肿瘤细胞治疗研究
英文原题：Trends in Nephrology: From nihilism to targeted treatment of antibody-mediated rejection.
抗CD38抗体目前构成了治疗AMR证据最强的药物类别。
抗体介导的排斥反应（AMR）是肾移植失功的主要原因之一。传统AMR治疗由小型且往往无对照的干预性研究组成。尽管在3期试验中阻断interleukin-6通路未能预防移植物丢失，但此前的个案证据曾提示潜在获益。同样，抗CD20抗体在移植物存活方面未被证明能改善AMR结局。Imlifidase可切割所有IgG，因而也切割所有供体特异性抗体，在一项AMR研究的实验组中显示出更高的移植物丢失率。终末补体抑制剂在样本量不足的试验中疗效不一致；目前，C3抑制剂是针对AMR的补体靶向策略中一个有前景的重点。基于令人鼓舞的2期研究结果，抗CD38抗体目前代表AMR最有前景的新型治疗选择。我们进一步讨论基因工程改造的CD38敲除多靶点NK 细胞，其表达抗B细胞成熟抗原（BCMA）CAR、IL-15RF和hnCD16，在此背景下与daratumumab（抗CD38）联合给药。这种方法代表了一种比嵌合HLA抗原受体（CHAR）T细胞疗法更便宜且更安全的替代方案。CHAR T细胞在体外识别其各自靶向抗HLA I类B细胞受体时显示出高特异性。来自体内试验的定量结果尚待公布。同样，我们假设使用双特异性T细胞衔接器，如CD19 blinatumomab或BCMA teclistamab，用于治疗AMR。此外，研究从calcineurin抑制剂转换为共刺激疗法如抗CD40L抗体的临床研究可能减少dnDSA和AMR。总之，抗CD38抗体目前构成了治疗AMR证据最强的药物类别。迄今为止，大多数CD38抗体已被证明是安全的，即使在多发性骨髓瘤患者中给药数年后也是如此。
Antibody-mediated rejection (AMR) is among the leading causes of kidney transplant attrition. Traditional AMR therapy consisted of interventional studies that were small and often uncontrolled. Although a blockade of the interleukin-6 pathway failed to prevent allograft loss in a phase 3 trial, anecdotal evidence had previously suggested potential benefit. Likewise, anti-CD20 antibodies have not been shown to improve AMR outcomes in terms of graft survival. Imlifidase, which cleaves all IgGs, and hence also all donor specific antibodies, showed a higher rate of graft loss in the experimental group of an AMR study. Terminal complement inhibitors showed inconsistent efficacy in underpowered trials; currently, C3 inhibitors are a promising focus for complement-targeted strategies against AMR. Anti-CD38 antibodies currently represent the most promising novel therapy option for AMR based on encouraging phase 2 study results. We furthermore discuss genetically engineered CD38 knock-out multitarget natural killer cells, expressing anti-B cell maturation antigen (BCMA) CAR, IL-15RF and hnCD16, administered in combination with daratumumab (anti-CD38) in this context. This approach represents a cheaper and safer alternative to chimeric HLA antigen receptor (CHAR) T cell therapy. CHAR T cells showed a high specificity in recognizing their respective target anti-HLA class I B cell receptors in-vitro. Quantitative results from in-vivo trials are pending. Likewise, we hypothesize the use of bi-specific T cell engagers such as CD19 blinatumomab or BCMA teclistamab for the treatment of AMR. In addition, clinical studies investigating conversion from calcineurin inhibitors to co-stimulation therapies such as anti-CD40L antibodies may reduce dnDSAs and AMR. In summary, anti-CD38 antibodies currently constitute the drug class with the strongest evidence for AMR treatment. To date, most CD38 antibodies have been shown to be safe, even after several years of administration in patients with multiple myeloma.
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