肿瘤细胞治疗研究
英文原题：Nicotinamide-Expanded Allogeneic Natural Killer Cells with CD38 Deletion, Expressing an Enhanced CD38 Chimeric Antigen Receptor, Target Multiple Myeloma Cells.
初步结果显示，几乎完全消除了自相残杀现象，自身裂解率从 mock 转染且未处理 NK 细胞的 19% 降低了 24 倍，降至 CD38 敲除 CAR NK 细胞的 0.8%。
自然杀伤（NK）细胞是癌症免疫监视的重要组成部分。它们能够提供快速而强效的免疫应答，包括直接细胞毒性和免疫系统动员，且无需抗原加工和呈递。与T细胞治疗方法相比，NK细胞可能具有更好的耐受性，并且易于进行多种基因操作。因此，NK细胞已成为广泛转化研究的焦点。Gamida Cell的烟酰胺（NAM）NK细胞培养平台为增强NK细胞的治疗潜力提供了机会。CD38是一种广泛表达于多种血液细胞表面的胞外酶，包括多发性骨髓瘤（MM）。它已被选为多种针对MM的单克隆治疗性抗体的主要靶点。单克隆抗体靶向CD38，通过多种抗体介导的机制如抗体依赖性细胞介导的细胞毒性（ADCC）、补体依赖性细胞毒性和抗体依赖性细胞吞噬作用，导致MM浆细胞裂解，显著改善复发或难治性MM患者的预后。然而，这种治疗策略存在固有局限性，例如抗CD38诱导的CD38表达NK细胞耗竭，从而阻碍ADCC。我们开发了针对MM治疗的基因工程NK细胞，其中使用CRISPR-Cas9技术敲除CD38，并通过mRNA电穿孔引入靶向CD38的增强型嵌合抗原受体（CAR）。这种联合基因方法允许增强针对CD38表达MM细胞的细胞毒性活性，同时避免NK细胞介导的自相残杀。初步结果显示，CD38敲除CAR NK细胞几乎完全消除了自相残杀，自身裂解率从mock转染且未处理NK细胞的19%降低了24倍至0.8%。此外，我们在体外观察到CD38介导的活性显著增强，导致对MM靶细胞系的裂解增加。CD38敲除CAR NK细胞在与未处理和CD38处理的MM细胞系共培养时，也表现出显著更高水平的NK活化标志物。这些经NAM培养、结合CD38敲除和添加CD38 CAR的NK细胞，代表了一种有前景的靶向MM的免疫治疗工具。
Natural killer (NK) cells are a vital component of cancer immune surveillance. They provide a rapid and potent immune response, including direct cytotoxicity and mobilization of the immune system, without the need for antigen processing and presentation. NK cells may also be better tolerated than T cell therapy approaches and are susceptible to various gene manipulations. Therefore, NK cells have become the focus of extensive translational research. Gamida Cell's nicotinamide (NAM) platform for cultured NK cells provides an opportunity to enhance the therapeutic potential of NK cells. CD38 is an ectoenzyme ubiquitously expressed on the surface of various hematologic cells, including multiple myeloma (MM). It has been selected as a lead target for numerous monoclonal therapeutic antibodies against MM. Monoclonal antibodies target CD38, resulting in the lysis of MM plasma cells through various antibody-mediated mechanisms such as antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis, significantly improving the outcomes of patients with relapsed or refractory MM. However, this therapeutic strategy has inherent limitations, such as the anti-CD38-induced depletion of CD38-expressing NK cells, thus hindering ADCC. We have developed genetically engineered NK cells tailored to treat MM, in which CD38 was knocked-out using CRISPR-Cas9 technology and an enhanced chimeric antigen receptor (CAR) targeting CD38 was introduced using mRNA electroporation. This combined genetic approach allows for an improved cytotoxic activity directed against CD38-expressing MM cells without self-inflicted NK-cell-mediated fratricide. Preliminary results show near-complete abolition of fratricide with a 24-fold reduction in self-lysis from 19% in mock-transfected and untreated NK cells to 0.8% of self-lysis in CD38 knock-out CAR NK cells. Furthermore, we have observed significant enhancements in CD38-mediated activity in vitro, resulting in increased lysis of MM target cell lines. CD38 knock-out CAR NK cells also demonstrated significantly higher levels of NK activation markers in co-cultures with both untreated and CD38-treated MM cell lines. These NAM-cultured NK cells with the combined genetic approach of CD38 knockout and addition of CD38 CAR represent a promising immunotherapeutic tool to target MM.
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