NK 细胞疗法 SNK01 可改善阿尔茨海默病患者的认知功能长达11周

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标签：#cell therapy

在接受评估的10名患者中，与试验中最后一剂后1周的基线相比，30%的患者表现出阿尔茨海默病综合评分的临床改善。

Among 10 patients evaluated, compared with their baseline at 1 week after receiving their final dose in the trial, 30% demonstrated clinical improvement on the Alzheimer’s disease composite score.

根据公司最近发布的一份公告，总结了2023年10月24日至27日在马萨诸塞州波士顿举行的阿尔茨海默病临床试验年会上提供的数据，在第一阶段ASK-AD临床试验（NCT04678453）中，接受NKGen自体自然杀伤（NK）细胞疗法NK01治疗的阿尔茨海默病（AD）患者表现出临床改善。

Patients with Alzheimer disease (AD) treated with NKGen’s autologousnatural killer (NK) cell therapySNK01 in the phase 1 ASK-AD clinical trial (NCT04678453) showed clinical improvement, according to a recent company announcement summarizing data presented at the Clinical Trials on Alzheimer’s Disease Annual Meeting, held October 24-27, 2023, in Boston, Massachusetts.

在接受评估的10名患者中，与接受试验最终剂量后1周的基线相比，30%的患者表现出阿尔茨海默病综合评分（ADCOMS）的临床改善，60%的患者表现出稳定的ADCOMS评分，1名先前ADCOMS评分为中度的患者达到了轻度的ADCOMS评分。此外，在10名患者中，有50%至70%的患者在临床痴呆评定总分（CDR-SB），阿尔茨海默病评估量表认知分量表和简易精神状态检查（MMSE）上显示出与基线相比稳定或改善的分数。

Among 10 patients evaluated, compared with their baseline at 1 week after receiving their final dose in the trial, 30% demonstrated clinical improvement on the Alzheimer’s disease composite score (ADCOMS), 60% of patients demonstrated a stable ADCOMS score, and 1 patient who previously had an ADCOMS score classified as moderate achieved an ADCOMS score classified as mild. Furthermore, 50% to 70% of the 10 patients showed scores that were stable or improved compared with baseline on the Clinical Dementia Rating-Sum of Boxes (CDR-SB), the Alzheimer’s Disease Assessment Scale-Cognitive Subscale, and the Mini-Mental State Examination (MMSE).

在接受最后一次给药12周后，在这一点上可评估疗效的9名患者中，44%至89%的患者在所有认知评分上表现出改善或保持稳定，而他们在最后一次剂量后1周的结果。此外，在最后一次给药后1周ADCOMS评分稳定的患者中，50%在最后给药后12周保持稳定。在安全性方面，没有报告与治疗相关的不良事件。该公司还指出，SNK01在所有患者中都表现出激活和扩张。

At 12 weeks after receiving their final dose, 44% to 89% of 9 patients evaluable for efficacy at this point either showed improvement or maintained stability on all cognitive scores compared with their results at 1 week after the final dose. Additionally, 50% of the patients who had a stable ADCOMS score at 1 week after the final dose remained stable at 12 weeks after the final dose. In terms of safety, no treatment-related adverse events were reported. The company also noted that SNK01 showed activation and expansion in all patients.

单中心剂量升级研究将患者分为3个队列，他们在1x109细胞、2x109细胞或4x109细胞接受SNK01剂量。患者每3周静脉注射4次。基线检查时，5例AD被归类为轻度，3例AD被分类为中度，2例AD被划分为重度。他们基线时的CDR-SB得分范围为4至18（中位数为9）。

The single-center, dose-escalation study divided patients into 3 cohorts, and they received doses of SNK01 at either 1x109cells, 2x109cells, or 4x109cells. Patients received the therapy intravenously in 4 administrations every 3 weeks. At baseline, 5 patients had AD classified as mild, 3 patients had AD classified as moderate, and 2 patients had AD classified as severe. Their CDR-SB scores at baseline ranged from 4 to 18 (median, 9).

NKGen Biotech首席执行官Paul Y.Song医学博士说：“我们很高兴展示我们的第一阶段AD研究的最终数据，进一步证明SNK01具有良好的耐受性，并似乎减少了试验患者中的蛋白质（pTau181和Aβ42/40）和神经炎症（GFAP[神经胶质原纤维酸性蛋白]）。”，在一份声明中说。1值得注意的是，尽管基线MMSE评分中位数为14分，并且三分之二的患者接受了我们认为是次优的剂量，但使用ADCOMS评分，90%的患者在11周后表现出认知功能改善或保持稳定，这表明SNK01不仅可以减缓疾病进展。

“We are pleased to present the final data from our phase 1 AD study further demonstrating that SNK01 is well tolerated and appears to reduce both proteins (pTau181 and Aβ42/40) and neuroinflammation (GFAP [glial fibrillary acidic protein]) among trial patients,” Paul Y. Song, MD, CEO of NKGen Biotech, said in a statement.1“Remarkably, despite a median baseline MMSE score of 14 and the fact that two-thirds of our patients received what we believe to be suboptimal dosing, using the ADCOMS score, 90% of patients demonstrated improvement or maintained stable cognitive function following 11 weeks, suggesting that SNK01 may do more than simply slow disease progression.”

