Project 3. Overcoming Melanoma Treatment Resistance with Cytokine Immunotherapy

项目 3. 通过细胞因子免疫疗法克服黑色素瘤治疗耐药性

• 批准号: 10711513
• 负责人: Aaron Michael Ring
• 金额: $ 38.34万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711513
• 关键词: Activated Natural Killer Cell; Address; Agonist; Animal Model; Award; Biological Markers; Biopsy; Blood; Blood specimen; CD8B1 gene; CTLA4 gene; Caring; Cell physiology; Cells; Characteristics; Clinical; Clinical Trials; Combined Modality Therapy; Development; Disease; Disease Resistance; Dose; Engineering; Evaluation; Feedback; Funding; Goals; Human; IL18 gene; Immune; Immune checkpoint inhibitor; Immune system; Immunity; Immunotherapeutic agent; Immunotherapy; Interferon Type II; Knock-out; Lead; Licensing; MHC Class I Genes; Malignant Neoplasms; Memory; Metastatic Melanoma; Methods; Modeling; Mus; Mutation; NK Cell Activation; Natural Killer Cells; PD-1 blockade; PD-1 inhibitors; Patients; Pharmaceutical Preparations; Phase; Phase I/II Clinical Trial; Pre-Clinical Model; Recombinant Interleukin-18; Recommendation; Recurrent disease; Refractory; Regimen; Resistance; Resistance development; Sampling; Series; Site; Skin Cancer; T cell response; T memory cell; T-Lymphocyte; Testing; Therapeutic; Time; Tumor-Infiltrating Lymphocytes; Universities; Unresectable; Up-Regulation; Work; antagonist; anti-PD-1; antigen-specific T cells; cancer therapy; career; clinically relevant; cytokine; effector T cell; efficacy evaluation; experimental study; first-in-human; immune checkpoint; improved; interleukin-18 binding protein; interleukin-18 receptor; melanoma; mouse model; neoplastic cell; novel; novel strategies; novel therapeutics; participant enrollment; patient subsets; pembrolizumab; phase I trial; preclinical study; programmed cell death protein 1; programs; response; single-cell RNA sequencing; stem; synergism; therapy resistant; transcriptomics; tumor; tumor microenvironment

PROJECT 3: PROJECT SUMMARY Major changes have occurred in treatment of unresectable melanoma in the last decade in which immune-based therapies have dramatically enhanced overall survival. Unfortunately, almost half the melanoma patients do not respond to immune checkpoint inhibitors (ICI) upfront, and others develop recurrent or resistant disease over time. Immunotherapies that can stimulate immunity in ICI-resistant melanoma are still therefore urgently needed. To this end, cytokines have potent immunostimulatory activities that make them attractive candidates for use in combination with ICIs to overcome resistance. Interleukin 18 (IL-18) is particularly appealing, because the IL-18 receptor (IL-18R) is specifically upregulated in CD8 tumor infiltrating lymphocytes and is widely expressed on natural killer (NK) cells. However, clinical trials of recombinant IL-18 were unsuccessful, likely due to upregulation of the endogenous IL-18 receptor antagonist or IL-18 binding protein, IL-18BP, which inhibits the immunostimulatory effects of IL-18. The Ring lab therefore created an engineered version of IL-18 that is resistant to the IL-18BP but fully retains its ability to activate the IL-18R. A clinical grade “decoy resistant” IL-18 (DR18) has been developed and licensed to Simcha Therapeutics by Yale University (ST-067). ST-067 is currently being investigated in a first-in-human clinical trial as monotherapy. In pre-clinical models, DR18 synergizes with anti-PD-1. Furthermore, in murine models, DR-18 is highly effective in treating ICI-resistant MHC class I deficient tumors, consistent with the ability of IL-18 to also activate NK cells. We hypothesize that combining DR-18 with immune checkpoint inhibitors can overcome ICI resistance in melanoma via activation of NK cells, T effector cells and stem-like memory T cells. We propose to conduct a series of pre- clinical studies (Aim 1) utilizing novel animal models developed in house with clinically relevant melanoma mutations to determine the mechanism of response and resistance of the combination of DR-18 with clinically approved ICIs (inhibitors of PD-1, CTLA-4 and LAG-3). We have engineered the murine models to enable evaluation of antigen-specific T cell responses to determine how T effector and memory function is improved. Seeing that class I MHC loss in tumor cells is a major cause of resistance to anti-PD-1 in humans, we will also study effects of DR-18 alone and with ICIs in B2m knockout models (MHC-I deficient). In Aim 2 we will conduct a phase I/II clinical trial of ST-067 with immune checkpoint inhibitors in patients whose disease has progressed on a prior regimen containing anti-PD-1. Tumor and blood samples from patients enrolled in the trial will be interrogated to determine cellular mechanisms of response/resistance in humans using cutting-edge spatial transcriptomics methods developed at Yale, and results will be compared to the murine samples collected in Aim 1. If successful, these studies will support further development of ST-067 with ICIs in patient subsets carefully defined by immune cell characteristics. This approach can be applied to patients with other types of anti-PD-1 resistant tumors as well, and these studies have the potential for far-reaching implications.

