Combinational Therapy of CAR T-cell and HDT/ASCT Demonstrates Impressive Clinical Efficacy and Improved CAR T-cell Behavior in Relapsed/refractory Large B-cell Lymphoma

Overview

Journal J Immunother Cancer

Specialties Allergy & Immunology
Oncology
Pharmacology

Date 2024 Apr 17

PMID 38631712

Authors

Wei Liu

Hesong Zou

Lianting Chen

Wenyang Huang

Rui Lv

Yan Xu

Huimin Liu

Yin Shi

Kefei Wang

Yi Wang

Wenjie Xiong

Shuhui Deng

Shuhua Yi

Weiwei Sui

Guangxin Peng

Yueshen Ma

Huijun Wang

Lulu Lv

Jianxiang Wang

Jun Wei

Lugui Qiu

Wenting Zheng

Dehui Zou

Affiliations

Soon will be listed here.

Abstract

Background: Approximately two-thirds of patients with relapsed or refractory large B-cell lymphoma (R/R LBCL) do not respond to or relapse after anti-CD19 chimeric antigen receptor T (CAR T)-cell therapy, leading to poor outcomes. Previous studies have suggested that intensified lymphodepletion and hematological stem cell infusion can promote adoptively transferred T-cell expansion, enhancing antitumor effects. Therefore, we conducted a phase I/II clinical trial in which CNCT19 (an anti-CD19 CAR T-cell) was administered after myeloablative high-dose chemotherapy and autologous stem cell transplantation (HDT/ASCT) in patients with R/R LBCL.

Methods: Transplant-eligible patients with LBCL who were refractory to first-line immunochemotherapy or experiencing R/R status after salvage chemotherapy were enrolled. The study aimed to evaluate the safety and efficacy of this combinational therapy. Additionally, frozen peripheral blood mononuclear cell samples from this trial and CNCT19 monotherapy studies for R/R LBCL were used to evaluate the impact of the combination therapy on the in vivo behavior of CNCT19 cells.

Results: A total of 25 patients with R/R LBCL were enrolled in this study. The overall response and complete response rates were 92.0% and 72.0%, respectively. The 2-year progression-free survival rate was 62.3%, and the overall survival was 68.5% after a median follow-up of 27.0 months. No unexpected toxicities were observed. All cases of cytokine release syndrome were of low grade. Two cases (8%) experienced grade 3 or higher CAR T-cell-related encephalopathy syndrome. The comparison of CNCT19 in vivo behavior showed that patients in the combinational therapy group exhibited enhanced in vivo expansion of CNCT19 cells and reduced long-term exhaustion formation, as opposed to those receiving CNCT19 monotherapy.

Conclusions: The combinational therapy of HDT/ASCT and CNCT19 demonstrates impressive efficacy, improved CNCT19 behavior, and a favorable safety profile.

Trial Registration Numbers: ChiCTR1900025419 and NCT04690192.

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References

Cao Y, Xiao Y, Wang N, Wang G, Huang L, Hong Z . CD19/CD22 Chimeric Antigen Receptor T Cell Cocktail Therapy following Autologous Transplantation in Patients with Relapsed/Refractory Aggressive B Cell Lymphomas. Transplant Cell Ther. 2021; 27(11):910.e1-910.e11. DOI: 10.1016/j.jtct.2021.08.012. View

Cheson B, Fisher R, Barrington S, Cavalli F, Schwartz L, Zucca E . Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014; 32(27):3059-68. PMC: 4979083. DOI: 10.1200/JCO.2013.54.8800. View

Locke F, Ghobadi A, Jacobson C, Miklos D, Lekakis L, Oluwole O . 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. 2018; 20(1):31-42. PMC: 6733402. DOI: 10.1016/S1470-2045(18)30864-7. View

Nguyen L, Ohashi P . Clinical blockade of PD1 and LAG3--potential mechanisms of action. Nat Rev Immunol. 2014; 15(1):45-56. DOI: 10.1038/nri3790. View

Turtle C, Hanafi L, Berger C, Hudecek M, Pender B, Robinson E . Immunotherapy of non-Hodgkin's lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Sci Transl Med. 2016; 8(355):355ra116. PMC: 5045301. DOI: 10.1126/scitranslmed.aaf8621. View

Barrington S, George Mikhaeel N, Kostakoglu L, Meignan M, Hutchings M, Mueller S . Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J Clin Oncol. 2014; 32(27):3048-58. PMC: 5015423. DOI: 10.1200/JCO.2013.53.5229. View

