LAG-3 overexpression in pediatric Hodgkin lymphoma.

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10531 Background: The role of the PD-1/PD-L1 axis in Hodgkin Lymphoma (HL) has led to FDA approval for use of inhibitors in chemotherapy-refractory HL. Numerous additional immune checkpoints may be useful targets, but have not yet been evaluated in HL. LAG-3, a related checkpoint, has been demonstrated to be overexpressed on tumor infiltrating lymphocytes (TILs) of a variety of cancers with associated poor outcomes. LAG-3 is known to inhibit T cell proliferation and activation, representing a possible therapeutic pathway for anti-tumor immunity. However, LAG-3 has yet to be evaluated in pediatric cancers. The purpose of this study is to characterize the expression pattern and clinical significance of LAG-3 in pediatric HL using immunohistochemistry. Methods: Patient tumor samples from prior Children’s Oncology Group clinical trials (AHOD0031) with matched patient outcome data containing 200 patient samples were obtained. 95% confidence intervals were calculated based on a range of observed prevalence of immune checkpoint expression. Using immunohistochemistry, paraffin embedded samples were tested for the expression of LAG-3 and PD-L1. Samples were stained for CD30 to better delineate Reed Sternberg cells from the remainder of the tumor microenvironment. Immune checkpoint staining was compared to positive controls of normal tonsil tissue, and negative controls of 3T3 cells. Expression intensity was scored by a Pediatric Pathologist. Results: 115 unique HL patient cases with evaluable HL tissue and correlating clinical outcome data were analyzed. Samples from 73/115 patients (63%) demonstrated positive LAG-3 staining, defined as over 10% of TILs expressing LAG-3. No demographic data including gender, race/ethnicity, age, or stage were significantly associated with LAG-3 expression. While not statistically significant there was a numerical difference in event free survival (EFS) and patients with LAG-3 expression demonstrated worse EFS. In terms of degree of LAG-3 expression, patients with the lowest positive expression were found to have the worst EFS, and those with highest expression demonstrated the best EFS. 97% of patient cases were found to be PD-L1 positive. 71/73 (97%) of patients who expressed LAG3 were also PDL1+, and 71/106 (67%) of PDL1+ cases were also LAG3+. LAG-3 and PD-L1 were found to be independent (p = 0.09). Conclusions: This project is innovative in its characterization of LAG-3 as an immune checkpoint target in pediatric HL. We hope that the information from this project will be used to support new clinical trials for pediatric patients with Hodgkin lymphoma.