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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，即使对于有效的癌症类型，许多患者也没有反应，或者癌症复发这种疗法对许多其他类型的癌症无效。越来越多的证据表明无效的检查点疗法通常是由于给定类型或特定类型的实例中缺乏新抗原。癌症，或对治疗产生获得性耐药性，这通常是由于MHC I抗原提呈丧失或新抗原表达。动员NK细胞的治疗剂可以显著地补充T细胞介导的抗肿瘤药物。肿瘤机制，因为NK细胞不依赖于新抗原，并且特别有效地对抗MHC- 缺陷型肿瘤，在检查点治疗期间出现。初步数据显示，先天激动剂，如 STING激动剂，与称为H9-MSA的IL-2超级因子显著协同，导致NK依赖性的不确定性。在具有已建立的MHC I缺陷型肿瘤的小鼠中的长期无肿瘤存活，包括冷B16-B2 m-/- 模型和MC-38-B2 m-/-模型，其对单独的每种疗法都是难治的。引人注目的是，这治疗组合也有效地“治愈”小鼠的MHC I+ B16肿瘤，由CD 8 T细胞介导，原发性甲基胆蒽（MCA）诱导的肉瘤，一种高度严格的本地癌症模型，也难治检查点疗法，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，检查点治疗的添加导致约一半动物的长期缓解。在临床试验中， STING激动剂单独在癌症患者中令人失望，但我们的新证据表明， STING激动剂和IL-2超级因子的组合表明，该组合可能具有在以下方面应用的巨大潜力：人类癌症治疗我们将询问这种组合的协同效应的机制，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，或协同作用防止NK脱敏。我们将在此基础上或之前进一步讨论检查点治疗的影响。治疗组合，包括了解T细胞和NK细胞如何合作。我们将为获得的通过选择肿瘤转移中MHC缺失变体表达的肿瘤对检查点疗法的抗性模型最后，我们将使用正在接受治疗的MCA肉瘤模型来测试T细胞在选择肿瘤细胞中的作用。 MHC I缺陷或其他NK敏感变体，以及NK细胞在潜在选择T细胞敏感变体中的作用。这些研究的成果将为理解和应用这种形式的联合治疗在人类癌症患者中的应用。