The primary objective of this study is to evaluate the safety and clinical activity of NKG2D-based CAR-T cells infusion in the treatment of relapsed/refractory NKG2DL+ solid tumors.

开始日期2020-03-17

申办/合作机构

九江学院附属医院

[+1]

NCT03415100 / Unknown status临床1期IIT

Pilot Study of NKG2D-Ligand Targeted CAR-NK Cells in Patients With Metastatic Solid Tumours

This is a single-centre, single arm, open-label pilot study to evaluate the safety and feasibility of CAR-NK cell treatment in subjects with metastatic solid tumours. Autologous or allogeneic NK cells are transfected by mRNA electroporation to prepare investigational CAR-NK cells with transiently enhanced specificity and activity against NKG2D-ligand expressing cancer cells.

开始日期2018-01-02

申办/合作机构

The Third Affiliated Hospital of Guangzhou Medical University

100 项与 NKG2D CAR-NK cells(The Third Affiliated Hospital of Guangzhou Medical University) 相关的临床结果

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100 项与 NKG2D CAR-NK cells(The Third Affiliated Hospital of Guangzhou Medical University) 相关的专利（医药）

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项与 NKG2D CAR-NK cells(The Third Affiliated Hospital of Guangzhou Medical University) 相关的文献（医药）

2023-07-01·Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology

[Construction of NKG2D CAR-NK92 cells and its killing effect on multiple myeloma cells].

Article

作者: Ye, Sishi ; Ke, Shanwen ; Wei, Cheng ; Long, Jing ; Duan, Deming ; Zheng, Rong ; Gao, Jimin

Objective This study aims to construct and identify the chimeric antigen receptor NK92 (CAR-NK92) cells targeting NKG2D ligand (NKG2DL) (secreting IL-15Ra-IL-15) and verify the killing activity of NKG2D CAR-NK92 cells against multiple myeloma cells. Methods The extracellular segment of NKG2D was employed to connect 4-1BB and CD3Z, as well as IL-15Ra-IL-15 sequence to obtain a CAR expression framework. The lentivirus was packaged and transduced into NK92 cells to obtain NKG2D CAR-NK92 cells. The proliferation of NKG2D CAR-NK92 cells was detected by CCK-8 assay, IL-15Ra secretion was detected by ELISA and killing efficiency was detected by lactate dehydrogenase (LDH) assay. The molecular markers of NKp30, NKp44, NKp46, the ratio of apoptotic cell population, CD107a, and the secretion level of granzyme B and perforin were detected using flow cytometry. In addition, the cytotoxic mechanism of NKG2D CAR-NK92 cells on the tumor was verified by measuring the degranulation ability. Moreover, after NKG2D antibody inhibited effector cells and histamine inhibited tumor cells, LDH assay was utilized to detect the effect on cell-killing efficiency. Finally, the multiple myeloma tumor xenograft model was constructed to verify its anti-tumor activity in vivo. Results Lentiviral transduction significantly increased NKG2D expression in NK92 cells. Compared with NK92 cells, the proliferation ability of NKG2D CAR-NK92 cells was weaker. The early apoptotic cell population of NKG2D CAR-NK92 cells was less, and NKG2D CAR-NK92 cells had stronger cytotoxicity to multiple myeloma cells. Additionally, IL-15Ra secretion could be detected in its culture supernatant. NKp44 protein expression in NKG2D CAR-NK92 cells was clearly increased, demonstrating an enhanced activation level. Inhibition test revealed that the cytotoxicity of CAR-NK92 cells to MHC-I chain-related protein A (MICA) and MICB-positive tumor cells was more dependent on the interaction between NKG2D CAR and NKG2DL. After stimulating NKG2D CAR-NK92 cells with tumor cells, granzyme B and perforin expression increased, and NK cells obviously upregulated CD107α. Furthermore, multiple myeloma tumor xenograft model revealed that the tumors of mice treated with NKG2D CAR-NK92 cells were significantly reduced, and the cell therapy did not sensibly affect the weight of the mice. Conclusion A type of CAR-NK92 cell targeting NKG2DL (secreting IL-15Ra-IL-15) is successfully constructed, indicating the effective killing of multiple myeloid cells.

2020-10-01·Cancer Immunology, Immunotherapy2区 · 医学

NKG2D-Fc fusion protein promotes antitumor immunity through the depletion of immunosuppressive cells

2区 · 医学

Article

作者: Feng, Po-Hao ; Hung, Chien-Fu ; Lam, Brandon ; Farmer, Emily ; Tseng, Ssu-Hsueh ; Cheng, Max A ; Kung, Yu-Jui

A major factor impeding the success of numerous therapeutic approaches in cancer is the immunosuppressive nature of the tumor microenvironment (TME). Hence, methods capable of reverting tumor immunosuppression through depletion or reprogramming of myeloid-derived suppressive cells (MDSCs) and regulatory T cells (Tregs) are of great clinical need. Here, we explore NKG2D-Fc as a modality to modulate antitumor immunity through the depletion of immunosuppressive MDSCs and Tregs in the TME. We have generated the NKG2D-Fc fusion protein and characterized its potential to mediate tumor control and overall survival in LL2 and MC38 murine models. Upon treatment of LL2 or MC38 tumor-bearing mice with NKG2D-Fc, we observe significant tumor control and enhanced survival compared to Fc control. When characterizing MDCSs and Tregs from tumor-bearing mice, we observe clear expression of NKG2D-ligand RAE1γ and subsequent binding of NKG2D-Fc fusion protein to both MDSCs and Tregs. Examining the immune profile of mice treated with NKG2D-Fc reveals significant depletion of MDSCs and Tregs in the TME, as well as an increase in NK cells likely due to the reversed suppressive TME. In conclusion, NKG2D-Fc induces antitumor immunity and tumor control through the depletion of MDSCs and Tregs, subsequently providing a niche for the infiltration and expansion of proinflammatory cells, such as NK cells. Strategies capable of modulating the immunosuppressive state in cancer are in high clinical demand. NKG2D-Fc is a simple, single tool capable of depleting both MDSCs and Tregs and should be further investigated as a therapeutic agent for the treatment of cancer.

2020-07-01·Immunotherapy4区 · 医学

Experimental Treatment of Colorectal Cancer in Mice with Human T Cells Electroporated with NKG2D RNA CAR

4区 · 医学

Article

作者: Chi, Zhixia ; Zhu, Jianqing ; Ng, Yu-Yang ; Xu, Xuehu ; Wang, Shu ; Chen, Can ; Li, Zhendong ; Ang, Wei-Xia ; Wang, Junjian ; Tay, Johan CK

Aim: Peritoneal metastasis is often present in end-stage neoplastic diseases, including recurrent colorectal cancer and is associated with decreased overall survival. Novel methods are needed. Materials & methods: We constructed first-, second- and third-generation chimeric antigen receptors (CARs) specific for NKG2D ligands and modified human T cells with mRNA electroporation. Results: NKG2D CAR expression was detectable for at least 6 days postelectroporation and mediated efficient cytotoxicity against NKG2DL+ tumor cells, but not NKG2DL-cells. Multiple infusions of the first-generation CAR-T cells into immunodeficient mice bearing established peritoneal colorectal xenografts led to significantly reduced tumor burden. Conclusion: mRNA CAR is an economical way to test new CARs and potentiates controlling on-target/off-tumor toxicity and cytokine storms. The use of NKG2D RNA CARs to treat colorectal peritoneal metastasis warrants further investigation.

项与 NKG2D CAR-NK cells(The Third Affiliated Hospital of Guangzhou Medical University) 相关的新闻（医药）

