Poster Presentation Melbourne Immunotherapy Spring Symposium 2025

Identification of immunological responses to blinatumomab treatment in B-Acute Lymphoblastic Leukaemia (B-ALL) patients (#134)

Joanne E Davis 1 2 , Mandy Ludford-Menting 1 2 , Yilei (Evelyn) Yang 1 2 , Shaun Fleming 3 4 , David Ritchie 1 2 4 , Rachel Koldej 1 2
  1. ACRF Translational Research Laboratory, The Royal Melbourne Hospital, Parkville, VIC, Australia
  2. Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia
  3. Alfred Hospital, Melbourne, VIC, Australia
  4. Clinical Haematology and Bone Marrow Transplantation Service, Department of Clinical Oncology and Haematology, The Royal Melbourne Hospital, Melbourne, VIC, Australia

Aim:
Blinatumomab is an anti-CD19 bispecific T cell engager designed to bring together CD3+ T cells with CD19+ malignant B cells to enable synapse formation and disease eradication of B-ALL. We hypothesised that the proportion of T cells and their ability to bind to their targets may may be a biomarker of response. In this study, we assessed the effect of blinatumomab co-administered with reduced intensity chemotherapy in newly diagnosed B-ALL patients.

 

Method:

Patients with untreated Ph-ve B-ALL aged 40-65 years were enrolled on the ALLG sponsored ALL08 study (ACTRN12617000084381) and treated with alternating cycles of blinatumomab and methotrexate/cytarabine. Peripheral blood mononuclear cells (PBMC) were collected from patients (n=32) at baseline and after C1D28, and healthy age matched donors (n=5). Immune phenotyping of PBMC (31-plex, Cytek Aurora), live video microscopy of purified T cells co-incubated with CD19+ Raji target cells +/- blinatumomab (10 ng/ml), and whole PBMC synapse assays +/- blinatumomab (BD Fortessa) were performed. Analysis was conducted using FlowJo, IMARIS, and PRISM software.

 

Results:

After 1 cycle of blinatumomab treatment, CD19+ B cells decreased and naïve CD8+TIM3+ T cells increased in the blood of B-ALL patients. Live video microscopy demonstrated reduced kinetics and number of synapses formed after C1D28, indicating impaired blinatumomab-mediated T cell function. Further analysis using the whole PBMC synapse assay indicated fewer T cell multimers bound to endogenous B cells when the tumour burden exceeded 20% of circulating PBMC. 

 

Conclusion:

Blinatumomab-driven synapse formation was reduced in patients with high B-ALL burden and resulted in increased naive CD8+ T cell frequency in the blood following one cycle of therapy. Despite ongoing T cell-B cell synapse formation there was a failure of clearance of residual B cells. Optimal blinatumomab therapeutic efficacy may require modifications of dosing schedule based on disease burden and demonstration of effective T cell engagement.