P09.01 The use of FDA approved JAK, mTOR and Src inhibitors to regulate T cell-bispecific antibody-induced cytokine release while not preventing T cell cytotoxicity

Background T cell bispecific antibodies (TCBs) are potent engagers, harboring a 2+1 format with one binder to the CD3ε chain and two binders specific tumor antigens. Crosslinking of CD3 antigens triggers activation proliferation, cytokine release killing. TCB treatment is sometimes associated safety liabilities due on-target on-tumor or off-tumor cytotoxicity release. Off-tumor activity may occur if targeted expressed on healthy cells, which potentially result in tissue damages compromise patient’s safety. Patients treated TCBs also experience Cytokine Release Syndrome (CRS), characterized by fever, hypotension respiratory deficiency pro-inflammatory cytokines such as IL-6, TNF-α, IFN-γ, IL-1β. Tyrosine kinases Src, mTOR JAK1/2 involved downstream signaling pathways after engagement receptor. Materials Methods 52 FDA approved kinase inhibitors were screened presence cells activated coated plates, mimicking stimulation. JAK selected based their capacity prevent both, proliferation. Using an vitro model target killing human peripheral blood mononuclear stimulated TCBs, we validated effects mTOR, Src TCB-induced activation, In vivo , effect was confirmed humanized NOD scid gamma (NSG) mice engrafted hematopoietic stem CD19-TCB. Results line previous reports for CAR-T dasatinib (a src inhibitor) found fully switch off functionality well other bosutinib ponatinib. contrast, temsirolimus, sirolimus everolimus (mTOR inhibitors) ruxolitinib, baricitinib, tofacitinib, fedratinib (JAK1/2 more potently without blocking TCB-mediated Conclusions These results provide evidence that mechanisms TCB-dependent can be uncoupled. The FDA-approved could used mitigate CRS whereas inhibitor rather stand potential antidote high-grade CRS. Disclosure Information G. Leclercq: A. Employment (full part-time); Modest; Roche. E. Ownership Interest (stock, stock options, patent intellectual property); H. Haegel: Schneider: Giusti: V. Pulko: Toso: T. Zimmermann: L. Green: N. Steinhoff: J. Sam: M. Bacac: P. Umaña: C. Klein: