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Updated: Jul 1, 2025
Advances in Human Induced Pluripotent Stem Cell-Derived Chimeric Antigen Receptor-Expressing Natural Killer Cells
Published on: February 14, 2025
Anti-metabolic agent pegaspargase plus PD-1 antibody sintilimab for first-line treatment in advanced natural killer T
Jie Xiong1, Shu Cheng1, Xiao Gao1
1Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Abstract:
Natural killer T cell lymphoma (NKTCL) is highly aggressive, with advanced stage patients poorly responding to intensive chemotherapy. To explore effective and safe treatment for newly diagnosed advanced stage NKTCL, we conducted a phase II study of anti-metabolic agent pegaspargase plus PD-1 antibody sintilimab (NCT04096690). Twenty-two patients with a median age of 51 years (range, 24-74) were enrolled and treated with induction treatment of pegaspargase 2500 IU/m2 intramuscularly on day 1 and sintilimab 200 mg intravenously on day 2 for 6 cycles of 21 days, followed by maintenance treatment of sintilimab 200 mg for 28 cycles of 21 days. The complete response and overall response rate after induction treatment were 59% (95%CI, 43-79%) and 68% (95%CI, 47-84%), respectively. With a median follow-up of 30 months, the 2 year progression-free and overall survival rates were 68% (95%CI, 45-83%) and 86% (95%CI, 63-95%), respectively. The most frequently grade 3/4 adverse events were neutropenia (32%, n = 7) and hypofibrinogenemia (18%, n = 4), which were manageable and led to no discontinuation of treatment. Tumor proportion score of PD-L1, peripheral blood high-density lipoprotein cholesterol, and apolipoprotein A-I correlated with good response, while PD-1 on tumor infiltrating lymphocytes and peripheral Treg cells with poor response to pegaspargase plus sintilimab treatment. In conclusion, the chemo-free regimen pegaspargase plus sintilimab was effective and safe in newly diagnosed, advanced stage NKTCL. Dysregulated lipid profile and immunosuppressive signature contributed to treatment resistance, providing an alternative therapeutic approach dual targeting fatty acid metabolism and CTLA-4 in NKTCL.
Insights
A novel chemo-free treatment combining pegaspargase and sintilimab shows promise for advanced Natural Killer T cell lymphoma (NKTCL). This combination therapy demonstrated significant response rates and manageable side effects in a phase II study.
Area of Science:
- Oncology
- Immunotherapy
- Pharmacology
Background:
- Natural Killer T cell lymphoma (NKTCL) is an aggressive malignancy with poor outcomes in advanced stages, often resistant to conventional chemotherapy.
- There is a critical need for effective and safe treatment strategies for newly diagnosed, advanced stage NKTCL patients.
Purpose of the Study:
- To evaluate the efficacy and safety of a chemo-free regimen comprising pegaspargase and the PD-1 antibody sintilimab in patients with newly diagnosed, advanced stage NKTCL.
- To identify potential biomarkers predicting response or resistance to this novel therapeutic approach.
Main Methods:
- A phase II clinical trial (NCT04096690) enrolled 22 patients with advanced stage NKTCL.
- Patients received induction treatment with pegaspargase and sintilimab for 6 cycles, followed by maintenance sintilimab for 28 cycles.
- Response rates, survival data, adverse events, and potential predictive biomarkers (PD-L1, lipid profiles, Treg cells) were assessed.
Main Results:
- The complete response rate after induction was 59%, with an overall response rate of 68%.
- Two-year progression-free survival was 68%, and overall survival was 86%.
- Common grade 3/4 adverse events included neutropenia and hypofibrinogenemia, which were manageable.
- Tumor PD-L1, HDL cholesterol, and apolipoprotein A-I correlated with favorable responses, while PD-1 on TILs and Treg cells indicated poor response.
Conclusions:
- The combination of pegaspargase and sintilimab offers an effective and safe chemo-free treatment option for newly diagnosed, advanced stage NKTCL.
- Dysregulated lipid metabolism and specific immunosuppressive signatures are implicated in treatment resistance, suggesting potential for dual targeting strategies.
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