Modulation of Target Antigen Density Improves CAR T-cell Functionality and Persistence.
Modulation of Target Antigen Density Improves CAR T-cell Functionality and Persistence.
复制标题
DOI：
10.1158/1078-0432.ccr-18-3784
复制
发表时间：
2019-09-01
期刊：
影响因子：
--
通讯作者：
Fry TJ
中科院分区：
文献类型：
--
作者：
Ramakrishna S;Highfill SL;Walsh Z;Nguyen SM;Lei H;Shern JF;Qin H;Kraft IL;Stetler-Stevenson M;Yuan CM;Hwang JD;Feng Y;Zhu Z;Dimitrov D;Shah NN;Fry TJ
针对CD22的嵌合抗原受体T细胞(CART)治疗可诱导70%的复发/难治性急性淋巴细胞白血病(ALL)患者缓解。然而，CD22-CART后的大多数缓解是短暂的，并与CD22表达的减少有关。我们评估了低抗原密度对CD22 Cart活性的影响，并提出了克服抗原逃逸的机制。使用所有CD22表达可变的细胞系，我们评估了在CD22低表达的情况下的细胞因子谱、细胞毒性和体内CART功能。我们开发了一种高亲和力的CD22汽车作为提高汽车敏感度的方法。我们还评估了Bryostatin1，一种治疗相关的药物，上调CD22和改善汽车功能。我们证明，CD22低表达对体外和体内CD22 CART功能产生负面影响，并损害体内CART的持久性。此外，白血病细胞的低抗原表达增加了顽固性CART的天真表型。增加CAR亲和力并不能改善对低抗原白血病的反应。Bryostatin1在单剂量照射后1周上调白血病和淋巴瘤细胞株上的CD22，改善CART功能和体内持久性。虽然Bryostatin1减弱了CART产生的干扰素-γ，但总体来说，CART在体外和体内的细胞毒性没有受到不利影响。最后，使用CD22CAR和Bryostein 1可导致更长的体内反应持续时间。我们证明，靶抗原调节是一种有前景的策略，可以提高白血病和淋巴瘤患者的CD22 CAR疗效和缓解持久性。
Chimeric antigen receptor T cell (CART) therapy targeting CD22 induces remission in 70% of patients with relapsed/refractory acute lymphoblastic leukemia (ALL). However, the majority of post-CD22 CART remissions are short and associated with reduction in CD22 expression. We evaluate the implications of low antigen density on the activity of CD22 CART and propose mechanisms to overcome antigen escape. Using ALL cell lines with variable CD22 expression, we evaluate the cytokine profile, cytotoxicity, and in vivo CART functionality in the setting of low CD22 expression. We develop a high-affinity CD22 CAR as an approach to improve CAR sensitivity. We also assess Bryostatin1, a therapeutically relevant agent, to upregulate CD22 and improve CAR functionality. We demonstrate that low CD22 expression negatively impacts in vitro and in vivo CD22 CART functionality and impairs in vivo CART persistence. Moreover, low antigen expression on leukemic cells increases naïve phenotype of persisting CART. Increasing CAR affinity does not improve response to low-antigen leukemia. Bryostatin1 upregulates CD22 on leukemia and lymphoma cell lines for 1 week following single-dose exposure, improves CART functionality and in vivo persistence. While Bryostatin1 attenuates IFN-gamma production by CART, overall in vitro and in vivo CART cytotoxicity is not adversely affected. Finally, administration of Bryostain1 with CD22 CAR results in longer duration of in vivo response. We demonstrate that target antigen modulation is a promising strategy to improve CD22 CAR efficacy and remission durability in patients with leukemia and lymphoma.