MEM-288

来自Moffitt癌症研究中心等机构的科学家们通过研究或有望开发出针对这类无响应患者的新型疗法策略。 能激活T细胞靶向作用癌细胞的免疫检查点抑制剂能够大大改善多种类型肿瘤患者的治疗效果，但并非所有患者都会对这种疗法产生反应，近日，一篇发表在国际杂志Cancer Immunology Research上题为“Combination IFNβ and membrane-stable CD40L maximize tumor dendritic cell activation and lymph node trafficking to elicit systemic T-cell immunity”的研究报告中，来自Moffitt癌症研究中心等机构的科学家们通过研究或有望开发出针对这类无响应患者的新型疗法策略。 文章中，研究者揭示了通过CD40和干扰素β（IFNβ）途径来刺激树突状细胞如何产生针对肿瘤的强大T细胞活性，并能与免疫检查点抑制剂共同作用从而产生更强大的反应，此外，研究人员还分享了一项在非小细胞肺癌患者机体中激活这些通路的溶瘤病毒MEM-288的1期临床研究的早期结果。树突细胞在激活T细胞识别感染性物质或外源性物质（包括癌细胞）上扮演着非常关键的角色；这些特征就表明，树突状细胞或许能作为一种重要的细胞组分来实现检查点抑制剂疗法的最佳反应。 医学博士Andreas N. Saltos说道，靶向作用T细胞的免疫检查点抑制剂给癌症治疗带来了革命性的变革，但如今科学家们越来越认识到，靶向作用负责T细胞激活的细胞类型（比如树突状细胞）或许有望让患者获得最佳治疗效果，然而，目前研究人员尚未确定能靶向作用树突状细胞并释放其全部治疗潜力的最佳策略。研究人员重点关注于已知能促进树突状细胞激活的两个独立的通路：CD40和IFNβ通路，他们利用一种能表达蛋白IFNβ和CD40配体的膜稳定版本（MEM40）的腺病毒进行了实验，结果发现，MEM40和IFNβ的联合表达或会导致树突状细胞的激活、成熟以及向淋巴结的迁移，同时还能在黑色素瘤和肺癌小鼠模型机体中产生抗肿瘤T细胞反应并减少机体肿瘤的生长，而且两种蛋白的联合表达还能产生较强的机体反应。 图片来源：https://aacrjournals-org.libproxy1.nus.edu.sg/cancerimmunolres/article-abstract/doi/10.1158/2326-6066.CIR-22-0927/716463/Combination-IFN-and-membrane-stable-CD40L-maximize?redirectedFrom=fulltext 研究人员还证明，直接向肿瘤中注射能表达MEM40和IFNβ的腺病毒或许就能减少所注射肿瘤的生长并降低其远端转移的能力，这或许就表明，被MEM40和IFNβ联合激活的树突状细胞能产生系统性的抗肿瘤效应，这种组合性的病毒疗法对于对检查点抑制剂不敏感的癌症小鼠模型而言或许是有效的，同时其还能与检查点抑制剂联合使用来产生更强的抗肿瘤活性。研究者Beg说道，我们相信本文研究结果或有望帮助开发出一种新型治疗性策略来最大限度地提高树突状细胞所诱导的T细胞激活，从而使其作为一种单一制剂并与免疫检查点抑制剂联合使用来让患者获益。 鉴于这些积极性的研究结果，目前研究人员正在通过联合研究来开发出能驱动MEM40和IFNβ表达的MEM-288溶瘤病毒，这种溶瘤病毒能优先在癌细胞中复制并对其进行裂解从而导致抗原释放并进一步促进机体的抗肿瘤免疫力，当在实验室中对这种溶瘤病毒进行检测后，研究人员在实体瘤患者中启动了I期临床试验来评估其安全性和有效应。来自非小细胞肺癌患者的早期研究结果表明，MEM-288能促使肿瘤体积缩小并增加整个肿瘤环境中的T细胞数量，更重要的是，其还能产生全身性的抗肿瘤T细胞免疫力，目前该临床试验正在进行中，而且研究人员还在继续招募患者进行试验。 下一步研究人员将会扩大1b期临床试验来调查MEM-288联合免疫检查点抑制剂在治疗非小细胞肺癌患者中的效益，研究人员非常激动能看到MEM-288疗法早期的临床治疗效应、安全性以及在机体中所产生的抗肿瘤免疫力，这对于MEM-288疗法与免疫检查点抑制剂进行协同发挥作用非常重要。1b期临床试验预期将会在2023年中期开始。（生物谷Bioon.com） 原始出处： Hong Zheng,Xiaoqing Yu,Mohammed L. Ibrahim，et al. Combination IFNβ and membrane-stable CD40L maximize tumor dendritic cell activation and lymph node trafficking to elicit systemic T-cell immunity, Cancer Immunology Research (2023). DOI:10.1158/2326-6066.CIR-22-0927

Researchers show how stimulating dendritic cells through certain pathways produces strong T cell activity against tumors and works in conjunction with immune checkpoint inhibitors to produce even stronger responses. The article also shares promising early results from a phase 1 clinical study of an oncolytic virus (MEM-288) that activates these pathways in patients with non-small cell lung cancer. In a new study published in the journal Cancer Immunology Research, our researchers, led by Amer A. Beg, Ph.D., show how stimulating dendritic cells through the CD40 and interferon β (IFNβ) pathways produces strong T cell activity against tumors and works in conjunction with immune checkpoint inhibitors to produce even stronger responses. The article also shares promising early results from a phase 1 clinical study of an oncolytic virus (MEM-288) that activates these pathways in patients with non-small cell lung cancer. Immune checkpoint inhibitors that activate T cells to target cancer cells have greatly improved patient outcomes across a variety of tumor types. But not all patients respond to the therapies. Moffitt Cancer Center researchers are working to identify new treatment options for this subset of patients. In a new study published in the journal Cancer Immunology Research, our researchers, led by Amer A. Beg, Ph.D., show how stimulating dendritic cells through the CD40 and iinterferon β (IFNβ) pathways produces strong T cell activity against tumors and works in conjunction with immune checkpoint inhibitors to produce even stronger responses. The article also shares promising early results from a phase 1 clinical study of an oncolytic virus (MEM-288) that activates these pathways in patients