Phase II trial of co‐administration of CD19‐ and CD20‐targeted chimeric antigen receptor T cells for relapsed and refractory diffuse large B cell lymphoma

Sang, Wei; Shi, Ming; Yang, Jingjing; Cao, Jiang; Xu, Linyan; Yan, Dongmei; Yao, Meixue; Liu, Hui; Li, Weidong; Zhang, Bing; Sun, Kemeng; Song, Xuguang; Sun, Cai; Jiao, Jun; Qin, Yuanyuan; Sang, Tingting; Ma, Yuanyuan; Wu, Menghuai; Gao, Xiang; Cheng, Hai; Zhang, Yan; Li, Depeng; Sun, Haiying; Zhu, Feng; Wang, Ying; Zeng, Lingyu; Li, Zhenyu; Zheng, Junnian; Xu, Kailin

doi:10.1002/cam4.3259

Cited by 38 publications

(23 citation statements)

References 29 publications

(57 reference statements)

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“…Seventeen patients reached OR with 11 patients in CR. And the toxicities were manageable [ 67 ]. The result indicated an accessible choice for patients with refractory or relapsed DLBCL.…”

Section: Discussion Of Clinical Trialsmentioning

confidence: 99%

Advances in chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma

2021

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B-cell non-Hodgkin lymphoma (B-NHL) is a group of heterogeneous disease which remains incurable despite developments of standard chemotherapy regimens and new therapeutic agents in decades. Some individuals could have promising response to standard therapy while others are unresponsive to standard chemotherapy or relapse after autologous hematopoietic stem-cell transplantation (ASCT), which indicates the necessity to develop novel therapies for refractory or relapsed B-NHLs. In recent years, a novel cell therapy, chimeric antigen receptor T-cell therapy (CAR-T), was invented to overcome the limitation of traditional treatments. Patients with aggressive B-NHL are considered for CAR-T cell therapy when they have progressive lymphoma after second-line chemotherapy, relapse after ASCT, or require a third-line therapy. Clinical trials of anti-CD19 CAR-T cell therapy have manifested encouraging efficacy in refractory or relapsed B-NHL. However, adverse effects of this cellular therapy including cytokine release syndrome, neurotoxicity, tumor lysis syndrome and on-target, off-tumor toxicities should attract our enough attention despite the great anti-tumor effects of CAR-T cell therapy. Although CAR-T cell therapy has shown remarkable results in patients with B-NHL, the outcomes of patients with B-NHL were inferior to patients with acute lymphoblastic leukemia. The inferior response rate may be associated with physical barrier of lymphoma, tumor microenvironment and low quality of CAR-T cells manufactured from B-NHL patients. Besides, some patients relapsed after anti-CD19 CAR-T cell therapy, which possibly were due to limited CAR-T cells persistence, CD19 antigen escape or antigen down-regulation. Quite a few new antigen-targeted CAR-T products and new-generation CAR-T, for example, CD20-targeted CAR-T, CD79b-targeted CAR-T, CD37-targeted CAR-T, multi-antigen-targeted CAR-T, armored CAR-T and four-generation CAR-T are developing rapidly to figure out these deficiencies.

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“…Seventeen patients reached OR with 11 patients in CR. And the toxicities were manageable [ 67 ]. The result indicated an accessible choice for patients with refractory or relapsed DLBCL.…”

Section: Discussion Of Clinical Trialsmentioning

confidence: 99%

Advances in chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma

2021

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“…All patients who received CAR T infusion developed CRS, and 6 of them were grade 3‐4. Five patients suffered CRES, 2 of which were grade 3‐4 63 …”

Section: Clinical Trial Of Dual‐target Car T‐cell Immunotherapymentioning

confidence: 99%

Preclinical and clinical advances in dual‐target chimeric antigen receptor therapy for hematological malignancies

