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Lymphoma, Non-Hodgkin

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Diffuse Large B-Cell Lymphoma

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Atezolizumab

Antibodies

Immunoglobulins

Immune Checkpoint Inhibitors

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All study participants will be allocated to this arm (single-arm study). Study participants will undergo a maximum of 3 89Zr-atezolizumab PET scans.

The anti-PDL1 antibody atezolizumab, labeled with Zirconium-89 (89Zr) will be used as a molecular imaging tracer for PET scanning.

These 89Zr-atezolizumab PET scans will be performed before and after induction therapy (R-CHOP) and at suspected relapse during or after consolidation treatment with atezolizumab (treatment trial HOVON 151).

89Zr-atezolizumab PET scans

Marcel Nijland, MD

Molecular imaging can be used for the noninvasive assessment of biodistribution of monoclonal antibodies. Atezolizumab has previously successfully been labeled with the radionucleotide Zirconium-89 (89Zr) and studied in solid malignancies (NCT02453984). The results of atezolizumab biodistribution can help to get a better understanding of the response mechanisms, the relation with minimal residual disease, the relation with the status of the T-cell and natural killer (NK)-cell repertoire and toxicity of programmed death ligand 1 (PDL1) checkpoint inhibition. Possibly in the future this will facilitate optimal patient selection. Sequential 89Zr-atezolizumab positron emission tomography (PET) scans can provide information on the dynamics of atezolizumab biodistribution over time. In combination with repeated characterization of tumor tissue and blood samples, these results can give inside in primary and acquired resistance.

In this parallel study of the HOVON 151 trial, 89Zr-atezolizumab-PET-scans will be used to evaluate 20 high risk DLBCL patients before and after induction (R-CHOP) therapy, and at suspected relapse during or after atezolizumab consolidation (HOVON 151).

Patients with a high risk diffuse large B-cell lymphoma (DLBLC) with an international prognostic score (IPI) \> 2, have a high risk of relapse even after achieving a metabolic complete remission with cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab (R-CHOP) chemo-immunotherapy. Outcome after relapse is dismal. In patients with varies types of relapsed lymphoma checkpoint inhibition have shown promising results.

In order to improve outcome patients with a high risk DLBCL will be treated in the HOVON 151 trial (EudracT 2017-002605-35) with the monoclonal antibody directed against the immune checkpoint program death ligand 1 (PDL1) atezolizumab for 1 year after achieving a complete metabolic remission with R-CHOP.

The observed percentage of PDL1 positive tumor cells in DLBCL cases ranges from 13 to 31%. For PD-1/PDL1 checkpoint inhibition PDL1 tumor surface expression was proposed as a potential predictive marker. Despite higher overall response rates in PDL1 positive malignancies compared to PDL1 negative tumors, responses are seen in PDL1 negative patients nevertheless. PDL1 status from resected specimens showed a poor correlation to the PDL1 status from matched biopsies. Furthermore it has been shown that PDL1 expression in tumor biopsies changes with treatment. Therefore, PDL1 expression assessed by one single biopsy might not be representative.

Molecular imaging can be used for the noninvasive assessment of biodistribution of monoclonal antibodies. Atezolizumab has previously successfully been labeled with the radionucleotide Zirconium-89 (89Zr) and studied in solid malignancies (NCT02453984). The results of atezolizumab biodistribution can help to get a better understanding of the response mechanisms, the relation with minimal residual disease, the relation with the status of the T-cell and natural killer (NK)-cell repertoire and toxicity of programmed death ligand 1 (PDL1) checkpoint inhibition. Possibly in the future this will facilitate optimal patient selections. Sequential 89Zr-atezolizumab PET scans can provide information on the dynamics of atezolizumab biodistribution over time. In combination with repeated characterization of tumor tissue and blood samples, these results can give inside in the primary and acquired resistance.

In this parallel study of the HOVON 151 trial, 89Zr-atezolizumab-PET-scans will be used to evaluate 20 high risk DLBCL patients before and after induction (R-CHOP) therapy, and at suspected relapse during or after atezolizumab consolidation (HOVON 151).

Molecular Imaging Using Radiolabeled Atezolizumab to Assess Atezolizumab Biodistribution in Lymphoma Patients

Molecular Imaging of Zirconium-89-labeled Atezolizumab as a Tool to Investigate Atezolizumab Biodistribution in High-risk Diffuse Large B-cell Lymphoma

Multi-parameter flowcytometry will be used to assess baseline and post induction-therapy status of the T- and NK-cell repertoire.

Baseline and post induction-therapy fecal samples will be collected for NGS analysis

The biodistribution of the tracer 89Zr-atezolizumab as assessed with 89Zr-atezolizumab PET scans.

Tumor and immune cell PDL1 and HLA expression on archival pre-treatment biopsy via IHC.

sPDL1 serum levels will be determined with ELISA

GEP via Nanostring analysis for cell-of origin will be perfomed on archival, paraffin fixed biopsies.

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