with non-small cell lung cancer. Dendritic cells play an important role in activating T cells to recognize infectious or foreign agents, including cancer cells. These characteristics suggest that dendritic cells may be an important cellular component in achieving optimum responses to checkpoint inhibitor therapy. "Immune checkpoint inhibitors that target T cells have revolutionized cancer treatment, but there is increasing realization that targeting cell types responsible for T cell activation, such as dendritic cells, may be required for optimal patient benefit. However, the best strategy to target dendritic cells to unleash their full therapeutic potential has remained undefined," said Andreas N. Saltos, M.D., clinical research medical director in the Department of Thoracic Oncology at Moffitt and principal investigator of the MEM-288 oncolytic virus clinical trial. Beg and a team of researchers focused their investigation on two separate pathways that are known to contribute to activation of dendritic cells, the CD40 and the IFNβ pathways. They performed laboratory experiments with an adenovirus that expressed the proteins IFNβ and a membrane-stable version of the CD40 ligand (MEM40). They found that the combined expression of both MEM40 and IFNβ resulted in dendritic cell activation, maturation and migration to lymph nodes. Both MEM40 and IFNβ produced anti-tumor T-cell responses and reduced tumor growth in mouse models of melanoma and lung cancer, with stronger responses observed with combined expression of both proteins. The researchers also demonstrated that direct tumor injection of the adenoviruses expressing MEM40 and IFNβ were able to reduce tumor growth within the injected tumor and reduce distant metastases, suggesting that dendritic cell activation by MEM40 and IFNβ can produce systemic anti-tumor effects. This combination virus treatment was effective in mouse cancer models that were insensitive to checkpoint inhibitors and could work in conjunction with checkpoint inhibitors to produce even stronger anti-tumor activity. "We believe our findings point to a new therapeutic strategy to maximize dendritic cell-induced T-cell activation with potential to benefit patients as a single agent and in combination with immune checkpoint inhibitors," said Beg, senior member of the Department of Immunology at Moffitt. Given these positive results, the Moffitt team worked in collaboration with Memgen, Inc., to create the MEM-288 oncolytic virus that drives expression of MEM40 and IFNβ. Oncolytic viruses preferentially replicate within cancer cells and lyse them, resulting in the release of antigens that promote further anti-tumor immunity. After testing their oncolytic virus in laboratory experiments, they initiated a phase 1 trial in patients with solid tumors to assess safety and efficacy. Early results from non-small cell lung patients reveal that MEM-288 caused tumors to shrink in size and increased T cell numbers throughout the tumor environment, and importantly, the potential ability to generate systemic anti-tumor T cell immunity. The clinical trial is ongoing and continuing to recruit patients. "The next phase of this study will be an expanded Phase 1b trial to investigate MEM-288 in combination with an immune checkpoint inhibitor in non-small cell lung cancer patients," said Mark Cantwell, Ph.D., chief scientific officer of Memgen and an author on this study. "We are excited to see early clinical activity, safety and generation of antitumor immunity by MEM-288, which may be crucial for synergy with immune checkpoint inhibitors." The Phase 1b trial is expected to start in mid-2023. These studies were supported by the National Cancer Institute (P30-CA076292 and P50CA168536), Memgen, Inc., the Moffitt Foundation and the Moffitt Lung Cancer Center of Excellence.