Wrzesinski C, Paulos C, Gattinoni L, Palmer D, Kaiser A, Yu Z . Hematopoietic stem cells promote the expansion and function of adoptively transferred antitumor CD8 T cells. J Clin Invest. 2007; 117(2):492-501. PMC: 1783812. DOI: 10.1172/JCI30414. View

Neelapu S, Locke F, Bartlett N, Lekakis L, Miklos D, Jacobson C . Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med. 2017; 377(26):2531-2544. PMC: 5882485. DOI: 10.1056/NEJMoa1707447. View

Wang M, Munoz J, Goy A, Locke F, Jacobson C, Hill B . KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma. N Engl J Med. 2020; 382(14):1331-1342. PMC: 7731441. DOI: 10.1056/NEJMoa1914347. View

10.

Deng Q, Han G, Puebla-Osorio N, Ma M, Strati P, Chasen B . Characteristics of anti-CD19 CAR T cell infusion products associated with efficacy and toxicity in patients with large B cell lymphomas. Nat Med. 2020; 26(12):1878-1887. PMC: 8446909. DOI: 10.1038/s41591-020-1061-7. View

11.

Crump M, Neelapu S, Farooq U, Van den Neste E, Kuruvilla J, Westin J . Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017; 130(16):1800-1808. PMC: 5649550. DOI: 10.1182/blood-2017-03-769620. View

12.

Ogasawara K, Lymp J, Mack T, DellAringa J, Huang C, Smith J . In Vivo Cellular Expansion of Lisocabtagene Maraleucel and Association With Efficacy and Safety in Relapsed/Refractory Large B-Cell Lymphoma. Clin Pharmacol Ther. 2022; 112(1):81-89. PMC: 9311712. DOI: 10.1002/cpt.2561. View

13.

Dean E, Mhaskar R, Lu H, Mousa M, Krivenko G, Lazaryan A . High metabolic tumor volume is associated with decreased efficacy of axicabtagene ciloleucel in large B-cell lymphoma. Blood Adv. 2020; 4(14):3268-3276. PMC: 7391155. DOI: 10.1182/bloodadvances.2020001900. View

14.

Hitz F, Connors J, Gascoyne R, Hoskins P, Moccia A, Savage K . Outcome of patients with primary refractory diffuse large B cell lymphoma after R-CHOP treatment. Ann Hematol. 2015; 94(11):1839-43. DOI: 10.1007/s00277-015-2467-z. View

15.

Schildberg F, Klein S, Freeman G, Sharpe A . Coinhibitory Pathways in the B7-CD28 Ligand-Receptor Family. Immunity. 2016; 44(5):955-72. PMC: 4905708. DOI: 10.1016/j.immuni.2016.05.002. View

16.

Nieto Y, Thall P, Valdez B, Andersson B, Popat U, Anderlini P . High-dose infusional gemcitabine combined with busulfan and melphalan with autologous stem-cell transplantation in patients with refractory lymphoid malignancies. Biol Blood Marrow Transplant. 2012; 18(11):1677-86. PMC: 4010147. DOI: 10.1016/j.bbmt.2012.05.011. View

17.

Wei J, Xiao M, Mao Z, Wang N, Cao Y, Xiao Y . Outcome of aggressive B-cell lymphoma with TP53 alterations administered with CAR T-cell cocktail alone or in combination with ASCT. Signal Transduct Target Ther. 2022; 7(1):101. PMC: 8995369. DOI: 10.1038/s41392-022-00924-0. View

18.

Hirayama A, Gauthier J, Hay K, Voutsinas J, Wu Q, Gooley T . The response to lymphodepletion impacts PFS in patients with aggressive non-Hodgkin lymphoma treated with CD19 CAR T cells. Blood. 2019; 133(17):1876-1887. PMC: 6484391. DOI: 10.1182/blood-2018-11-887067. View

19.

Wu J, Meng F, Cao Y, Zhang Y, Zhu X, Wang N . Sequential CD19/22 CAR T-cell immunotherapy following autologous stem cell transplantation for central nervous system lymphoma. Blood Cancer J. 2021; 11(7):131. PMC: 8282870. DOI: 10.1038/s41408-021-00523-2. View

20.

Abramson J, Palomba M, Gordon L, Lunning M, Wang M, Arnason J . 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. DOI: 10.1016/S0140-6736(20)31366-0. View