Enhancing antitumor immunity with anti-PD-1 antibody in follicular lymphoma.

利用抗 PD-1 抗体增强滤泡性淋巴瘤的抗肿瘤免疫力。

基本信息

批准号：
8007379
负责人：
Sattva S Neelapu
金额：
$ 27.98万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-01 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8007379
关键词：
Activated Natural Killer Cell Age Antibodies Antibody Therapy Autologous Tumor Cell B-Lymphocytes Binding Blocking Antibodies CD14 gene CD8B1 gene Cells Cessation of life Chemotherapy-Oncologic Procedure Clinical Colon Carcinoma Development Diagnosis Disease Disease remission Dose Elderly Enhancing Antibodies Enrollment Epitopes Fatal Outcome Follicular Lymphoma Frequencies Gene Expression Profile Goals Growth Hematologic Neoplasms Human Immune Immune response Immune system Immunity Immunoglobulin G Immunologic Memory Immunosuppressive Agents Immunotherapeutic agent Indolent Infusion procedures Lead Ligands Lymphoma Malignant neoplasm of lung Mediating Monoclonal Antibodies Monoclonal Antibody CD20 Mus Myeloid Cells Natural Killer Cells Neoplasms Non-Malignant Outcome Pathway interactions Patients Pattern Pharmaceutical Preparations Phase I Clinical Trials Phase II Clinical Trials Population Production Progression-Free Survivals Recombinants Relapse Respiratory Diaphragm Safety Serious Adverse Event T memory cell T-Cell Depletion T-Lymphocyte T-Lymphocyte and Natural Killer Cell Toxic effect Variant antibody-dependent cell cytotoxicity arm clinical efficacy clinical remission cytokine fibrosarcoma improved in vivo leukemia/lymphoma malignant breast neoplasm melanoma mouse model novel preclinical study programs public health relevance receptor response rituximab tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): The observation of spontaneous clinical remissions, correlation of gene expression signatures of infiltrating nonmalignant immune cells in the tumor with survival, and the high response rates following administration of rituximab, an anti-CD20 monoclonal antibody suggest that follicular lymphomas are particularly immune responsive. However, immunosuppressive factors in the tumor microenvironment may render the endogenous anti-tumor immune responses ineffective. Recently, the inhibitory receptor programmed death 1 (PD-1), a negative regulator of activated T cells and natural killer cells, was demonstrated to be markedly upregulated on intratumoral CD4+ and CD8+ T cells in patients with follicular lymphoma. PD-1 expression was associated with impaired function of CD4+ and CD8+ T cells and blockade of the PD-1/PD-ligand pathway with antibody against PD-1 significantly enhanced proliferation of intratumoral CD4+ and CD8+ T-cells and induced production of TH1 but not TH2 cytokines in response to autologous tumor cells obtained from patients with follicular lymphoma. In the current proposal, we intend to reverse the inhibitory effects of the PD-1/PD-ligand pathway in patients with follicular lymphoma. The central hypothesis of this proposal is that blockade of the interaction of PD-1 with its ligands by using CT-011, an anti-PD-1 blocking antibody, will enhance the endogenous antitumor T-cell and natural killer-cell immune responses in patients with follicular lymphoma and lead to clinical regression of the tumors. Furthermore, we hypothesize that CT-011 will enhance the antibody-dependent cell-mediated cytotoxicity mediated by natural killer cells and lead to increased clinical efficacy following administration of rituximab. To accomplish the objectives of this proposal, we will conduct a phase 2 clinical trial of CT-011 combined with rituximab in patients with relapsed follicular lymphoma. Three Specific Aims are proposed: 1) determine the safety and clinical efficacy of CT-011 administered in combination with rituximab in patients with relapsed follicular lymphoma, 2) determine the effects of CT-011 on the frequency and function of tumor-specific T cells in patients with follicular lymphoma, and 3) determine the effects of CT-011 on the function of natural killer cells in patients with follicular lymphoma. The combination of the two drugs, CT-011 and rituximab is expected to improve the clinical efficacy without increasing the toxicity. Given that the median age of FL patients at diagnosis is 60 years, developing such nontoxic but efficacious immunotherapeutic approaches is highly desirable. PUBLIC HEALTH RELEVANCE: The combined use of the two antibody therapies, CT-011 and rituximab is likely to be complementary and may be even synergistic and lead to enhanced clinical efficacy without increasing the toxicity in patients with follicular lymphoma. Development of such efficacious but nontoxic immunotherapeutic approaches is highly desirable for the treatment of follicular lymphoma since it is most commonly diagnosed in the elderly population. Due to activation of multiple arms of the immune system using this approach, it can potentially minimize the emergence of tumor variants that escape the immune system and therefore can improve the chance of our goal to find a curative therapy for this disease.

描述（由申请人提供）：自发性临床缓解的观察，肿瘤中浸润非明位的免疫细胞的基因表达特征的相关性以及生存后的较高反应率，rituximab（一种抗CD20单克隆抗体）的高反应率表明纤维淋巴结尤其是免疫反应的。但是，肿瘤微环境中的免疫抑制因子可能会使内源性抗肿瘤免疫反应无效。最近，在卵泡淋巴瘤患者的肿瘤内CD4+和CD8+ T细胞中，抑制性受体编程死亡1（PD-1）是活化T细胞和天然杀伤细胞的负调节剂。 PD-1的表达与CD4+和CD8+ T细胞的功能受损以及对PD-1抗体的PD-1/PD-RIGAND途径的阻断相关，可显着增强肿瘤内CD4+和CD8+ T细胞的增殖，以及诱导TH1的产生Th2细胞因子，但对自体肿瘤细胞的产生而不是诱导的Th2细胞因子，该细胞因子响应于自体型肿瘤细胞中获得的Th2细胞因子。在当前的提案中，我们打算扭转PD-1/PD配体途径对卵泡淋巴瘤患者的抑制作用。该提案的中心假设是，通过使用CT-011（一种抗PD-1阻断抗体）阻断PD-1与配体的相互作用，将增强内源性抗肿瘤T细胞T细胞T细胞和天然杀伤剂细胞免疫反应，并在患有卵泡性淋巴瘤的患者中并导致肿瘤临床回归。此外，我们假设CT-011将增强由天然杀伤细胞介导的抗体依赖性细胞介导的细胞毒性，并导致利妥昔单抗给药后临床疗效提高。为了实现该提案的目标，我们将在复发性卵泡淋巴瘤患者中进行CT-011与利妥昔单抗结合使用的2期临床试验。提出了三个具体目的：1）确定在复发性卵泡淋巴瘤患者中与中利妥昔单抗结合使用的CT-011的安全性和临床功效，2）确定CT-011对follicular淋巴瘤患者的肿瘤特异性T细胞频率和功能的影响，以及3）确定CT-011患者对CT-011患者的影响。淋巴瘤。两种药物CT-011和利妥昔单抗的组合有望提高临床功效而不会增加毒性。鉴于诊断时FL患者的中位年龄为60年，因此非常需要发展这种无毒但有效的免疫治疗方法。公共卫生相关性：两种抗体疗法的综合使用CT-011和利妥昔单抗可能是互补的，甚至可能具有协同作用，并且可以提高临床疗效，而不会增加卵泡淋巴瘤患者的毒性。对于治疗卵泡淋巴瘤的治疗非常需要开发这种有效但无毒的免疫治疗方法，因为它在老年人群中最常被诊断出来。由于使用这种方法激活了免疫系统的多个臂，它可能会最大程度地减少逃避免疫系统的肿瘤变异体的出现，因此可以提高我们目标的机会，以找到治疗这种疾病的治疗疗法。