Strategies to predict and overcome resistance to cancer immunotherapy

预测和克服癌症免疫治疗耐药性的策略

基本信息

批准号：
10638167
负责人：
STEVEN L REINER
金额：
$ 54.75万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10638167
关键词：
Address Antigens Biological Markers Blood Blood Tests Blood specimen CD8-Positive T-Lymphocytes Cancer Patient Cell Differentiation process Cell division Cells Cellular biology Clinical Clinical Trials Clone Cells Confocal Microscopy Consensus Defense Mechanisms Dose Equilibrium Flow Cytometry Frequencies Functional disorder Head and Neck Squamous Cell Carcinoma Image Cytometry Immunity Immunofluorescence Immunologic Immunotherapy Lesion Link Malignant Neoplasms Malignant Squamous Cell Neoplasm Minority Mitotic Morphology Mus Nature Non-Small-Cell Lung Carcinoma Operative Surgical Procedures Output PD-1 blockade PIK3CG gene Patients Peripheral Blood Mononuclear Cell Persons Pharmaceutical Preparations Physiologic pulse Production Proliferating Radiation therapy Resistance Siblings Signal Transduction Sister T cell differentiation T-Cell Activation T-Cell Proliferation T-Lymphocyte Testing Tissues Tumor Immunity Tumor Tissue Work advanced disease anti-PD-1 anti-PD1 therapy anti-cancer blood treatment cancer care cancer immunotherapy cancer type candidate marker cell regeneration chemotherapy clinical practice confocal imaging daughter cell disorder control experimental study immune checkpoint blockade improved in vivo insight kindred novel strategies patient response peripheral blood pre-clinical predictive marker progenitor receptor regenerative response response biomarker self-renewal stem cells stem-like cell translational applications transmission process tumor tumor growth

项目摘要

Immunotherapies such as PD-1 blockade have revolutionized cancer care. Yet most patients do not experience sustained (durable) benefit from blockade of T cell inhibitory receptors. Unfortunately, current biomarkers do not adequately predict patient response or resistance to immunotherapy; and successful strategies to overcome immunotherapy resistance have been lacking. Both gaps reflect our incomplete understanding of how durable immunity carried out by T cells is achieved. Progenitor T cells normally balance the mutually opposing demands of differentiation and self- renewal by transmitting unequal anabolic activating signals to daughter cells. In the setting of cancer, however, sustained T cell activation skews the normal regenerative equilibrium of balanced differentiation and renewal towards progressive dysfunction of differentiated cells along with progressive loss of self-renewing T cells. It was previously presumed that PD-1 blockade acted by restoring potency to the most dysfunctional T cells. Instead, emerging consensus has demonstrated that PD-1 blockade can only function by inducing greater division and differentiation of self- renewing T cells, which are already in peril. This preclinical and translational application marshals our basic discoveries concerning the signaling and cell biology of T cell regeneration to tackle a major clinical roadblock in cancer care. Performing the aims of this proposal will enable determination of 1) whether anti-cancer immunity and immunotherapy impact the self-renewal of CD8+ T cells; 2) whether immunotherapy can be improved by augmenting CD8+ T cell self-renewal; and 3) whether patient response and resistance to immune checkpoint blockade can be predicted from the abundance of self-renewing T cells. This proposal would address two critical unmet patient needs: a non-invasive predictive biomarker for response and resistance to immunotherapy across cancer types; and a novel strategy for resistance-directed treatment enabling immunotherapy to benefit the majority, rather than the minority of patients.

PD-1 阻断等免疫疗法彻底改变了癌症治疗。然而大多数患者不会从 T 细胞阻断中获得持续（持久）的益处抑制性受体。不幸的是，目前的生物标志物并不能充分预测患者的病情对免疫疗法的反应或抵抗；以及成功的克服策略缺乏免疫治疗耐药性。这两个差距都反映出我们的不完整了解 T 细胞如何实现持久免疫。祖T 细胞通常平衡分化和自我修复的相互对立的需求通过向子细胞传递不均匀的合成代谢激活信号来进行更新。在然而，在癌症的背景下，持续的 T 细胞激活会扭曲正常的 T 细胞平衡分化和更新的再生平衡分化细胞功能障碍以及自我更新 T 细胞的逐渐丧失。它之前推测 PD-1 阻断是通过将效力恢复到最大程度来发挥作用的。 T 细胞功能失调。相反，新出现的共识表明 PD-1 封锁只能通过诱导更大的自我分裂和分化来发挥作用。更新已经处于危险之中的 T 细胞。该临床前和转化应用整理了我们关于 T 细胞信号传导和细胞生物学的基本发现再生以解决癌症治疗中的主要临床障碍。执行目标该提案将能够确定 1) 是否具有抗癌免疫力和免疫疗法影响CD8+ T细胞的自我更新； 2）免疫治疗是否可以通过增强 CD8+ T 细胞的自我更新来改善； 3) 患者是否有反应并且可以从丰度来预测对免疫检查点封锁的抵抗力自我更新的 T 细胞。该提案将解决两个关键的未满足的患者需求：对免疫疗法的反应和耐药性的非侵入性预测生物标志物跨癌症类型；以及一种针对耐药性的治疗的新策略免疫疗法使大多数患者受益，而不是少数患者。