项目3：项目摘要 在过去的十年中，在治疗不可切除的黑色素瘤方面发生了重大变化 疗法已大大提高了总体生存率。不幸的是，几乎一半的黑色素瘤患者没有 对免疫粘液抑制剂（ICI）的反应 时间。因此，仍然需要急需刺激ICI抗性黑色素瘤中免疫组织化学的免疫疗法。 为此，细胞因子具有潜在的免疫刺激活动，使其成为有吸引力的候选人 与ICIS结合以克服抗性。白介素18（IL-18）特别有吸引力，因为IL-18 受体（IL-18R）在CD8肿瘤浸润淋巴细胞中专门更新，并在 天然杀手（NK）细胞。但是，重组IL-18的临床试验未成功，可能是由于上调 内源性IL-18受体拮抗剂或IL-18结合蛋白IL-18BP的 IL-18的免疫刺激作用。因此，环实验室创建了IL-18的工程版本， 对IL-18BP有抵抗力，但完全保留了激活IL-18R的能力。临床级“诱饵” IL-18 （DR18）已由耶鲁大学（ST-067）开发并获得了SIMCHA治疗剂的许可。 ST-067是 目前正在一项人类临床试验中作为单一疗法进行调查。在临床前模型中，DR18 与抗PD-1协同作用。此外，在鼠模型中，DR-18在治疗抗ICI的MHC方面非常有效 I类缺乏肿瘤，与IL-18也激活NK细胞的能力一致。我们假设这一点 将DR-18与免疫粘点抑制剂结合起来可以克服黑色素瘤中的ICI耐药性 NK细胞，T效应细胞和茎状记忆T细胞的激活。我们建议进行一系列预先 临床研究（AIM 1），使用具有临床相关黑色素瘤的内部新型动物模型 突变以确定DR-18与临床的响应机理和抗性的机理 批准的ICI（PD-1，CTLA-4和LAG-3的抑制剂）。我们已经设计了鼠模型以启用 评估抗原特异性T细胞反应，以确定如何改善T效应器和记忆功能。 看到肿瘤细胞中I类MHC损失是对人类抗PD-1抗药性的主要原因，我们也将 单独使用DR-18和ICI的研究影响B2M敲除模型（MHC-I缺乏）。在AIM 2中，我们将进行 ST-067的I/II期临床试验与疾病进展的患者中具有免疫切除剂抑制剂 在含有抗PD-1的先前方案上。参加试验的患者的肿瘤和血液样本将是 询问以使用尖端空间来确定人类反应/抗性的细胞机制 耶鲁大学开发的转录组学方法将与AIM收集的鼠样品进行比较 1。如果成功，这些研究将支持患者子集中ICI的ST-067进一步发展 由免疫细胞特征定义。这种方法可以应用于其他类型的抗PD-1的患者 耐药性肿瘤也有可能产生深远影响。