MODULATION OF CD5 SIGNALING TO ENHANCE ADOPTIVE T-CELL THERAPIES FOR CANCER

调节 CD5 信号传导以增强癌症过继性 T 细胞疗法

基本信息

批准号：
10609068
负责人：
Marco Ruella
金额：
$ 51.7万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2022-04-12 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10609068
关键词：
Affinity Antigens B lymphoid malignancy B-Cell Leukemia B-Lymphocytes Behavior CBL gene CD19 gene CD8-Positive T-Lymphocytes CRISPR/Cas technology CTAG1 gene Calcium Signaling Cell Death Induction Cell physiology Cells Chronic Clinical Clinical Trials Complex Data Development Disease remission Disinhibition ERBB2 gene Exposure to Flow Cytometry Goals Grant Hematology Human Immune checkpoint inhibitor Immunocompetent Immunotherapy In Vitro Investigation Knock-out Knowledge Lymphoma Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of pancreas Malignant neoplasm of prostate Mediating Mediator Mission Modeling Multiple Myeloma Mus Outcome PD-1/PD-L1 PTPN6 gene Pathway interactions Patients Peripheral Persons Phosphorylation Pre-Clinical Model Process Production Proliferating Public Health Receptor Signaling Refractory Relapse Reporting Research Role Safety Scientific Advances and Accomplishments Signal Pathway Signal Transduction Solid Solid Neoplasm T cell therapy T-Cell Activation T-Cell Leukemia T-Cell Lymphoma T-Cell Receptor T-Lymphocyte Technology Testing Work Xenograft Model Xenograft procedure antitumor effect cancer immunotherapy cancer therapy chimeric antigen receptor T cells clinical practice clinically relevant cytokine cytotoxicity digital effector T cell engineered T cells exhaustion experience first-in-human growth factor receptor-bound protein 2 human model immunological synapse immunoregulation improved in vivo innovation leukemia/lymphoma melanoma mesothelin mouse model next generation novel patient subsets performance tests programmed cell death protein 1 refractory cancer release of sequestered calcium ion into cytoplasm response safety testing scavenger receptor side effect single-cell RNA sequencing transcription factor tumor tumor microenvironment tumor-immune system interactions

项目摘要

PROJECT SUMMARY Adoptive T-cell immunotherapies and, in particular, chimeric antigen receptor T cells (CART) generated unprecedented responses in patients with highly refractory CD19+ B cell malignancies. However, only a limited number of patients treated with anti-CD19 CART will experience prolonged remission while most patients either do not respond or eventually relapse. Moreover, in the setting of solid cancers, CART cells have generally been disappointing. Increasing CART effector function against cancer would represent a vertical improvement in the field of adoptive T-cell immunotherapy. In this proposal, we aim at increasing the anti-tumor efficacy of CAR T cells by reducing the inhibition of CAR activation. Current approaches to enhance CART efficacy focus on reducing long-term T cell exhaustion by targeting the PD-1/PD-L1 axis. However, there is a lack of investigation on strategies to enhance early CAR and T cell receptor (TCR) signaling, which is critical for effective tumor killing, especially in the setting of the immunosuppressive tumor microenvironment. To this goal, we studied the scavenger receptor CD5. CD5 associates with the TCR complex and inhibits its activation through several mediators, including SHP-1, CBL, CBL-B, and GRB2. The central hypothesis of this grant is that CD5 deletion increases the anti-tumor efficacy of engineered T cells through enhancement of TCR signaling. In our preliminary work, we have found that CRISPR-Cas9 CD5 knock out in CART cells enhances their anti-tumor activity in xenograft models of B-cell leukemia (CART19) and T-cell lymphoma (CART5). Moreover, we demonstrated that, upon stimulation, CD5 knocked-out CART cells show higher phosphorylation of key CAR signaling mediators as compared to wild-type. In Aim#1, we will test the hypothesis that the deletion of CD5 in T cells broadly enhances the anti-tumor efficacy of adoptive T-cell immunotherapies, by studying CD5 knockout in the setting of CAR T cells for solid tumors. In Aim#2, we will test the hypothesis that CD5 deletion augments T-cell anti-tumor activity by disinhibiting CAR signaling by performing in vitro and in vivo mechanistic studies. We will also test the safety of this approach. This hypothesis-driven proposal is highly innovative as it proposes the study of a novel immunomodulatory target - CD5 - and uses cutting edge technologies like digital spatial profiling and single-cell RNA sequencing to investigate CD5 deleted CAR T-cell in vivo in both human and murine models. A successful outcome of the proposed investigations is expected to impact the field of cancer immunotherapy significantly, providing a rational and generalizable approach to improving T-cell immunotherapies and ultimately drive the development of a first-in-human clinical trial of CD5 knocked-out CART for refractory cancers.

项目摘要生成的T细胞免疫疗法，特别是产生的嵌合抗原受体T细胞（CART）高度难治性CD19+ B细胞恶性肿瘤患者的空前反应。但是，只有有限用抗CD19手推车治疗的患者人数会长时间缓解，而大多数患者却有大多数患者不要回应或最终复发。此外，在固体癌症的情况下，推车单元通常是令人失望。对癌症的推车效应功能的提高将代表垂直改善收养T细胞免疫疗法领域。在此提案中，我们旨在提高汽车的抗肿瘤功效通过减少CAR激活的抑制来通过细胞。当前增强购物车功效的方法关注通过靶向PD-1/PD-L1轴来减少长期T细胞耗尽。但是，缺乏调查关于增强早期汽车和T细胞受体（TCR）信号的策略，这对于有效肿瘤杀死至关重要，特别是在免疫抑制肿瘤微环境的环境中。为此，我们研究了清道夫受体CD5。 CD5与TCR复合物相关联，并通过几种抑制其激活介体，包括SHP-1，CBL，CBL-B和GRB2。该赠款的中心假设是CD5删除通过增强TCR信号传导，提高了工程T细胞的抗肿瘤功效。在我们的初步中工作，我们发现CRISPR-CAS9 CD5在CART细胞中敲出会增强其在 B细胞白血病（CART19）和T细胞淋巴瘤（CART5）的异种移植模型。此外，我们证明了这一点，刺激后，CD5敲除手推车细胞显示关键CAR信号介体的较高磷酸化，因为与野生型相比。在AIM＃1中，我们将检验以下假设：T细胞中CD5的缺失广泛增强通过在CAR T的环境中研究CD5敲除，采用T细胞免疫疗法的抗肿瘤功效实体瘤的细胞。在AIM＃2中，我们将测试CD5缺失增强T细胞抗肿瘤活性的假设通过通过体外和体内机械研究来抑制CAR信号传导。我们还将测试安全性这种方法。该假设驱动的建议具有高度创新性，因为它提出了一项新颖的研究免疫调节目标-CD5-并使用尖端技术，例如数字空间分析和单细胞 RNA测序研究CD5在人体和鼠模型中都在体内删除了CAR T细胞。成功拟议的调查的结果预计将对癌症免疫疗法的领域产生重大影响，提供一种合理且可推广的方法来改善T细胞免疫疗法并最终推动开发了CD5敲除耐火罐的CD5临床试验的开发。