1):1.
- Rafelson W, Olszewski A.. What a headache! Double-hit lymphoma with CNS recurrence - role of chimeric antigen receptor (CAR) T-cell therapy. Leuk Lymphoma. 2020;61(4):757-762.
- Abramson JS, Palomba ML, Arnason JE, et al. . Lisocabtagene maraleucel (liso-cel) treatment of patients (pts) with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) and secondary CNS lymphoma: Initial results from TRANSCEND NHL 001. J Clin Oncol. 2019;37(15 suppl):7515.
- Tu S, Zhou X, Guo Z, et al. . CD19 and CD70 dual-target chimeric antigen receptor T-cell therapy for the treatment of relapsed and refractory primary central nervous system diffuse large B-cell lymphoma. Front Oncol. 2019;9(1350):1350.
- Cheson BD, Fisher RI, Barrington SF, et al. ; United Kingdom National Cancer Research Institute . Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3067.
- Wang X, Huynh C, Urak R, et al. . The cerebroventricular environment modifies CAR T cells for potent activity against both central nervous system and systemic lymphoma. Cancer Immunol Res. 2020;9(1):75-88.
- Wang X, Popplewell LL, Wagner JR, et al. . Phase 1 studies of central memory-derived CD19 CAR T-cell therapy following autologous HSCT in patients with B-cell NHL. Blood. 2016;127(24):2980-2990.
- Lee DW, Gardner R, Porter DL, et al. . Current concepts in the diagnosis and management of cytokine release syndrome [published correction appears in Blood. 2015;126(8):1048]. Blood. 2014;124(2):188-195.
- Bishop MR, Maziarz RT, Waller EK, et al. . Tisagenlecleucel in relapsed/refractory diffuse large B-cell lymphoma patients without measurable disease at infusion. Blood Adv. 2019;3(14):2230-2236.
- Parker KR, Migliorini D, Perkey E, et al. . Single-cell analyses identify brain mural cells expressing CD19 as potential off-tumor targets for CAR-T immunotherapies. Cell. 2020;183(1):126-142.e17.
- Wang X, Huynh C, Urak R, et al. . The cerebroventricular environment reprograms locally infused CAR T cells for superior activity against both CNS and systemic B cell lymphoma. Blood. 2018;132(suppl 1):965.
- Priceman SJ, Tilakawardane D, Jeang B, et al. . Regional delivery of chimeric antigen receptor-engineered T cells effectively targets HER2+ breast cancer metastasis to the brain. Clin Cancer Res. 2018;24(1):95-105.
- Brown CE, Aguilar B, Starr R, et al. . Optimization of IL13Rα2-targeted chimeric antigen receptor T cells for improved anti-tumor efficacy against glioblastoma. Mol Ther. 2018;26(1):31-44.
Source: PubMed