2023-10-21

·生物探索

抗衰老CAR-T细胞可在大型动物体内追捕并消除衰老细胞

尽管衰老在肿瘤抑制、伤口愈合以及可能的胚胎发育中发挥着有益的作用，但衰老细胞在组织中的异常积累会导致与年龄相关的慢性疾病和退行性疾病。为了解决这个问题，已经开发了senolytics，主要使用针对衰老细胞的化学药物。这些senolytics已被证明可以使衰老的组织恢复活力并延长小鼠的寿命。然而，由于衰老细胞的异质性，仍有必要开发更多的senolytics。细胞衰老以稳定的细胞周期停滞为特征，在衰老和年龄相关病理中发挥着重要作用。消除衰老细胞使衰老组织恢复活力，并改善与年龄相关的疾病。2023年8月16日，四川大学赵旭东及明尼苏达大学邓义斌共同通讯在Science Translational Medicine 在线发表了题为“NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates”的研究论文，该研究揭示NKG2D-CAR T细胞消除衰老小鼠和非人灵长类动物的衰老细胞。该研究发现，在体外衰老细胞中，无论诱导细胞衰老的刺激如何，以及在体内衰老小鼠和非人灵长类动物的各种组织中，自然杀伤细胞2族成员D配体（NKG2DL）都会上调。该研究开发并证明了靶向人NKG2DL的嵌合抗原受体（CAR）T细胞在体外选择性且有效地减少由致癌应激、复制应激、DNA损伤或P16INK4a过表达诱导的衰老的人类细胞。用小鼠NKG2D-CAR T细胞靶向衰老细胞减轻了多种衰老相关的病理，并改善了辐照和衰老小鼠的身体表现。携带人NKG2D CAR的自体T细胞有效地删除了老年非人类灵长类动物中自然存在的衰老细胞，没有任何观察到的不良反应。总之，研究结果表明，NKG2D-CAR T细胞可以作为衰老和衰老引起的年龄相关疾病的有效和选择性的促衰老剂。特异性靶向细胞表面抗原的免疫疗法在治疗逃避内源性免疫监测的疾病（如癌症）方面显示出有希望的结果。使用这种方法，一种潜在的破坏衰老细胞的免疫治疗策略是通过疫苗接种。例如，一种靶向糖蛋白非转移性黑色素瘤蛋白B（GPNMB）的疫苗已被证明可以清除动脉粥样硬化小鼠的衰老血管内皮细胞和白细胞。一种针对CD153的疫苗也被发现可以耗尽高脂肪饮食诱导的肥胖小鼠的衰老T细胞。最近的一项研究使用senolytic嵌合抗原受体（CAR）T细胞靶向表达尿激酶型纤溶酶原激活物受体（uPAR）的衰老细胞。uPAR-CAR T细胞治疗通过选择性消除丝裂原活化蛋白激酶（MEK）和细胞周期蛋白依赖性激酶4/6（CDK4/6）抑制剂治疗诱导的衰老肿瘤细胞，延长了携带肺腺癌的小鼠的生存期。CAR T细胞还通过去除四氯化碳或饮食诱导的表达uPAR的衰老细胞来减轻小鼠的肝纤维化。尽管NKG2DL在衰老细胞中高度表达，而在正常细胞中不表达，但表达NKG2DL的衰老细胞逃脱了内源性自然杀伤（NK）细胞介导的先天免疫清除。因此，研究者进行了一项研究，以确定NKG2D-CAR T细胞的过继转移是否可以选择性和有效地消除表达NKG2DL的衰老细胞，并探索它们在靶向表达NKG2DLs的天然衰老细胞中的促衰老作用，潜在地延缓或阻断体内衰老表型。该研究登上本期Science Translational Medicine 杂志封面该研究表明，NKG2D-CAR T细胞可以通过选择性和有效地消耗衰老小鼠和非人类灵长类动物体内表达NKG2DL的衰老细胞，安全地用作促衰老剂。此外，在两个独立的衰老小鼠模型中使用小鼠NKG2D-CAR T细胞逆转了衰老相关表型，突出了它们在治疗衰老和年龄相关疾病方面的潜力。mNKG2D-CAR T 细胞清除自然衰老小鼠体内表达 NKG2DLs 的衰老细胞（图源自Science Translational Medicine ）目前，基于NKG2D的CAR T细胞已经在各种类型的癌症中进行了临床试验，并在人类中显示出良好的安全性和耐受性。未观察到剂量限制性毒性、细胞因子释放综合征或自身免疫反应，直到每2周将剂量增加到每次注射3×108个CAR T细胞，持续三次给药，所有这些都通过标准治疗解决。在该研究中，NKG2D-CAR T细胞在辐射诱导和自然衰老的小鼠中有效地消除了衰老细胞，并改善了与年龄相关的器官功能下降，而没有明显的副作用。当用1×106/kg的剂量治疗时，非人类灵长类动物只经历了短暂的体重减轻，但此后在没有任何额外治疗的情况下恢复了。总之，研究者基于细胞的研究和动物实验有力地支持了工程化NKG2D-CAR T细胞作为选择性、有效和安全的senolytics的功能。尽管NKG2D-CAR T细胞在癌症临床试验中显示出良好的安全性，但通过临床研究彻底研究其在老年人中的安全性和潜在毒性至关重要。NKG2DLs在老年人的衰老细胞中高度表达，该研究表明，NKG2D-CAR T细胞在老年小鼠和非人灵长类动物中没有表现出明显的毒性。这些发现表明，携带 NKG2D-CAR的工程化T细胞的过继转移，特别是靶向表达NKG2DLs的天然衰老细胞，可能会对老年医学领域产生影响。文章来源“iNature”责编|文竞择校对|文竞择End往期精选围观历史性突破！不需卵子和精子就可以合成人类胚胎热文富豪用儿子血浆“回春”科学吗？Science：血液牛磺酸缺乏驱动衰老热文世界首例！35岁的她，通过机器人操刀移植的子宫，成功诞下宝宝热文为了避免心脏骤停，53岁的他成为“第一个”植入开创性除颤器的心脏病患者热文首次披露！175家生物制药公司的薪资数据：薪资中位数达20万美元点击“阅读原文”，了解更多~

