Optimization of dose and regimen of letetresgene autoleucel for the treatment of synovial sarcoma: simulation of dose dependence and split dosing using QSP modeling

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Authors: Oleg Demin Jr (1), Galina Kolesova (1), Stefan Zajic (2), Lourdes Cucurull-Sanchez (3)

Affiliation: (1) InSysBio CY, Paphos, Cyprus; (2) GlaxoSmithKline, Collegeville, PA 19426, USA; (3) GlaxoSmithKline, Stevenage, Hertfordshire, UK

Background: Letetresgene autoleucel (lete-cel) is an autologous genetically modified T-cell therapy targeting NY-ESO-1 expressed by cancer cells in synovial sarcoma (SS). The aim of the work is to predict overall response rate (ORR) to lete-cel in SS for various doses and to investigate the effect of split dosing on ORR and cytokine peak levels using quantitative systems pharmacology (QSP) modeling.

Methods: The developed QSP model consists of 1 lymphodepletion including pharmacokinetics (PK) of fludarabine and cyclophosphamide, their effects on lymphocytes and IL-7 and IL-15 levels 2 ; tumor growth and microenvironment in SS including biomarkers in blood; 3 PK and distribution of lete-cel after intravenous infusion 4 ; killing of NY-ESO-1 positive cancer cells by lete-cel and activation of engineered T-cells followed by their expansion and cytokine secretion (IFNg, TNFa, IL-6). The model was calibrated against in vitro data, baseline patient disease characteristics, and lete-cel clinical longitudinal data. Validation of the model was done against lete-cel clinical data on ORR and PFS.

Results: ORR dose dependence was simulated for doses from 0.05 to 50 billion cells. Maximal ORR was 41% (95% CI: 33% - 57%). median peak IL-6 levels stayed below cytokine release syndrome thresholds. 2 – 4 Several 10 billion cell splitdose regimens were simulated: (1) 100% of dose on day 1; (2) 30% of dose on day 1 and 70% on day 8; (3) 10% on day 1, 30% on day 2, 60% on day 3; (4) 5% on day 1 and 95% on day 3. Regimen 3 showed almost similar median ORR to single dose (34.2% vs 36.7%), whereas regimens 2 and 4 showed lower median ORR (26.7% and 31.7%, respectively). All split dosing regimens resulted in lower peak levels of IL6 than single dose.

Conclusions: Maximal ORR to lete-cel in SS was predicted to be 41% (95% CI: 33% - 57%) and . The optimal spilt-dose regimen among tested was 10% of the dose on day 1, 30% on day 2 and 60% on day 3. Split-dose cell therapy regimens may provide an improved safety profile while delivering comparable efficacy compared to single dose.

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