肿瘤细胞治疗研究
英文原题：Preclinical development of three novel CARs targeting CD79b for the treatment of non-Hodgkin's lymphoma and characterization of the loss of the target antigen.
基于特异性、疗效和靶抗原丢失，CARLY3 代表了一种针对非霍奇金淋巴瘤的潜在新型 CAR 治疗。
背景：靶向CD19的嵌合抗原受体（CAR）T细胞输注治疗非霍奇金淋巴瘤（NHL）取得了极佳应答，促使抗CD19 CAR-T（CART19；阿基仑赛和lisocabtagene maraleucel）获批用于成人复发/难治性NHL二线治疗。遗憾的是，仍有60%的患者在CART19治疗后复发，原因包括肿瘤细胞靶抗原CD19丢失（见于27%的复发患者）、CAR-T持久性不足及肿瘤微环境抑制等其他机制。临床上为防止靶抗原丢失，采用序贯治疗方式使用靶向CD20或CD22的CAR，但随后也出现第二种抗原丢失，提示应考虑靶向不易丢失的其他抗原。CD79b表达于NHL细胞，也是抗体药物偶联物（ADC）的治疗靶点，但ADC疗效有限，提示靶向CD79b的CAR可能改善治疗效果。 方法：研究设计了3种新型CD79b CAR，命名为淋巴瘤CAR（CARLY）1、2和3。比较其疗效、表型和炎症特征与可治疗NHL的CART19（ARI0001）及CARTBCMA（ARI0002h），并分析靶抗原CD79b、CD19和B细胞成熟抗原（BCMA）丢失情况。 结果：研究发现CARLY2和CARLY3对B细胞上的CD79b具有高亲和力和特异性。体外所有CAR-T细胞对NHL疗效相近，且在CD19阴性复发NHL模型中仍保留疗效。体内CARLY3效果最佳。靶抗原丢失分析显示，CARLY细胞可诱导NHL细胞下调CD79b和CD19，同时这些抗原发生抗原啃噬并转移至T细胞；这一现象在对CD79b和CD19亲和力最高的CARLY2中最明显，支持选择CARLY3开发NHL新疗法。最后，研究者构建了基于CD79b和BCMA双靶向的CAR疗法，以避免靶抗原丢失。该疗法疗效最高，且未导致靶抗原丢失。 结论：基于特异性、疗效和靶抗原丢失结果，CARLY3是NHL潜在的新型CAR治疗方案。
BACKGROUND: Infusion of T cells modified with a chimeric antigen receptor (CAR) targeting CD19 has achieved exceptional responses in patients with non-Hodgkin's lymphoma (NHL), which led to the approval of CAR targeting CD19 (CART19) (Axi-cel and Liso-cel) as second line of treatment for adult patients with relapsed/refractory NHL. Unfortunately, 60% of patients still relapse after CART19 due to either a loss of expression of the target antigen (CD19) in the tumor cell, observed in 27% of relapsed patients, a limited CAR-T persistence, and additional mechanisms, including the suppression of the tumor microenvironment. Clinic strategies to prevent target antigen loss include sequential treatment with CARs directed at CD20 or CD22, which have caused loss of the second antigen, suggesting targeting other antigens less prone to disappear. CD79b, expressed in NHL, is a target in patients treated with antibody-drug conjugates (ADC). However, the limited efficacy of ADC suggests that a CAR therapy targeting CD79b might improve results. METHODS: We designed three new CARs against CD79b termed CAR for Lymphoma (CARLY)1, 2 and 3. We compared their efficacy, phenotype, and inflammatory profiles with CART19 (ARI0001) and CARTBCMA (ARI0002h), which can treat NHL. We also analyzed the target antigen's expression loss (CD79b, CD19, and B-cell maturation antigen(BCMA)). RESULTS: We found that CARLY2 and CARLY3 had high affinity and specificity towards CD79b on B cells. In vitro, all CAR-T cells had similar anti-NHL efficacy, which was retained in an NHL model of CD19 - relapse. In vivo, CARLY3 showed the highest efficacy. Analysis of the loss of the target antigen demonstrated that CARLY cells induced CD79b and CD19 downregulation on NHL cells with concomitant trogocytosis of these antigens to T cells, being most notorious in CARLY2, which had the highest affinity towards CD79b and CD19, and supporting the selection of CARLY3 to design a new treatment for patients with NHL. Finally, we created a CAR treatment based on dual targeting of CD79b and BCMA to avoid losing the target antigen. This treatment showed the highest efficacy and did not cause loss of the target antigen. CONCLUSIONS: Based on specificity, efficacy, and loss of the target antigen, CARLY3 represents a potential novel CAR treatment for NHL.
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