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Mechanisms underlying combination therapy mobilizing NK cells

联合治疗动员 NK 细胞的机制

基本信息

批准号：
10623188
负责人：
DAVID H RAULET
金额：
$ 46.54万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-17 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10623188
关键词：
Activated Natural Killer Cell Address Agonist Animals Antigen Presentation Antitumor Response CD8-Positive T-Lymphocytes CD8B1 gene CPG-oligonucleotide Cancer Model Cancer Patient Cells Clinical Trials Combined Modality Therapy Complement Cytotoxic T-Lymphocytes Data Dedications Disease remission Effectiveness Granzyme Human I-antigen Immunotherapy Interferons Interleukin-2 Laboratories Ligands MC38 Malignant Neoplasms Mediating Methods Methylcholanthrene Modeling Molecular Mus Mutation Natural Killer Cells Outcome Patients Proteins Recurrent Malignant Neoplasm Recurrent tumor Refractory Regimen Resistance Role STING agonists Stress System T cell response T cell therapy T-Lymphocyte Testing Therapeutic Treatment Efficacy Variant Work antigen processing antitumor effect cancer immunotherapy cancer recurrence cancer therapy cancer type cell killing checkpoint therapy comparative cytokine desensitization effective therapy exhaustion mouse model neoantigens neoplastic cell prevent refractory cancer response sarcoma synergism therapy resistant tool transcriptomics tumor

项目摘要

Checkpoint therapy is remarkably effective against many malignancies that were previously devoid of effective treatment options. Nevertheless, even for the types of cancer where it is effective, many patients do not respond, or their cancers recur. The therapy is ineffective in many other types of cancer. Evidence has accumulated that ineffective checkpoint therapy is often due to either the dearth of neoantigens in a given type or example of cancer, or acquired resistance to therapy, which is frequently due to loss of MHC I antigen presentation or neoantigen expression. Therapeutics that mobilize NK cells may dramatically complement T cell mediated anti- tumor mechanisms, because NK cells do not depend on neoantigens, and are especially effective against MHC- deficient tumors, which arise during checkpoint therapy. Preliminary data show that innate agonists, such as a STING agonist, dramatically synergize with an IL-2 superkine called H9-MSA, leading to NK-dependent indefinite long term tumor free survival in mice with established MHC I-deficient tumors, including the cold B16-B2m-/- model and the MC-38-B2m-/- model, which were otherwise refractory to each therapy alone. Strikingly, this therapy combination was also effective in “curing” mice of MHC I+ B16 tumors, mediated by CD8 T cells, and primary methylcholanthrene (MCA)-induced sarcomas, a highly stringent autochthonous model of cancer that was also refractory to checkpoint therapy, where both T cells and NK cells mediated antitumor effects. In the latter model, the addition of checkpoint therapy led to long term remissions in ~half the animals. In clinical trials, STING agonists alone have been disappointing in cancer patients, but our new evidence of great synergy of STING agonists and IL-2 superkine suggests that the combination may have great potential for applications in human cancer therapy. We will interrogate the mechanisms of synergistic efficacy of this combination, including whether STING agonist, via IFN, protects NK cells from fratricide induced by the superkine, or cooperatively prevents NK desensitization. We will further address the impact of checkpoint therapy on top of or preceding this therapy combination, including understanding how T cells and NK cells cooperate. We will model the acquired resistance of tumors to checkpoint therapy via selection of MHC-loss variants expression in a tumor transfer model. Finally, we will employ the MCA sarcoma model undergoing therapy to test the roles of T cells in selecting MHC I deficient or other NK sensitive variants, and of NK cells in potentially selecting T cell sensitive variants. The culmination of these studies will provide a strong basis for understanding and applying this form of combination therapy in human patients with cancer.

检查点疗法对许多以前缺乏有效治疗的恶性肿瘤非常有效治疗方案。然而，即使对于它有效的癌症类型，许多患者也没有反应，或者他们的癌症复发。该疗法对许多其他类型的癌症无效。已经积累的证据表明检查点治疗无效通常是由于特定类型或特定类型中缺乏新抗原所致癌症或获得性治疗耐药性，这通常是由于 MHC I 抗原呈递丧失或新抗原表达。调动 NK 细胞的疗法可能会显着补充 T 细胞介导的抗肿瘤机制，因为 NK 细胞不依赖新抗原，并且对 MHC-特别有效在检查点治疗期间出现的缺陷肿瘤。初步数据表明，先天激动剂，例如 STING 激动剂，与称为 H9-MSA 的 IL-2 超级因子显着协同作用，导致 NK 依赖性无限期具有 MHC I 缺陷型肿瘤（包括冷 B16-B2m-/-）的小鼠的长期无瘤生存模型和 MC-38-B2m-/- 模型，否则单独使用每种疗法都难以治愈。引人注目的是，这联合治疗也能有效“治愈”由 CD8 T 细胞介导的 MHC I+ B16 肿瘤小鼠，原发性甲基胆蒽 (MCA) 诱导的肉瘤是一种高度严格的本土癌症模型，检查点疗法也难以治愈，其中 T 细胞和 NK 细胞都介导抗肿瘤作用。在在后一种模型中，添加检查点疗法使约一半的动物获得了长期缓解。在临床试验中，单独使用 STING 激动剂对癌症患者的效果令人失望，但我们的新证据表明，STING 激动剂具有良好的协同作用 STING 激动剂和 IL-2 超级因子表明该组合可能具有巨大的应用潜力人类癌症治疗。我们将探讨这种组合的协同功效机制，包括 STING 激动剂是否通过 IFN 保护 NK 细胞免受超级因子诱导的自相残杀，或者协同作用防止 NK 脱敏。我们将进一步讨论检查点疗法在此之上或之前的影响治疗组合，包括了解 T 细胞和 NK 细胞如何合作。我们将对获得的模型进行建模通过选择肿瘤转移中 MHC 缺失变异表达来抵抗肿瘤对检查点治疗的抵抗模型。最后，我们将利用正在接受治疗的 MCA 肉瘤模型来测试 T 细胞在选择中的作用。 MHC I 缺陷或其他 NK 敏感变体，以及 NK 细胞潜在选择 T 细胞敏感变体的情况。这些研究的成果将为理解和应用这种形式提供坚实的基础。人类癌症患者的联合治疗。