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

Xi Chen,Xi Chen,Xi Chen,Tao Lei,Tao Lei,Tao Lei,Xiaowu Dong,Cong Li,Cong Li,Cong Li,Linxiang Luo,Shuiyun Han,Haiying Kong,Haifeng Yu,Haifeng Yu,Haifeng Yu,Shuailing Peng,Na Guo,Na Guo,Na Guo,Haiyan Yang,Haiyan Yang,Haiyan Yang,Meijuan Wu,Meijuan Wu,Meijuan Wu

doi:10.1186/s12885-021-09028-4

Abstract

PurposeWe 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.ResultsAll 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.ConclusionsPD-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 underestimated in R/R cHL. Further study is needed to elucidate the anti-tumor mechanism of PD-1 inhibitor and PD-L1 inhibitor treatment.

Highlights

Hodgkin lymphoma is a relatively rare malignant disease that tends to have excellent outcomes
The results showed differential expression of programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2) in cells in classical Hodgkin lymphoma (cHL), especially in Hodgkin Reed-Sternberg (HRS) and background cells, as well as Tumor-associated macrophages (TAMs); all of these cells are in contact with each other (Supplementary Fig. 2)
We retrospectively reviewed five patients with R/R cHL treated with a programmed cell death 1 (PD-1) inhibitor after disease progression during treatment with a PD-L1 inhibitor

Summary

Introduction

Hodgkin lymphoma is a relatively rare malignant disease that tends to have excellent outcomes. Doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) with or without radiotherapy is the most widely accepted firstline therapy for patients with classical Hodgkin lymphoma (cHL). Some patients may experience recurrence even after ASCT; new agents are needed to resolve this problem. Tissues samples from cHL patients show sparse tumor cells (Hodgkin Reed-Sternberg [HRS] cells) in an inactive inflammatory/immune milieu. This observation led to the suggestion that it may be possible to reverse cellular immunosuppression in the tumor microenvironment (TME) to kill tumor cells. This led to research on immune therapies targeting the PD-1 axis.

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