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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

基本信息

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
项目类别：
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

项目摘要

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：项目总结