Vol. 152 No. 2526 (2022)
Introducing innovative cellular therapies into the clinic: a 2-year retrospective experience of a chimeric antigen receptor T-cell programme at a single centre in Switzerland
- Sebastian Stolz
- Marco Roncador
- Wiebke Rösler
- Thorsten Zenz
- Markus G. Manz
- Antonia M.S. Müller
- Corinne C. Widmer
AIM OF THE STUDY: Chimeric antigen receptor T (CAR-T) cells are a powerful form of immune-cell therapy for patients with relapsed/refractory B-cell lymphoma and acute B lymphoblastic leukaemia. CAR-T cells have been commercially available in Switzerland since 2018. Because of the complexity and costs of this treatment it is critical to review patient outcomes in real-world settings, to examine whether the promising results from pivotal trials can be reproduced and to identify clinical parameters that determine their efficacy.
METHODS: Here we present results of a retrospective study analysing outcomes of patients treated with CAR-T cells in a single academic centre in Switzerland during the first two years after commercial approval (BASEC-No. 2020-02271). Cytokine release syndrome (CRS), immune-cell associated neurotoxicity syndrome (ICANS), responses to treatment, ancillary laboratory studies and administrative specifics of CAR-T treatment were examined and are discussed.
RESULTS: From October 2018 to August 2020 CAR-T cell therapy was evaluated in 34 patients, mostly with relapsed/refractory aggressive B-cell lymphoma (87% had refractory disease). Thirty-one patients underwent leukapheresis. Three of 31 patients (9.6%) died of rapid disease progression before the CAR-T cell product was delivered, two patients were enrolled into a clinical trial, three patients were not given CAR-T cells for other reasons. Ultimately, 23 patients were infused with a commercial CAR-T cell product and included in this analysis. Fourteen (61%) patients received bridging therapy while waiting for a median of 41 days (range 31–62) for delivery of the CAR-T cell product. Toxicity and severe side effects were rare (CRS >3 in 13%, ICANS > grade 3 in 10% of patients), manageable and resolved completely thereafter. The best overall response rate was 65%, with complete responses in 38% of lymphoma patients. At 12 months postinfusion, 61% of patients were alive and 35% progression free. With a median follow-up of 14 months, 13/23 (56%) patients were alive at the time of writing.
CONCLUSION: CAR-T cell therapy proved to be safe and manageable under adequate hospital conditions. Outcomes resemble results from pivotal trials. The majority of patients was heavily pretreated and refractory at the time of CAR-T cell infusion. Patient selection, time point of leukapheresis, bridging strategies and timing of CAR-T cell infusion may be critical to further improve outcomes.
- Philip T, Guglielmi C, Hagenbeek A, Somers R, Van der Lelie H, Bron D, et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med. 1995 Dec;333(23):1540–5. https://doi.org/10.1056/NEJM199512073332305
- Gisselbrecht C, Schmitz N, Mounier N, Singh Gill D, Linch DC, Trneny M, et al. Rituximab maintenance therapy after autologous stem-cell transplantation in patients with relapsed CD20(+) diffuse large B-cell lymphoma: final analysis of the collaborative trial in relapsed aggressive lymphoma. J Clin Oncol. 2012 Dec;30(36):4462–9. https://doi.org/10.1200/JCO.2012.41.9416
- Crump M, Neelapu SS, Farooq U, Van Den Neste E, Kuruvilla J, Westin J, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017 Oct;130(16):1800–8. https://doi.org/10.1182/blood-2017-03-769620
- Van Den Neste E, Schmitz N, Mounier N, Gill D, Linch D, Trneny M, et al. Outcome of patients with relapsed diffuse large B-cell lymphoma who fail second-line salvage regimens in the International CORAL study. Bone Marrow Transplant. 2016 Jan;51(1):51–7. https://doi.org/10.1038/bmt.2015.213
- Kochenderfer JN, Dudley ME, Kassim SH, Somerville RP, Carpenter RO, Stetler-Stevenson M, 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 Feb;33(6):540–9. https://doi.org/10.1200/JCO.2014.56.2025
- Kochenderfer JN, Somerville RP, Lu T, Yang JC, Sherry RM, Feldman SA, et al. Long-Duration Complete Remissions of Diffuse Large B Cell Lymphoma after Anti-CD19 Chimeric Antigen Receptor T Cell Therapy. Mol Ther. 2017 Oct;25(10):2245–53. https://doi.org/10.1016/j.ymthe.2017.07.004
- Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med. 2017 Dec;377(26):2531–44. https://doi.org/10.1056/NEJMoa1707447
- Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N Engl J Med. 2018 Feb;378(5):439–48. https://doi.org/10.1056/NEJMoa1709866
- Schuster SJ, Svoboda J, Dwivedy Nasta S, Porter DL, Chong EA, Mahnke Y, et al. Phase IIa Trial of Chimeric Antigen Receptor Modified T Cells Directed Against CD19 (CTL019) in Patients with Relapsed or Refractory CD19+ Lymphomas. Blood. 2014 Dec;124(21):3087–. https://doi.org/10.1182/blood.V124.21.3087.3087
- Locke FL, Ghobadi A, Jacobson CA, Miklos DB, Lekakis LJ, Oluwole OO, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019 Jan;20(1):31–42. https://doi.org/10.1016/S1470-2045(18)30864-7
- Abramson JS, Palomba ML, Gordon LI, Lunning MA, Wang M, Arnason J, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020 Sep;396(10254):839–52. https://doi.org/10.1016/S0140-6736(20)31366-0
- Wang M, Munoz J, Goy A, Locke FL, Jacobson CA, Hill BT, et al. KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma. N Engl J Med. 2020 Apr;382(14):1331–42. https://doi.org/10.1056/NEJMoa1914347
- Munshi NC, Anderson LD Jr, Shah N, Madduri D, Berdeja J, Lonial S, et al. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2021 Feb;384(8):705–16. https://doi.org/10.1056/NEJMoa2024850
- Chmielewski M, Hombach AA, Abken H. Antigen-Specific T-Cell Activation Independently of the MHC: Chimeric Antigen Receptor-Redirected T Cells. Front Immunol. 2013 Nov;4:371. https://doi.org/10.3389/fimmu.2013.00371
- Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. 2019 Apr;25(4):625–38. https://doi.org/10.1016/j.bbmt.2018.12.758
- Neelapu SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke FL, et al. Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. Nat Rev Clin Oncol. 2018 Jan;15(1):47–62. https://doi.org/10.1038/nrclinonc.2017.148
- O’Hara MH, Stashwick C, Plesa G, Tanyi JL. Overcoming barriers of car T-cell therapy in patients with mesothelin-expressing cancers. Immunotherapy. 2017 Aug;9(9):767–80. https://doi.org/10.2217/imt-2017-0026
- Mueller KT, Maude SL, Porter DL, Frey N, Wood P, Han X, et al. Cellular kinetics of CTL019 in relapsed/refractory B-cell acute lymphoblastic leukemia and chronic lymphocytic leukemia. Blood. 2017 Nov;130(21):2317–25. https://doi.org/10.1182/blood-2017-06-786129
- Novo M, Sidiqi MH, Paludo J, Gandhi S, Kubusek J, Truong T, et al. Peak Lymphocyte Count after CAR T Infusion Is a Clinically Accessible Test That Correlates with Clinical Response in Axicabtagene Ciloleucel Therapy for Lymphoma. Blood. 2019 Nov;134 Supplement_1:4106. https://doi.org/10.1182/blood-2019-127094
- Davila ML, Brentjens RJ. CD19-Targeted CAR T cells as novel cancer immunotherapy for relapsed or refractory B-cell acute lymphoblastic leukemia. Clin Adv Hematol Oncol. 2016 Oct;14(10):802–8.
- Santomasso BD, Park JH, Salloum D, Riviere I, Flynn J, Mead E, et al. Clinical and Biological Correlates of Neurotoxicity Associated with CAR T-cell Therapy in Patients with B-cell Acute Lymphoblastic Leukemia. Cancer Discov. 2018 Aug;8(8):958–71. https://doi.org/10.1158/2159-8290.CD-17-1319
- Brudno JN, Kochenderfer JN. Recent advances in CAR T-cell toxicity: Mechanisms, manifestations and management. Blood Rev. 2019 Mar;34:45–55. https://doi.org/10.1016/j.blre.2018.11.002
- Hay KA, Hanafi LA, Li D, Gust J, Liles WC, Wurfel MM, et al. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy. Blood. 2017 Nov;130(21):2295–306. https://doi.org/10.1182/blood-2017-06-793141
- Yakoub-Agha I, Chabannon C, Bader P, Basak GW, Bonig H, Ciceri F, et al. Management of adults and children undergoing chimeric antigen receptor T-cell therapy: best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE). Haematologica. 2020 Jan;105(2):297–316. https://doi.org/10.3324/haematol.2019.229781
- Abbasi A, Peeke S, Shah N, Mustafa J, Khatun F, Lombardo A, 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 Jan;13(1):1. https://doi.org/10.1186/s13045-019-0838-y
- Bennani NN, Maurer MJ, Nastoupil LJ, Jain MD, Chavez JC, Cashen AF, et al. Experience with Axicabtagene Ciloleucel (Axi-cel) in Patients with Secondary CNS Involvement: Results from the US Lymphoma CAR T Consortium. Blood. 2019 Nov;134 Supplement_1:763. https://doi.org/10.1182/blood-2019-129097