Related Experiment Video
Updated: Jul 26, 2026
An Efficient and Simple Method to Establish NK and T Cell Lines from Patients with Chronic Active Epstein-Barr Virus Infection
Published on: March 30, 2018
Determinants of response to daratumumab in Epstein-Barr virus-positive natural killer and T-cell lymphoma
Nurulhuda Mustafa1,2, Adina Huey Fang Nee2, Jing Yuan Chooi3
1Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore mdcnm@nus.edu.sg.
Background:
The potential therapeutic efficacy of daratumumab in natural killer T-cell lymphoma (NKTL) was highlighted when its off-label usage produced sustained remission in a patient with highly refractory disease. This is corroborated recently by a phase II clinical trial which established that daratumumab monotherapy is well tolerated and displayed encouraging response in relapsed/refractory NKTL patients. However, little is known regarding the molecular factors central to the induction and regulation of the daratumumab-mediated antitumor response in NKTL.
Methods:
CD38 expression was studied via immunohistochemistry, multiplex immunofluorescence and correlated with clinical characteristics of the patient. The therapeutic efficacy of daratumumab was studied in vitro via CellTiter-Glo (CTG) assay, complement-dependent cytotoxicity (CDC), antibody-dependent cell cytotoxicity (ADCC), and in vivo, via a patient-derived xenograft mouse model of NKTL, both as a single agent and in combination with L-asparaginase. Signaling mechanisms were characterized via pharmacologic treatment, RNA silencing, flow cytometry and corroborated with public transcriptomic data of NKTL.
Results:
Epstein-Barr virus-positive NKTL patients significantly express CD38 with half exhibiting high expression. Daratumumab effectively triggers Fc-mediated ADCC and CDC in a CD38-dependent manner. Importantly, daratumumab monotherapy and combination therapy with L-asparaginase significantly suppresses tumor progression in vivo. Ablation of complement inhibitory proteins (CIP) demonstrate that CD55 and CD59, not CD46, are critical for the induction of CDC. Notably, CD55 and CD59 expression were significantly elevated in the late stages of NKTL. Increasing the CD38:CIP ratio through sequential CIP knockdown, followed by CD38 upregulation via All-Trans Retinoic Acid treatment, potently augments complement-mediated lysis in cells previously resistant to daratumumab. The CD38:CIP ratio consistently demonstrates a statistically superior correlation to antitumor efficacy of daratumumab than CD38 or CIP expression alone.
Conclusion:
This study characterizes CD38 as an effective target for a subset of NKTL patients and the utilization of the CD38:CIP ratio as a more robust identifier for patient stratification and personalisation of treatment. Furthermore, elucidation of factors which sensitize the complement-mediated response provides an alternative approach toward optimizing therapeutic efficacy of daratumumab where CDC remains a known limiting factor. Altogether, these results propose a strategic rationale for further evaluation of single or combined daratumumab treatment in the clinic for NKTL.
Insights
Daratumumab shows promise for natural killer T-cell lymphoma (NKTL) by targeting CD38. The CD38:CIP ratio effectively predicts treatment response, guiding personalized daratumumab therapy for NKTL patients.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Daratumumab has shown therapeutic potential in refractory natural killer T-cell lymphoma (NKTL).
- Clinical trials indicate daratumumab monotherapy is well-tolerated and effective in relapsed/refractory NKTL.
- Molecular mechanisms of daratumumab's anti-NKTL activity require further elucidation.
Purpose of the Study:
- To investigate CD38 expression in NKTL and its correlation with treatment response.
- To evaluate the efficacy of daratumumab in vitro and in vivo models of NKTL.
- To identify molecular factors regulating daratumumab-mediated antitumor responses in NKTL.
Main Methods:
- CD38 expression analyzed by immunohistochemistry and multiplex immunofluorescence.
- In vitro assays (CTG, CDC, ADCC) and in vivo patient-derived xenograft models assessed daratumumab efficacy.
- Signaling pathways investigated via pharmacologic treatments, RNA silencing, and flow cytometry.
Main Results:
- Epstein-Barr virus-positive NKTL patients exhibit significant CD38 expression.
- Daratumumab induces Fc-mediated ADCC and CDC in a CD38-dependent manner.
- The CD38:CIP ratio is a superior predictor of daratumumab efficacy compared to CD38 or CIP alone.
Conclusions:
- CD38 is a viable therapeutic target in a subset of NKTL patients.
- The CD38:CIP ratio can guide patient stratification and personalized daratumumab treatment.
- Optimizing complement-mediated lysis offers a strategy to enhance daratumumab efficacy in NKTL.
