Co-targeting of the thymic stromal lymphopoietin receptor to decrease immunotherapeutic resistance in CRLF2-rearranged Ph-like and Down syndrome acute lymphoblastic leukemia

IF 12.8 1区 医学 Q1 HEMATOLOGY
Tommaso Balestra, Lisa M Niswander, Asen Bagashev, Joseph P Loftus, Savannah L Ross, Robert K Chen, Samantha M McClellan, Jacob J Junco, Diego A Bárcenas López, Karen R. Rabin, Terry J Fry, Sarah K Tasian
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Abstract

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.

Abstract Image

共同靶向胸腺基质淋巴生成素受体,降低 CRLF2 重排的 Ph 型和唐氏综合征急性淋巴细胞白血病的免疫治疗抗药性
50%的类Ph和唐氏综合征(DS)相关B型急性淋巴细胞白血病(ALL)存在CRLF2重排,并诱导构成性激酶信号转导,目前临床研究中的JAK1/2抑制剂鲁索利替尼(ruxolitinib)可作为其靶点。虽然嵌合抗原受体 T 细胞(CART)免疫疗法在复发/难治性 B-ALL 儿童中取得了显著的缓解率,但约 50% 的 CD19CART 治疗患者会再次复发,其中许多患者的 CD19 抗原丢失。我们曾报道过胸腺基质淋巴细胞生成素受体靶向细胞免疫疗法(TSLPRCART)对CRLF2表达缺失的ALL具有临床前活性,可作为一种替代方法。在这项研究中,我们假设TSLPRCART和鲁索利替尼的组合疗法将具有更优越的活性,并首次在体外CRLF2重组ALL细胞系和体内Ph-like和DS-ALL患者衍生异种移植(PDX)模型中验证了TSLPRCART诱导的强效白血病增殖抑制作用。然而,在初始CART扩增期间同时进行TSLPRCART/ruxolitinib或CD19CART/ruxolitinib治疗会减少T细胞增殖、减弱细胞因子的产生和/或促进白血病复发,而按时间顺序/延迟ruxolitinib联合暴露可减轻这种情况。重要的是,Ruxolitinib联合用药可防止ALL PDX小鼠出现致命的TSLPRCART细胞因子相关毒性。停用鲁索利替尼后,TSLPRCART的功能在体内恢复,并在随后的ALL再挑战中被清除。这些转化研究证明了一种有效的双管齐下的治疗策略,既能减轻急性 CART 诱导的高炎症反应,又能为 CRLF2 重排的 Ph-like 和 DS-ALL 提供潜在的抗白血病 "维持性 "复发预防。
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来源期刊
Leukemia
Leukemia 医学-血液学
CiteScore
18.10
自引率
3.50%
发文量
270
审稿时长
3-6 weeks
期刊介绍: Title: Leukemia Journal Overview: Publishes high-quality, peer-reviewed research Covers all aspects of research and treatment of leukemia and allied diseases Includes studies of normal hemopoiesis due to comparative relevance Topics of Interest: Oncogenes Growth factors Stem cells Leukemia genomics Cell cycle Signal transduction Molecular targets for therapy And more Content Types: Original research articles Reviews Letters Correspondence Comments elaborating on significant advances and covering topical issues
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