免疫疗法细胞疗法疫苗临床研究

2023-05-13

·生物制品圈

CAR-T细胞疗法在在实体瘤治疗中的挑战与机遇

在过去的十年中，CAR-T(嵌合抗原受体细胞疗法)已经成为一种有前途的免疫治疗方法来对抗癌症。这种方法由基因工程修饰的免疫细胞组成，表达一种表面受体，称为CAR，专门针对肿瘤细胞表面表达的抗原。在血液系统恶性肿瘤，如白血病、骨髓瘤和非霍奇金B细胞淋巴瘤中，CAR-T细胞疗法已显示出治疗化疗难治性患者的疗效。然而，这种疗法在实体瘤中的价值仍然不确定，并且受到几个障碍的限制，包括有限的肿瘤浸润能力，免疫抑制肿瘤微环境的存在，会产生一定的不良反应。随着研究的深入，越来越多的CAR细胞疗法如 CAR-NK(自然杀伤细胞)、CAR-M(巨噬细胞)，展现出应对实体肿瘤的疗效。本文综合讨论CAR-T、CAR-NK和CAR-M细胞在实体肿瘤中的新作用。并且比较了CAR-NK和CAR-M细胞相对于CAR-T细胞的优缺点。前言癌症发病率和死亡率不断上升，包括手术、放疗和化疗在内的传统治疗方法存在重大缺陷，许多转移性或复发性疾病患者仍然面临比较差的治疗效果。在过去的十年中，基于分子医学和免疫肿瘤学的发展，各种靶向治疗有了很大的发展，使得精准医学的发展成为一种更特异性并且毒性更小的癌症治疗方法。抗肿瘤免疫疗法主要是通过调节免疫系统增强其识别和破坏恶性肿瘤细胞的能力，为癌症治疗提供了重大进展。一种广泛成功的抗肿瘤细胞免疫治疗方法包括工程免疫细胞表达能够识别肿瘤细胞表面表达的抗原并摧毁它们的细胞表面受体。随后，基因修饰的免疫细胞通过嵌合抗原受体(Chimeric Antigen Receptor, CAR)被重定向到肿瘤细胞。目前，已批准的CAR-T细胞治疗靶点主要是针对多发性骨髓瘤B细胞成熟抗原(BCMA)，以及针对各种淋巴细胞恶性肿瘤的B细胞抗原CD19。根据已发表的抗BCMA CAR-T细胞临床试验，61例复发/难治性多发性骨髓瘤患者的完全缓解率达到29%至60%。靶向CD19的CAR-T细胞可使高达85%的急性淋巴细胞白血病患者获得初始完全缓解，高达100%的难治性或复发性B细胞急性淋巴细胞白血病患者获得完全缓解。从实体瘤的角度来看，利用CAR-T细胞治疗实体肿瘤的临床试验正在进行中，包括胶质母细胞瘤、肺癌、肝癌、胃癌、肾癌、前列腺癌等。这种免疫治疗方法产生了有希望的临床结果。然而，它也显示出一些根本性的局限性，如细胞毒性T细胞难以浸润肿瘤，实体瘤细胞分泌的趋化因子异常导致T细胞募集不足到肿瘤部位，以及免疫抑制肿瘤微环境。此外，CAR-T细胞有一定副作用，包括，靶外肿瘤毒性和细胞因子释放综合征。此外，CAR-T细胞诱导的其他毒性，如肿瘤裂解综合征、神经毒性、细胞减少等也是该疗法的常见局限性。为了克服这些障碍，目前正在研究各种创新战略。此外，科学家们正在寻找替代的免疫效应细胞，这些细胞可以与CAR一起进行工程设计，用于抗肿瘤细胞免疫治疗。随着研究的深入，研发人员将研究重点从CAR-T扩展到CAR-NK和CAR-M细胞免疫治疗。本文就CART、CAR-NK和CAR-M细胞在实体瘤患者治疗中的临床应用现状、面临的挑战和前景进行了讨论。我们还强调了CAR-NK和CAR-M细胞相对于CAR-T细胞的潜在优势。图1 CAT-CELL作用机制示意图CAR-T细胞在实体瘤中的应用以及挑战近年来，CAR修饰的T细胞在治疗B细胞白血病和淋巴瘤方面表现出良好的效果，证明了其抗癌治疗潜力。两种CAR-T细胞疗法Tisagenlecleucel和Axicabtagen-ciloleucel已被EMA和FDA批准用于治疗复发或难治性弥漫性大B细胞淋巴瘤患者。