High efficacy of PD-1 inhibitor after initial failure of PD-L1 inhibitor in Relapsed/Refractory classical Hodgkin Lymphoma

We sought to understand the clinical course and molecular phenotype of patients who showed disease progression after programmed cell death ligand 1 (PD-L1) inhibitor treatment but subsequently responded to PD-1 inhibitor treatment. We also explored the response to PD-1-axis targeted therapy of classical Hodgkin lymphoma (cHL) according to genetically driven PD-L1 and programmed cell death ligand 2 (PD-L2) expression.
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High efficacy of PD-1 inhibitor after initial failure of PD-L1 inhibitor in Relapsed/Refractory classical Hodgkin LymphomaChenetal. BMC Cancer (2022) 22:9https://doi.org/10.1186/s12885-021-09028-4 RESEARCH Open AccessHigh efficacy ofPD-1 inhibitor afterinitialfailure ofPD-L1 inhibitor inRelapsed/Refractoryclassical Hodgkin LymphomaXiChen1,2†, HaiyingKong3†, LinxiangLuo4†, ShuiyunHan1,2, TaoLei1,2, HaifengYu1,2, NaGuo2,5, CongLi1,2,ShuailingPeng1,2, XiaowuDong6, HaiyanYang1,2*and MeijuanWu2,5*  Abstract  Purpose:  We sought to understand the clinical course and molecular phenotype of patients who showed disease progression after programmed cell death ligand 1 (PD-L1) inhibitor treatment but subsequently responded to PD-1 inhibitor treatment. We also explored the response to PD-1-axis targeted therapy of classical Hodgkin lymphoma (cHL) according to genetically driven PD-L1 and programmed cell death ligand 2 (PD-L2) expression. Methods:  Five patients in a phase II clinical trial of CS1001 (PD-L1 inhibitor) for relapsed or refractory (R/R) cHL were retrospectively reviewed. Formalin-fixed, paraffin-embedded whole tissues from the five patients were evaluated for 9p24.1 genetic alterations based on FISH and the expression of PD-L1, PD-L2, PD-1, major histocompatibility complex (MHC) class I–II, and the tumor microenvironment factorsCD163 and FOXP3 in the microenvironmental niche, as revealed by multiplex immunofluorescence. Results:  All five patients showed primary refractory disease during first-line treatment. Four patients received PD-1 inhibitor after dropping out of the clinical trial, and all demonstrated at least a partial response. The progression-free survival ranged from 7 to 28 months (median = 18 months), and 9p24.1 amplification was observed in all five patients at the PD-L1/PD-L2 locus. PD-L1 and PD-L2 were colocalized on Hodgkin Reed-Sternberg (HRS) cells in four of the five (80%) patients. There was differential expression of PD-L1 and PD-L2 in cells in the tumor microenvironment in cHL, especially in HRS cells, background cells and tumor-associated macrophages. Conclusions:  PD-L1 monotherapy may not be sufficient to block the PD-1 pathway; PD-L2 was expressed in HRS and background cells in cHL. The immunologic function of the PD-L2 pathway in anti-tumor activity may be under- estimated in R/R cHL. Further study is needed to elucidate the anti-tumor mechanism of PD-1 inhibitor and PD-L1 inhibitor treatment. Keywords:  Hodgkin lymphoma, PD-1 inhibitor, PD-L1 inhibitor, PD-L2, Molecular phenotype, Tumor microenvironment Background*Correspondence: haiyanyang1125@163.com; wumj@zjcc.org.cn† Xi Chen, Haiying Kong and Linxiang Luo contributed equally to this Hodgkin lymphoma is a relatively rare malignant dis-work. ease that tends to have excellent outcomes. Doxorubicin,1 Department ofLymphoma, Cancer Hospital oftheUniversity ofChinese bleomycin, vinblastine and dacarbazine (ABVD) with orAcademy ofSciences (Zhejiang Cancer Hospital), Hangzhou, China5 Department ofPathology, Cancer Hospital oftheUniversity ofChinese without radiotherapy is the most widely accepted first-Academy ofSciences (Zhejiang Cancer Hospital), No. 1 Banshan East line therapy for patients with classical Hodgkin lym-Road, Hangzhou, China phoma (cHL). Nonetheless, about 25% of patients relapseFull list of author information is available at the end of the article © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. The Creative Commons Public Domain Dedication waiver (http://​creat​iveco​ mmons.​org/​publi​cdoma​in/​zero/1.​0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Chenetal. BMC Cancer (2022) 22:9 Page 2 of 8or experience a refractory event [1]. Second-line treat- Methodsment followed by autologous stem cell transplantation Study population(ASCT) is the standard approach for R/R cHL, but may We retrospectively reviewed the data of five patientsnot be appropriate for elderly and unfit patients. In addi- from a phase II clinical trial of CS1001 (PD-L1 inhibitor)tion, some patients may experience recurrenc ...