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.

New molecular targets in Hodgkin and Reed-Sternberg cells

“…Finally, deciphering how PD-L1 reverse signaling and CD30 signaling may influence the chromatin remodeling, and vice versa . Chen and coworkers recently indicated the high efficacy of anti- PD-1 treatment after failure of anti- PD-L1 therapy in relapsed/refractory HL, although the patient group in this study was of limited size ( 35 ). Moreover, a multicenter phase 1-2 clinical study, iMATIX, revealed the limited efficacy of the anti-PD-L1 inhibitor atezolizumab in HL treatment ( 159 ).…”

“…Tonsils, placenta, dendritic cells, monocytes in the liver and lungs are the only normal tissues that express PD-L1 ( 33 ). A unique feature of HRS cells is increased expression of PD-L1 and PD-L2 ( 34 , 35 ).…”

Glycan-Controlled Human PD-1 Variants Displaying Broad-Spectrum High Binding to PD-1 Ligands Potentiate T Cell

“…In addition, PD-1 inhibitor treatment, which inhibits both PD-1−PD-L1 and PD-1−PD-L2 interactions, has shown improved therapeutic efficacy in patients with relapsed or refractory Hodgkin lymphomas. 60 These results highlight the need to inhibit not only PD-1−PD-L1 but also PD-1−PD-L2 interactions and suggest that isolated hPD-1 variants that can inhibit both interactions may have greater therapeutic efficacy than hPD-1 variants that can only inhibit the PD-1−PD-L1 interaction.…”

Immune Checkpoint Inhibitors in Hodgkin Lymphoma and Non-Hodgkin Lymphoma

“…Besides PD-1 blockade, targeting PD-L1 is an alternative strategy to avoid PD-1/ PD-L1 immune checkpoints. However, it should be noted that PD-L1 and PD-L2, the two ligands to PD-1, are differentially expressed in the tumor microenvironment of cHL [29,99]. Therefore, anti-PD-L1 monotherapy may be not sufficient to completely inhibit the PD-1 pathway, its efficacy may be lower than PD-1 inhibition alone.…”