CD34+CD19-CD22+ B-cell progenitors may underlie phenotypic escape in patients treated with CD19-directed therapies.
CD34+CD19-CD22+ B-cell progenitors may underlie phenotypic escape in patients treated with CD19-directed therapies.
复制标题
DOI：
10.1182/blood.2021014840
复制
发表时间：
2022-07-07
期刊：
影响因子：
20.3
通讯作者：
Menendez, Pablo
中科院分区：
文献类型：
--
作者：
Bueno, Clara;Barrera, Susana;Bataller, Alex;Ortiz-Maldonado, Valentin;Elliot, Natalina;O'Byrne, Sorcha;Wang, Guanlin;Rovira, Montse;Gutierrez-Aguera, Francisco;Trincado, Juan L.;Gonzalez-Gonzalez, Maria;Morgades, Mireia;Sorigue, Marc;Barcena, Paloma;Romina Zanetti, Samanta;Torrebadell, Montse;Vega-Garcia, Nerea;Rives, Susana;Mallo, Mar;Sole, Francesc;Mead, Adam J.;Roberts, Irene;Thongjuea, Supat;Psaila, Bethan;Juan, Manel;Delgado, Julio;Urbano-Ispizua, Alvaro;Maria Ribera, Josep;Orfao, Alberto;Roy, Anindita;Menendez, Pablo
本期三篇文章介绍了旨在改进复发性B细胞和T细胞急性淋巴细胞白血病(T-ALL)免疫治疗方法的临床前数据。针对复发的T-ALL的嵌合抗原受体T(CAR-T)细胞治疗由于难以识别健康T细胞上不表达的靶抗原而受到阻碍，有可能导致T细胞再生障碍和CAR-T细胞的丧失。Maciocia和他的同事发现CCR9是一种抗原，表达在85%的复发T-ALL和5%的正常T细胞上，在细胞系和患者来源的异种移植中证明了针对CCR9的CAR-T细胞具有强大的抗白血病活性，而没有任何抗凝血剂的证据。在第二篇文章中，Müler等人探索了CD47和CD38双重抗体靶向在T-ALL临床前模型中的潜力；尽管CD47不能避免再生障碍性疾病的风险，但它与daratumab联合治疗复发的T-ALL和根除MRD显示了有效性。最后，第三篇文章讨论了CD19指导的B-ALL免疫治疗后的复发，这可能是由CD19阴性白血病的复发所介导的。Bueno等人在确诊和复发的患者中发现了CD34+CD19ALL CD22+细胞；他们进一步表明CD22的表达先于CD19的表达，并且该人群具有与B-−克隆相同的遗传异常。他们提出，这可能代表了可能导致B-ALL复发的祖细胞群体，支持使用CAR-T联合疗法，可能针对CD19和CD22。在接受−定向免疫治疗的患者中，白血病前期CD34+CD19CD22+未成熟祖细胞可能是表型逃逸的原因。这项研究有助于确定CD19靶向治疗失败的B-ALL患者。CD19导向的免疫疗法使晚期B细胞急性淋巴细胞白血病(B-ALL)的治疗发生了革命性变化。尽管最初的完全缓解(CR)率令人印象深刻，但许多患者最终复发。成功接受CD19T细胞治疗的B-ALL患者最终复发，再加上CD22在B细胞发育过程中较早开始表达，表明先前存在的CD34+CD22+CD19CD19(前)-−白血病细胞代表了表型逃逸到CD19指导的免疫治疗的“早期祖细胞起源相关”机制。我们证明在B细胞发育过程中CD22的表达先于CD19的表达。70%的B-ALL患者初诊和复发的骨髓标本中存在CD34+CD19CAR−CD22+细胞，经CD19CAR T细胞治疗后∼患者中CD34+CD19CAR+细胞的比例增加了一倍。治疗前CD_(34)+CD_(19)−CD_(22)+细胞的中位数是治疗前的三倍(中位数随访24个月)。流式分选细胞群和异种移植模型的荧光原位杂交分析表明，CD34+CD19CD22+细胞存在诊断时存在的遗传异常，并在体内启动白血病的发生。我们的数据表明，白血病前期CD34+CD19CD22+祖细胞是CD19导向免疫治疗后表型逃逸的基础，并加强了正在进行的旨在将CD19/CD22双靶向作为减少CD19−复发的策略的临床研究。鼓励在临床实验室实施CD34/CD19/CD22免疫表型分型，以便在CD19靶向治疗期间对B-ALL患者进行初步诊断和后续监测。
Three article in this issue present preclinical data aimed at improving immunotherapeutic approaches for relapsed B- and T-cell acute lymphoblastic leukemia (T-ALL). Chimeric antigen receptor T (CAR-T) cell therapy directed against relapsed T-ALL is hampered by difficulty in identifying a target antigen that is not also expressed on healthy T cells, risking “fratricide” with T-cell aplasia and loss of the CAR-T cells. Maciocia and colleagues identify CCR9 as an antigen expressed on >85% of relapsed T-ALL and on <5% of normal T cells, demonstrating in cell lines and patient-derived xenografts that CAR-T cells targeting CCR9 have potent anti-leukemic activity without any evidence of fratricide. In the second article, Müller et al explore the potential of dual antibody targeting of CD47 and CD38 in a preclinical models of T-ALL; although CD47 does not avoid the risk of aplasia, it shows efficacy in combination with daratumumab in treating relapsed T-ALL and eradicating MRD. Finally, the third article addresses relapse following CD19-directed immunotherapies for B-ALL, which may be mediated by recurrence of CD19-negative leukemia. Bueno et al identify