另外两种产品也被批准用于这些适应症:套膜淋巴瘤和，滤泡性淋巴瘤。这一成功在很大程度上是由于选择了靶标B细胞标记CD19，以不依赖MHC的方式产生针对恶性B细胞的T细胞免疫应答。这些在血液学恶性肿瘤治疗方面的重大突破，使得越来越多的研究人员尝试CAR-T细胞应用于实体肿瘤的治疗。如图一所示，目前有多种针对实体瘤的CAR-T疗法处于临床实验或者获批上市。图2 CAR-T针对实体瘤的常用靶点靶向HER2的CAR-T疗法：在一项I/ II期临床研究中，使用HER2-CAR-T细胞治疗19例HER2阳性肉瘤(16例骨肉瘤、1例原始神经外胚层肉瘤、1例尤因肉瘤和1例原纤维母细胞小圆细胞瘤)获得较好的临床实验结果。在本研究中，19例患者的中位总生存期为10.3个月 (从5.1个月到29.1个月)。大剂量CAR-T细胞治疗后，除1例患者出现高烧外，未观察到任何不良事件。此外，一项针对17例胶质母细胞瘤患者的HER2特异性CAR-T细胞治疗的I期研究报告了对CAR-T细胞给予剂量的巨大耐受性，治疗后8例患者和诊断后24.5个月的中位总生存期(OS)为11.1个月。靶向GD2的CAR-T疗法：在神经母细胞瘤细胞中，GD2是高表达的，可能被认为是CAR-T细胞的潜在靶点。一项评估GD-2 CAR-T细胞对11例神经母细胞瘤患者疗效的I期临床试验(NCT00085930)显示，3例患者完全缓解。靶向ROR1的CAR-T疗法：ROR1也是CAR-T细胞治疗的候选靶点，它在许多淋巴和上皮恶性肿瘤表面表达。一项I临床实验结果表明，靶向ROR1的CAR-T疗法具有较好的安全性。靶向EGFR的CAR-T疗法：表皮生长因子受体（EGFR）在实体瘤的发展和进展中起着重要作用，并已成为不同类型癌症的重要治疗靶点，如非小细胞肺癌、乳腺癌、胃食管癌和结直肠癌。此外，已经对靶向EGFR的CAR-T细胞进行了许多临床试验，用于治疗EGFR阳性的实体瘤。对11例EGFR+难治/复发非小细胞肺癌（NSCLC）患者进行EGFR-CAR-T细胞治疗的一期临床试验表明，2例患者获得部分缓解，5例患者病情稳定2至8个月，无严重毒性。靶向CEA的CAR-T疗法：已知高水平的癌胚抗原（CEA）与癌症预后不良有关。因此，CEA已成为治疗肺癌、乳腺癌、胰腺癌和胃癌的靶向药物，被认为是最有希望治疗结直肠癌（CRC）的靶点之一。一项针对转移性CRC中表达的CEA的CAR-T细胞治疗的I期递增剂量试验报告称，10名患者中有7名病情稳定，持续时间长达30周，2名患者肿瘤缩小，无不良事件。靶向CD133的CAR-T疗法：CD133被广泛用作鉴定CRC干细胞和内皮祖细胞的标志物。它还可用于预测CRC的肿瘤进展、患者生存率和放化疗抵抗，是各种肿瘤类型中癌症干细胞（CSC）最具特征性的标记物之一，包括肝细胞癌（HCC）。在一项I/II期临床试验中，对21名晚期肝细胞癌患者给予CD133 CAR-T细胞。这项研究证明了抗肿瘤的疗效和较低的治疗相关毒性。在21名可评估的患者中，1例出现部分反应，14例病情稳定2至16.3个月，6例在给予CAR-T细胞后病情进展。只有4名患者出现3级高胆红素血症，2名患者出现三级贫血，无其他严重不良事件。靶向的CAR-T疗法：Claudin18.2是Claudin-18的一种胃特异性亚型，在70%的原发性胃癌及其转移中表达。它被认为是治疗这些恶性肿瘤的潜在靶点。CT041是一种抗CLDN18.2 CAR-T细胞产品，已获得美国食品药品监督管理局的研究新药（IND）批准，用于CLDN18.2分泌型胃、胰腺和胃食管交界腺癌患者。IND清除率得到了一项I期试验（NCT03874897）的支持，该试验发现Claudin18.2 CAR-T细胞在癌症患者中的总有效率和疾病控制率分别为57.1%和75.0%，6个月的总生存率为81.2%。