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

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

• Authors: Xi Chen, Haiying Kong, Linxiang Luo, Shuiyun Han, Tao Lei, Haifeng Yu, Na Guo, Cong Li, Shuailing Peng, Xiaowu Dong, Haiyan Yang, Meijuan Wu
• Journal: BMC cancer (BMC Cancer) Vol. 22 Issue 1 Pg. 9 (Jan 03 2022) ISSN: 1471-2407 [Electronic] England
• PMID: 34980000 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s).

Chemical References

• Antigens, CD
• Antigens, Differentiation, Myelomonocytic
• B7-H1 Antigen
• CD163 antigen
• FOXP3 protein, human
• Forkhead Transcription Factors
• Histocompatibility Antigens
• Immune Checkpoint Inhibitors
• PDCD1 protein, human
• Programmed Cell Death 1 Ligand 2 Protein
• Programmed Cell Death 1 Receptor
• Receptors, Cell Surface

Topics

• Adult
• Antigens, CD (immunology)
• Antigens, Differentiation, Myelomonocytic (immunology)
• B7-H1 Antigen (antagonists & inhibitors)
• Clinical Trials, Phase II as Topic
• Female
• Forkhead Transcription Factors (immunology)
• Histocompatibility Antigens (immunology)
• Hodgkin Disease (drug therapy, immunology)
• Humans
• Immune Checkpoint Inhibitors (therapeutic use)
• Male
• Middle Aged
• Programmed Cell Death 1 Ligand 2 Protein (antagonists & inhibitors)
• Programmed Cell Death 1 Receptor (immunology)
• Progression-Free Survival
• Receptors, Cell Surface (immunology)
• Recurrence
• Retrospective Studies
• Treatment Outcome
• Tumor Microenvironment (immunology)