共靶向胸腺基质淋巴细胞生成素受体以减少 CRLF2 重排的 Ph 样和唐氏综合征急性淋巴细胞白血病的免疫治疗耐药性

CRLF2 rearrangements occur in >50% of Ph-like and Down syndrome (DS)-associated B-acute lymphoblastic leukemia (ALL) and induce constitutive kinase signaling targetable by the JAK1/2 inhibitor ruxolitinib under current clinical investigation. While chimeric antigen receptor T cell (CART) immunotherapies have achieved remarkable remission rates in children with relapsed/refractory B-ALL, ~50% of CD19CART-treated patients relapse again, many with CD19 antigen loss.

We previously reported preclinical activity of thymic stromal lymphopoietin receptor-targeted cellular immunotherapy (TSLPRCART) against CRLF2-overexpressing ALL as an alternative approach. In this study, we posited that combinatorial TSLPRCART and ruxolitinib would have superior activity and first validated potent TSLPRCART-induced inhibition of leukemia proliferation in vitro in CRLF2-rearranged ALL cell lines and in vivo in Ph-like and DS-ALL patient-derived xenograft (PDX) models.

However, simultaneous TSLPRCART/ruxolitinib or CD19CART/ruxolitinib treatment during initial CART expansion diminished T cell proliferation, blunted cytokine production, and/or facilitated leukemia relapse, which was abrogated by time-sequenced/delayed ruxolitinib co-exposure.

Importantly, ruxolitinib co-administration prevented fatal TSLPRCART cytokine-associated toxicity in ALL PDX mice. Upon ruxolitinib withdrawal, TSLPRCART functionality recovered in vivo with clearance of subsequent ALL rechallenge. These translational studies demonstrate an effective two-pronged therapeutic strategy that mitigates acute CART-induced hyperinflammation and provides potential anti-leukemia 'maintenance' relapse prevention for CRLF2-rearranged Ph-like and DS-ALL.