未报告严重不良事件。CAR-T疗法面临的挑战：CAR-T细胞治疗实体瘤的主要挑战包括识别真正特异性的肿瘤抗原作为靶点，克服肿瘤抗原逃逸，提高CAR-T细胞对肿瘤的浸润和扩增，以及它们在敌对肿瘤微环境中的持久性和功能。CAR-NK细胞在实体瘤中的应用考虑到CAR-T细胞的缺点，有必要研究用于CAR治疗的其他免疫细胞，由于NK细胞具有非MHC限制性识别、较强浸润肿瘤组织的能力、细胞溶解能力、和较小的毒副作。因此，CAR-NK细胞可以被认为是治疗实体瘤的潜在有效手段。包括到目前为止，只有少数临床研究评估了基于NK92、PB-NK和UCB-NK的CAR-NK细胞产物，对一些常见的肿瘤靶点如ROBO1、NKG2D、MSLN、HER2和MUC1的作用。MUC-1特异性CAR-NK细胞被设想用于多发复发或难治性实体瘤治疗。在这项研究中，在8名可评估的患者中，有7名患者病情稳定，无严重不良事件。此外，一项I期临床试验研究了NKG2D CAR-NK92细胞治疗复发/难治性实体瘤的效果。目前，一项I期临床试验正在招募转移性实体瘤患者，以评估NKG2DL靶向CAR-NK细胞的安全性。CAR-M细胞在实体瘤中的应用目前，持续的研究正试图确定靶向实体瘤的理想CAR细胞类型。巨噬细胞由于其吞噬功能、抗原呈递和对肿瘤微环境的自然渗透，最近已成为治疗实体瘤的竞争候选物。与CAR-NK类似，CAR-M可以从不同的来源产生，包括外周血、iPSC和人类白血病单核细胞系THP-1。PBMC衍生的M1巨噬细胞的特征是其重要的促炎因子产生，如IL-8、IL-6和TNF-α，以及炎性表面标志物的显著表达，如钠尿肽受体（NPR）、CD14和CD68。iPSCs可被诱导为表达CAR的巨噬细胞（CAR-IMAC），发挥先天免疫功能，如M2表型以抗原依赖的方式重新极化为促炎M1，分泌免疫相关细胞因子，以及吞噬作用和抗肿瘤能力。此外，THP-1细胞在受到脂多糖（LPS）和IFN-γ刺激后可以产生M1巨噬细胞，并且易于培养和分化为巨噬细胞。总之，与CAR-T细胞不同，CAR-M可以使用几种可靠的来源产生。作为一个额外的优势，CAR-M的GvHD风险较低。因此，CAR-M方法可能是一种有吸引力的实体瘤异基因细胞免疫疗法。增强CAR细胞功能的潜在联用疗法如图三所示，CAR-T细胞可以与化疗、放疗、溶瘤病毒以及免疫检查点抑制剂联用来增加疗效。图3 CAR-T治疗与其他疗法潜在联用治疗方案联合化疗当以低剂量给药时，化疗发挥免疫调节作用；它促进树突细胞活化和肿瘤抗原向CAR-T细胞呈递，抑制性免疫细胞，导致CAR-T细胞的持久性增加，并通过促进颗粒酶B渗透到肿瘤细胞中使肿瘤细胞对CAR-T细胞活性敏感。最近有研究表明化疗与CAR-T细胞治疗相结合具有积极作用。这种联合治疗可以解决CAR-T细胞肿瘤转移到TME的问题，从而产生更明显的抑瘤反应，并增加肿瘤排斥反应率，从而提高生存率。联合放疗使用：放射治疗可以通过凋亡和坏死直接杀死癌症细胞，从而诱导树突状细胞成熟和活化，并促进肿瘤抗原的提呈。辐射后，损伤相关分子模式（DAMPS）和INF-γ被释放，导致CAR-T细胞向肿瘤的迁移和浸润增加，因此，CAR-T细胞治疗与放射治疗相结合发挥协同抗肿瘤作用。联合溶瘤病毒使用：另一种组合策略是CAR-T细胞与溶瘤病毒的组合。这种组合克服了限制CAR-T细胞单独治疗疗效的挑战。首先，病毒可以突破肿瘤细胞，这对CAR-T细胞治疗来说是一项艰巨的任务。其次，溶瘤病毒可以通过破坏一些实体瘤用来逃避免疫系统攻击的分子屏障来诱导肿瘤消退。这种作用可以增强CAR-T细胞向肿瘤部位的浸润。第三，溶瘤病毒使免疫抑制TME恢复到促炎环境，导致CAR-T细胞的增殖和存活增加。联合PD-1使用策略：研究广泛表明，被称为免疫检查点抑制剂(ICIs)的PD-1阻断抗体可以重新激活CTL的抗肿瘤功能。CAR与ICIs的结合显示出令人鼓舞的结果。有趣的是，PD-1阻断CAR-T细胞自身分泌的抗体可竞争性地与PD-1结合，增强CAR-T细胞的增殖和细胞毒性。总结与展望近年来，CAR-T细胞治疗实体瘤的临床发展取得了巨大的进展。然而，CAR-T细胞治疗实体瘤面临的一些挑战与肿瘤微环境有关，如缺乏肿瘤特异性抗原、CAR-T细胞运输效率低、迁移到肿瘤部位以及存在免疫抑制肿瘤微环境。其他主要挑战与CAR-T细胞直接相关，包括“非肿瘤”毒性等。这些缺陷可以使用CAR-NK以及CAR-M细胞疗法来尝试替代。CAR-NK细胞疗法也已经在临床前得到了很好的研究并转化为临床应用。事实上，NK细胞释放的细胞因子降低了CRS和神经毒性的风险。此外，CAR-NK细胞可以从不同的来源产生，其异体反应性风险较低，并且可以通过CAR依赖和CAR独立的方式攻击肿瘤，这被认为是NK细胞的独特优势。然而，CAR-NK细胞也观察到与CAR-T细胞相关的一些其他挑战，包括浸润肿瘤组织并抵抗其免疫抑制微环境。CAR-M细胞介导疗法为当前CAR -T细胞疗法面临的挑战提供了解决策略，通过结合先天免疫系统和适应性免疫系统，从而对肿瘤发起多管齐下的攻击。最近的研究结果强调了修饰或未修饰巨噬细胞与T细胞或NK细胞相互作用在肿瘤消退中的重要性。考虑到这些优势，我们建议CAR-M与CAR-NK细胞或CAR-T细胞联合使用(图四)，以增强其抗肿瘤效果。研究人员目前正在寻求通过使用包括人工智能(AI)在内的各种策略来提高car细胞治疗的疗效，这可能有助于克服与CAR细胞治疗相关的许多障碍。图4 CAR-T、CAR-NK、CAR-M联用策略参考文献[1] Maalej et al. CAR-cell therapy in the era of solid tumor treatment: current challenges and emerging therapeutic advances [J] Molecular Cancer, (2023) 22:20.https://doi.org/1 0.1186/s 12943-023-01723-z[2] World Health Organization (WHO) Cancer [https:// www. who. int/ news- room/ fact- sheets/ detail/ cancer[3] Orzetti S, Tommasi F , Bertola A, Bortolin G, Caccin E, Cecco S, et al. Genetic Therapy and Molecular Targeted Therapy in Oncology: Safety, Pharmacovigilance, and Perspectives for Research and Clinical Practice. Int J Mol Sci. 2022;23:3012.[4] Fang F , Xie S, Chen M, Li Y, Yue J, Ma J, et al. Advances in NK cell production. Cell Mol Immunol. 2022;19:460–81识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

