The influence of immune checkpoints on Blinatumomab-mediated effects on primary T cells

Masetti, Michael (2021): The influence of immune checkpoints on Blinatumomab-mediated effects on primary T cells. Dissertation, LMU München: Medizinische Fakultät

Abstract

Relapse and non-responsiveness to standard chemotherapy remain major causes of treatment failure in pediatric B-lineage acute lymphoblastic leukemia and are associated with dismal prognosis. The bi-specific, CD3/CD19 targeting antibody construct Blinatumomab represents a novel immunotherapeutic approach with the ability to re-direct endogenous anti-tumor activity against lymphoblastic cells. Despite encouraging clinical success of Blinatumomab, a significant subset of patients does not respond to treatment and ultimately suffer from relapse. Since the upregulation of inhibitory immune checkpoints on tumor cells represents a highly effective mechanism to undermine endogenous cancer immunosurveillance, further investigation of the immune-suppressive influence of inhibitory immune checkpoints on Blinatumomab-mediated anti-leukemic activity is urgently needed. The present study confirms Blinatumomab as a potent stimulus to enhance anti-leukemic T-cell effector functions in vitro including specific target cells lysis, T-cell proliferation and production of pro-inflammatory cytokines. Furthermore, this study provides evidence that the immune checkpoint expression by lymphoblastic cells can control Blinatumomab-mediated anti-leukemic effects in vitro. The study outlines PD‑L1 upregulation by lymphoblastic cells as a highly effective immune evasive mechanism to diminish Blinatumomab-induced anti-leukemic activity. Taken together, these findings provide further insights into the complex interactions of immune checkpoints on Blinatumomab-mediated effects which will help to develop novel immunotherapeutic strategies against pediatric leukemia. Combinatory approaches with immune checkpoint blocking antibodies may open the possibility to finally achieve the urgently needed improvement of the outcome for children with relapsed and refractory B-lineage ALL.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: Immune checkpoint, Blinatumomab, acute lymphoblastic leukemia, ALL, akut lymphatische Leukämie
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 10. November 2021
• 1. Bericht­erstatter:in: Feuchtinger, Tobias