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.

检查点疗法对许多先前缺乏有效的恶性肿瘤非常有效治疗选择。然而，即使对于有效的癌症类型，许多患者也没有反应或他们的癌症反复出现。该疗法在许多其他类型的癌症中无效。证据积累了无效的检查点疗法通常是由于给定类型中的新抗原的死亡或癌症或获得治疗的抗药性，这通常是由于MHC I抗原表现的损失或新抗原表达。动员NK细胞的治疗剂可能会极大地补充T细胞介导的抗抗 - 肿瘤机制，因为NK细胞不依赖新抗原，并且特别有效地针对MHC- 缺乏肿瘤，这是在检查点疗法期间出现的。初步数据表明，先天激动剂，例如刺痛的激动剂，与称为H9-MSA的IL-2超级币显着协同，导致NK依赖性不确定已建立的MHC I缺陷肿瘤的小鼠的长期无肿瘤生存期，包括冷B16-B2M - / - 模型和MC-38-B2M - / - 模型，它们仅对每种治疗而难治性。令人惊讶的是，这个治疗组合在MHC I+ B16肿瘤的“固化”小鼠中也有效，由CD8 T细胞介导，和原代甲基胆碱（MCA）诱导的肉瘤，肉瘤是一种高度严格的癌症模型，也对检查点疗法难治性，其中T细胞和NK细胞都介导了抗肿瘤作用。在后一种模型，增加检查点疗法导致一半动物的长期恢复。在临床试验中仅凭刺痛的激动剂一直在癌症患者中令人失望，但是我们的新证据证明了很大的协同作用 Sting激动剂和IL-2 Superkine表明，该组合可能具有巨大的应用潜力人类癌症治疗。我们将询问该组合的协同效率的机制，包括无论是通过IFN而刺激激动剂，都可以保护NK细胞免受超级币诱导的杂化剂或合作防止NK脱敏。我们将进一步解决检查点疗法对此之前或之前的影响治疗组合，包括了解T细胞和NK细胞如何配合。我们将建模肿瘤对检查点治疗的抗性通过选择肿瘤转移中的MHC-loss变体表达模型。最后，我们将采用接受治疗的MCA肉瘤模型来测试T细胞在选择中的作用 MHC I缺乏或其他NK敏感变体以及潜在选择T细胞敏感变体的NK细胞。这些研究的高潮将为理解和应用这种形式提供强大的基础人类癌症患者的联合疗法。