Inhibition of the immunoregulatory programmed cell death-protein-1 (PD-1)/PD-ligand (PD-L)-pathway by PD-1 blocking antibodies has resulted in high response rates in patients with relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL). Nevertheless, the majority of r/r cHL patients relapse on anti-PD-1 treatment. To address the unsolved question of mechanisms of resistance to anti-PD-1 blockade in cHL we retrospectively examined sequential biopsies of nine r/r cHL-patients with progressive disease or relapse during anti-PD-1 treatment. We found a striking increase of PD-1-positive T-cells in four and a slight increase in the other cases with progressive disease during anti-PD-1 treatment, whereas a strong PD-L1 expression on Hodgkin-and Reed Sternberg cells (HRSC) prior to anti-PD-1 blockade and at relapse/progression was detected. The observation from our case series indicates that upregulation of PD-1 on T-cells in the microenvironment (ME) contributes the development of resistance. This hypothesis needs to be further explored by analysis of larger patient cohorts.Classical HL is characterized by rare HRSC, which are embedded in an anergic inflammatory cellular ME.1 Constitutional and high expression of PD-L1 by HRSC indicates a role of PD-1/PD-L1 interaction in cHL. 2-5Inhibition of PD-1/PD-L1 interaction by anti-PD1 blockade has shown impressive response rates in r/r cHL. Although durable responses to anti-PD-1 treatment have been documented, the majority of patients eventually relapse. [4][5][6] To address the important, but so far unsolved issue of mechanisms of resistance to PD-1 blockade, we retrospectively assessed sequential biopsies of r/r cHL patients developing progressive disease (PD) or relapse on anti-PD-1 treatment with regard to microenvironmental changes and PD-1 as well as PD-L1 expression.In nine cHL patients' formalin fixed paraffin embedded biopsy specimen prior to and a second biopsy at relapse/progression under anti-PD-1-treatment were available including three patients with three available biopsies (two patients with two biopsies before and one patient with two biopsies under anti-PD-1-treatment). All patients gave their informed consent for this study which had been approved by our local ethics committee.Biopsy specimens were stained for CD30, CD15, EBER or LMP1, CD20, and CD3 to characterize HRSC and to confirm the diagnosis using established protocols ( were performed on a Leica-Bond automated stainer to characterize the ME and to quantify PD-1-and PD-L1-expression. The total number of PD-1, PD-L1, CD8 and CD4 positive microenvironmental cells was counted by two expert pathologists in three high-power fields (HPF, 1000-fold magnification using oil immersion) and the average value was used for further analysis (table 1 supplements The time interval between the most recent application of the anti-PD-1-antibody and the biopsy at progressive disease or relapse ranged from 6 days to 6 months with seven of eight sequential biopsies being taken within 6 weeks after documentation of PD.B...
Classical Hodgkin lymphoma is dominated by the non-neoplastic microenvironment, while the neoplastic Hodgkin-Reed-Sternberg cells compose only a minority of cells in the lymphoma tissue. Both the Hodgkin-Reed-Sternberg cells due to their expression of CD30 and PD-L1 and the microenvironment with abundant T cells and expression of PD1 are specifically targeted by new treatment concepts. We aimed to understand the dynamics of therapeutic targets in patients treated with conventional chemotherapy. We analyzed sequential biopsy specimens obtained at diagnosis and at relapse from the same patient for morphology, immunophenotype, and microenvironmental components. The morphological subtype changed between primary and relapse biopsy in 20% of cases. The immunophenotype was stable with respect to CD30, CD3, and LMP1 but variable with respect to CD15 and CD20 expression. Gene expression revealed 8 upregulated and 20 downregulated genes at relapse (p ≤ 0.05) with a consistent logarithmic fold change direction in at least 75% of all cases. For PD1, we found discrepant results between gene expression analysis (decrease at relapse) and number of PD1-positive cells assessed by immunohistochemistry (unchanged at relapse). PD-L1 in the neoplastic cells appeared unchanged between primary diagnosis and relapse. The expression of the therapeutic targets CD30, PD1, and PD-L1 can reliably be assessed in tumor specimen at first diagnosis and is unchanged under conventional chemotherapy.
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