Abstract 1023: Understanding the anti-tumor activities of daratumumab in natural killer/T cell lymphoma (NKTCL)
Authors: Zhou Tianyuan , Qing Min , Abraham Yann , Perova Tatiana , Sweeney Cheryl , Krevvata Maria 
Published: July 2021

Abstract
Background: NKTCL is an aggressive and heterogenous type of non-Hodgkin's lymphoma that is characterized by malignant proliferation of cytotoxic natural killer (NK) or T cells and is associated with Epstein-Barr virus (EBV). Previous studies have shown that NKTCL tumors variably express CD38. Thus daratumumab (DARA), a human IgGκ monoclonal antibody targeting CD38 with direct on-tumor and immunomodulatory mechanism of action, was hypothesized to be a novel therapeutic option for patients with relapsed or refractory (R/R) NKTCL. The open-label, single-arm, multicenter, phase 2 study NKT2001 (NCT02927925) assessed the safety and efficacy of DARA in patients with R/R NKTCL, with an overall response rate of 25% and a 55 day median duration of response (DOR). Baseline serum EBV and CD38 expression levels did not show a clear correlation with clinical response. One NKTCL patient whose tumors did not express CD38 responded to treatment, suggesting that the immunomodulatory activities of DARA may be sufficient to confer clinical benefit. To understand the suboptimal response rate and short DOR, we interrogated the environmental, viral, and immune profile of NKTCL patients from NKT2001 in the context of DARA anti-tumor activity.
Methods: CD38 expression was assessed by immunohistochemistry. Patient immune landscapes were assessed by cytometry by time-of-flight (CyTOF), multi-parameter flow cytometry (MPFC), clonal sequencing, and serum EBV level measurements.
Results: Based on CyTOF and MPFC, high levels of baseline naive CD38- B cells with low percentage of CD38+ B cell populations (including transitional B, plasmablast, and plasma cells) were found to be significantly correlated with clinical response. However, subsequent B and T cell receptor sequencing did not detect clear relationships between pre-existing or treatment-emergent EBV-related B or T cell clones with clinical response. CyTOF analyses demonstrated a reduction of CD38+ NK cells, NK T cells, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs) with DARA treatment. Nevertheless, persisting NK and NK T cells maintained cell surface markers indicative of functionality. Total Tregs and MDSCs levels did not change despite diminished CD38 expression, suggesting that DARA did not reverse the immune suppression mediated by Tregs or MDSCs. In contrast, there was a trend towards a decrease in CD4/CD8 ratio from baseline in responders but not in nonresponders, suggesting modulation of the immune environment is crucial for DARA anti-tumor activities in NKTCL.
Conclusion: These results demonstrate that DARA can lead to clinical response in patients with NKTCL by modulating the immune environment.
Citation Format: Tianyuan Zhou, Min Qing, Yann Abraham, Tatiana Perova, Cheryl Sweeney, Maria Krevvata. Understanding the anti-tumor activities of daratumumab in natural killer/T cell lymphoma (NKTCL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1023.