CD34+CD19−CD22+ cells in patients at diagnosis and relapse; they further show that CD22 expression precedes CD19 expression and that this population harbors the same genetic abnormalities of the B-ALL clone. They propose that this may represent a progenitor population that can give rise to B-ALL recurrence, supporting the use of combined CAR-T therapies, perhaps directed at both CD19 and CD22. Preleukemic CD34+CD19−CD22+ immature progenitors may underlie phenotypic escape in patients treated with CD19-directed immunotherapies. The study contributes to identifying patients with B-ALL at risk of failure of CD19-targeted therapy. CD19-directed immunotherapies have revolutionized the treatment of advanced B-cell acute lymphoblastic leukemia (B-ALL). Despite initial impressive rates of complete remission (CR) many patients ultimately relapse. Patients with B-ALL successfully treated with CD19-directed T cells eventually relapse, which, coupled with the early onset of CD22 expression during B-cell development, suggests that preexisting CD34+CD22+CD19− (pre)-leukemic cells represent an “early progenitor origin-related” mechanism underlying phenotypic escape to CD19-directed immunotherapies. We demonstrate that CD22 expression precedes CD19 expression during B-cell development. CD34+CD19−CD22+ cells are found in diagnostic and relapsed bone marrow samples of ∼70% of patients with B-ALL, and their frequency increases twofold in patients with B-ALL in CR after CD19 CAR T-cell therapy. The median of CD34+CD19−CD22+ cells before treatment was threefold higher in patients in whom B-ALL relapsed after CD19-directed immunotherapy (median follow-up, 24 months). Fluorescence in situ hybridization analysis in flow-sorted cell populations and xenograft modeling revealed that CD34+CD19−CD22+ cells harbor the genetic abnormalities present at diagnosis and initiate leukemogenesis in vivo. Our data suggest that preleukemic CD34+CD19−CD22+ progenitors underlie phenotypic escape after CD19-directed immunotherapies and reinforce ongoing clinical studies aimed at CD19/CD22 dual targeting as a strategy for reducing CD19− relapses. The implementation of CD34/CD19/CD22 immunophenotyping in clinical laboratories for initial diagnosis and subsequent monitoring of patients with B-ALL during CD19-targeted therapy is encouraged.
登录
查看更多内容
影响因子：
82.9
作者：
Cordoba S;Onuoha S;Thomas S;Pignataro DS;Hough R;Ghorashian S;Vora A;Bonney D;Veys P;Rao K;Lucchini G;Chiesa R;Chu J;Clark L;Fung MM;Smith K;Peticone C;Al-Hajj M;Baldan V;Ferrari M;Srivastava S;Jha R;Arce Vargas F;Duffy K;Day W;Virgo P;Wheeler L;Hancock J;Farzaneh F;Domning S;Zhang Y;Khokhar NZ;Peddareddigari VGR;Wynn R;Pule M;Amrolia PJ
通讯作者：
Amrolia PJ
影响因子：
16.6
作者：
Jacoby E;Nguyen SM;Fountaine TJ;Welp K;Gryder B;Qin H;Yang Y;Chien CD;Seif AE;Lei H;Song YK;Khan J;Lee DW;Mackall CL;Gardner RA;Jensen MC;Shern JF;Fry TJ
通讯作者：
Fry TJ
DOI：
10.1038/s41571-019-0184-6
发表时间：
2019-06
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
Shah NN;Fry TJ
通讯作者：
Fry TJ
影响因子：
5.3
作者：
Bagashev A;Sotillo E;Tang CH;Black KL;Perazzelli J;Seeholzer SH;Argon Y;Barrett DM;Grupp SA;Hu CC;Thomas-Tikhonenko A
通讯作者：
Thomas-Tikhonenko A
影响因子：
4.4
作者：
van Zelm, MC;van der Burg, M;van Dongen, JJM
通讯作者：
van Dongen, JJM