免疫疗法细胞疗法

2023-04-11

·GlobeNewswire-Health Care

Catamaran Bio Announces Preclinical Data from Allogeneic CAR-NK Cell Therapy Pipeline for Solid Tumors to be Presented at the American Association for Cancer Research (AACR) Annual Meeting 2023

Two allogeneic CAR-NK cell therapies demonstrate significant efficacy in tumor xenograft models Data underscore potential of TAILWIND® platform to create effective CAR-NK treatments for solid tumors BOSTON, April 11, 2023 (GLOBE NEWSWIRE) -- Catamaran Bio, Inc., a biotechnology company developing off-the-shelf natural killer (NK) cell therapies to treat cancer, today announced new data demonstrating preclinical pharmacology and in vivo efficacy from the Company’s two CAR-NK cell therapies in solid tumors have been selected for poster presentations during the American Association for Cancer Research (AACR) Annual Meeting taking place April 14-19, 2023, at the Orange County Convention Center in Orlando, FL. “The data we’ll share at AACR demonstrate the strength of our TAILWIND® platform to design and manufacture highly effective, unique and differentiated CAR-NK products,” said Vipin Suri, PhD, MBA, Chief Scientific Officer of Catamaran Bio. “We can efficiently manufacture multi-functional CAR-NK products which have demonstrated significant efficacy in solid tumor xenograft models. These advances are part of our continuing progress toward the clinic and lay the foundation for our first in-human studies in solid tumors to begin in 2024.” Both posters will be presented on Monday, April 17, 2023, from 1:30-5:00 p.m. ET during the PO.IM01.02 - Natural Killer and Natural Killer T Cell-based Cellular Therapies poster session. Details of the presentations are as follows: CAT-248, an allogeneic CD70-directed CAR-NK cell therapy effectively controls CD70-positive tumor xenografts Highlights from the presentation supporting Catamaran’s lead program, CAT-248, include: Demonstration that CAT-248 significantly reduces growth of 786-O renal cell carcinoma xenografts in both intraperitoneal and subcutaneous in vivo modelsUse of a novel, single-step engineering solution for simultaneous, non-viral delivery of a CAR, TGFβ dominant-negative receptor (DNR) and secreted IL-15 in combination with CRISPR/Cas9 knockout of CD70 in primary human peripheral blood NK cells to prevent fratricideEvidence that the incorporation of a TGFβ DNR provides protection from TGFβ-mediated immunosuppressionThe use of secreted IL-15 leads to enhanced NK cell persistence These data establish CAT-248 as a highly differentiated CAR-NK cell therapy with the potential to provide durable responses in renal cell carcinoma and other CD70-expressing cancers. CAT-179, an allogeneic NK cell product expressing HER2-CAR, IL-15 and TGFβ dominant negative receptor, durably regresses HER2-expressing xenograft tumors in mice Highlights of data from Catamaran’s second CAR-NK cell therapy construct engineered using its TAILWIND® platform include: Demonstration that a single dose of TAILWIND®-engineered CAR-NK cells induces durable regression in multiple HER2 xenograft modelsFunctional persistence is conferred by the components engineered into the cell (TGFβ DNR and secreted IL-15) via the TAILWIND® processEngineered NK cells effectively infiltrate tumor tissueNovel PK/PD analysis demonstrating a direct linkage between NK cell numbers, IL-15 levels and efficacy These results demonstrate the ability of CAT-179 to infiltrate and regress tumors in multiple in vivo models, and support further development of CAT-179 for the treatment of HER2+ solid tumors. Both posters will be available on the Catamaran Bio website upon commencement of the meeting. About Catamaran BioCatamaran Bio is developing novel, off-the-shelf chimeric antigen receptor-natural killer (CAR-NK) cell therapies designed to treat a broad range of cancers, including solid tumors. Our proprietary capabilities enable us to harness the natural cancer-fighting properties of NK cells and enhance and tailor their effectiveness with the power of synthetic biology and innovative non-viral cell engineering. We are using our TAILWIND® platform, an integrated suite of technologies, to specifically address the end-to-end methods of engineering, processing and manufacturing NK cells and rapidly advance our pipeline of CAR-NK cell therapy programs. Our team combines experienced biopharmaceutical leadership with founding scientists who are pioneers in NK cell biology, engineering, manufacturing and clinical application. Catamaran is backed by leading financial and corporate investors, including SV Health Investors, Sofinnova Partners, Lightstone Ventures, Takeda Ventures, Astellas Venture Management and the UMN Discovery Capital investment program. For more information, please visit www.catamaranbio.com and follow us on LinkedIn and @CatamaranBio on Twitter. Catamaran Contact:Michael DeRidder, PhD, SVP Corporate Strategy267-496-6534mderidder@catamaranbio.com Media Contact:Gina Cestari6 Degrees917-797-7904gcestari@6degreespr.com

细胞疗法AACR会议免疫疗法临床研究

100 项与 NKG2D CAR-NK cells(The Third Affiliated Hospital of Guangzhou Medical University) 相关的药物交易

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