Guo

et al. 2021

Cancer Science

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Immunotherapy can mobilize the natural antitumor ability to achieve targeted elimination of tumor cells, with minimal toxicity to normal cells. Adoptive cell therapy has evolved over several generations, from the earliest lymphokine-activated killer cells (first generation) and cytokine-induced killer cells (second generation), to tumorinfiltrating lymphocytes (third generation), antigen-specific cytotoxic T lymphocytes (fourth generation), and chimeric antigen receptor (CAR; fifth generation) T cells. In recent years, CAR T-cell therapy has

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“…Dual targeting CAR T-cells: Preclinical studies demonstrated high anti-tumor potency with tandem CD19/CD20 CAR T-cells (23,24), sequential infusion of CD19 and CD79b CARs (25), coinfusion of CD19 and CD38 CAR T-cells (26), and CD19/CD37 constructs (27). The clinical benefit of tandem CD19/CD20 CARs (28)(29)(30), co-infusion of CD19 and CD20 CARs (31), and mixed infusions of CD22 and CD19 CAR T-cells (32,33) has been evaluated in small early phase clinical trials with demonstrated feasibility and varying levels of efficacy and safety.…”

Section: Summary Of the Evidence Prior To This Studymentioning

confidence: 99%

Efficacy and Safety of Innovative Experimental Chimeric Antigen Receptor (CAR) T-cells versus Axicabtagene ciloleucel (Yescarta) for the Treatment of Relapsed/Refractory Large B-Cell Lymphoma (LBCL): Matching Adjusted Indirect Comparisons (MAICs) and Systematic Review

et al. 2021

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Despite favorable results of CAR T-cell therapy for relapsed/refractory large B-cell lymphoma (R/R LBCL), several challenges remain, including incomplete response, immune-mediated toxicity, and antigen-loss relapse. We delineated the relative clinical benefit of the novel approaches compared to the currently approved CAR T-cell therapies. In the absence of head-to-head comparisons and randomized controlled trials, we performed Matching Adjusted Indirect Comparisons to quantify the relative efficacy and safety of experimental CARs against Axicabtagene ciloleucel (Yescarta), the first FDA-approved CAR. A total of 182 R/R LBCL patients from 15 clinical trials with individual patient data (IPD) were pooled into eight populations by their CAR T-cell constructs and +/- ASCT status. The study endpoints were Progression-Free Survival (PFS), grade ≥ 3 cytokine release syndrome (CRS), and grade ≥ 3 neurotoxicity (NT). Tandem CD19.CD20.4-1BBζ CARs indicated favorable efﬁcacy and safety, whereas the co-infusion of CD19 & CD20 with 4-1BBζ showed no clinical benefit compared to Yescarta. Third generation CD19. CD28. 4-1BBζ, and sequential administration of autologous stem cell transplantation (ASCT) and CD19. CARs presented statistically insignificant yet improved PFS and safety except for ASCT combined intervention which had suggestively higher NT risk than Yescarta. CARs with modified co-stimulatory domains to reduce toxicity (Hu19. CD8.28Zζ and CD19. BBz.86ζ) presented remarkable safety with no severe adverse events; however, both presented worse PFS than Yescarta. Third-generation CARs demonstrated statistically significantly lower NT than Yescarta. CD20. 4-1BBζ data suggested targeting CD20 antigen alone lacks clinical or safety benefit compared to Yescarta. Further comparisons with other FDA-approved CARs are needed.

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Phase II trial of co‐administration of CD19‐ and CD20‐targeted chimeric antigen receptor T cells for relapsed and refractory diffuse large B cell lymphoma

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 38 publications

References 29 publications

Advances in chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma

Advances in chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma

Preclinical and clinical advances in dual‐target chimeric antigen receptor therapy for hematological malignancies

Efficacy and Safety of Innovative Experimental Chimeric Antigen Receptor (CAR) T-cells versus Axicabtagene ciloleucel (Yescarta) for the Treatment of Relapsed/Refractory Large B-Cell Lymphoma (LBCL): Matching Adjusted Indirect Comparisons (MAICs) and Systematic Review

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