SNK01还在临床试验中被评估为单一疗法，以及与其他疗法（如检查点抑制剂和细胞接合剂）的联合疗法的一部分，用于治疗晚期难治性实体肿瘤患者。今年2月，SNK01被FDA批准用于治疗帕金森病患者。

SNK01 is also being evaluated in clinical trials as a monotherapy and as part of combination therapies with other treatments, such as checkpoint inhibitors and cell engagers, for the treatment of patients with advanced refractory solid tumors.2In February of this year, SNK01 was approved by the FDA for compassionate usein a patient with Parkinson disease.

“当我们首次提出使用增强型NK细胞治疗神经退行性疾病时，我们遭到了怀疑，”宋继续说。1但多亏了Angeles医院的临床团队，他们与我们合作，获得了Comisión Federal para la Protección contra Riesgos Sanitarios和研究伦理委员会的全面批准，我们能够进行这项突破性的试验，这为我们提供了宝贵的临床和生物标志物数据，无疑有助于我们获得美国试验新药（IND）中度AD患者1/2a阶段研究的批准。虽然这项第一阶段试验是一项剂量升级试验，在11周内只给4个总剂量，但我们新的IND批准要求使用更高的剂量和延长给药方案。我们非常兴奋地开始下一阶段的工作，希望为更高级的患者建立一个全新的治疗模式。”

“When we first proposed the use of our enhanced NK cells for neurodegenerative diseases, we were met with skepticism,” Song continued.1“But thanks to the clinical team at Hospital Angeles, who worked with us to get full Comisión Federal para la Protección contra Riesgos Sanitarios and Research Ethics Board approval, we were able to conduct this groundbreaking trial, which has provided us with invaluable clinical and biomarker data that undoubtedly helped us receive US investigational new drug (IND) clearance for a phase 1/2a study in patients with moderate-stage AD.

Whereas this phase 1 trial was a dose-escalation trial that only gave 4 total doses over 11 weeks, our new IND approval calls for using a higher dose and a prolonged dosing regimen. We are very excited to begin this next phase in hopes of establishing an entirely new treatment paradigm for more advanced patients.”

Nadezhda Omelchenko，医学博士，位于圣莫尼卡的南加州癌症中心的研究助理，谈到了SNK01在肉瘤中的案例研究，她于5月16日至20日在加利福尼亚州洛杉矶举行的美国基因和细胞治疗学会2023年年会上作了介绍。奥梅尔琴科详细介绍了3名患者的关键结果，他们有不同形式的耐化学药物软组织肉瘤。这些病例在剂量和其他因素方面是独特的，但在每个病例中都观察到了一些积极的结果。

Nadezhda Omelchenko, MD, a research associate at Cancer Center of Southern California in Santa Monica, spoke about case studies for SNK01 in sarcomas that she presented at the American Society of Gene and Cell Therapy 2023 Annual Meeting, held May 16-20, in Los Angeles, California.4Omelchenko went over the key results from each of the 3 patients, who had different forms of chemotherapy-resistant soft tissue sarcoma. The cases were unique in terms of dosing and other factors, but some positive results were observed in each.

奥梅尔琴科说：“这项研究的基本原理是利用人类自身的先天免疫系统来进行抗癌活动。”在这种情况下，NK细胞被用作必需的先天性免疫系统细胞。它们首先从外周血中提取，然后在体外实验室中增强和扩增，然后以增加的治疗剂量返回给患者。我们将其与免疫检查点抑制因子联合使用，该抑制因子不仅抑制T细胞的免疫抑制活性，而且还可清除ak在肿瘤微环境中，这使得它能够躲避免疫系统。据信，这两种免疫治疗药物的结合可以更好、更有效地提高一个人自身固有免疫系统的活性，这在抗癌活动中发挥着至关重要的作用。

“The rationale of the study was to use people’s own innate immune system in a manner of anticancer activity,” Omelchenko said. “In this case, NK cells were used as the essential innate immune system cells. They were first taken from the peripheral blood, then enhanced and amplified in the laboratory ex vivo, and then administered back to the patients in an increased therapeutic dose. We used it in combination with immune checkpoint inhibitors, which not only inhibit immunosuppressive activity of T cells, but also uncloak in the tumor microenvironment, which allows it to evade the immune system. It is believed the combination of these 2 immunotherapy drugs could lead to better and more effective increased activity in a person's own innate immune system, which has a crucial role in anticancer activity.”

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