Recombinant Interleukin-33 Immunotherapy for Pancreatic Cancer

重组白细胞介素 33 胰腺癌免疫疗法

• 批准号: 10708752
• 负责人: Vinod P Balachandran
• 金额: $ 55.25万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708752
• 关键词: Acceleration; Address; Advanced Malignant Neoplasm; Albumins; Antitumor Response; Biological Markers; Biology; CD8-Positive T-Lymphocytes; Cancer Patient; Canis familiaris; Cell Density; Cells; Clinic; Clinical; Clinical Trials; Coculture Techniques; Combined Modality Therapy; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Genetic Transcription; Half-Life; Human; Immunity; Immunologics; Immunotherapy; Infiltration; Interleukins; Knowledge; Laboratory Study; Lead; Life Extension; Liver; Lung; Lymphocyte; Lymphoid Cell; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Memorial Sloan-Kettering Cancer Center; Metastatic Adenocarcinoma; Modeling; Molecular; Morals; Mus; Nature; Neoplasm Metastasis; Organoids; PD-1 blockade; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Peritoneum; Pharmaceutical Preparations; Pharmacology; Phenotype; Pre-Clinical Model; Primary Neoplasm; Proteins; Recombinant Interleukins; Recombinants; Reporter; Resistance; Safety; Sampling; Signal Transduction; Site; Specimen; Survivors; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Tissues; Toxicology; Translating; Translations; Tumor Expansion; Tumor Immunity; Work; anti-PD-1; anti-PD1 antibodies; anti-PD1 therapy; biomarker driven; biomarker identification; cancer immunotherapy; cancer therapy; checkpoint inhibition; chemokine; clinic ready; cohort; cytokine; cytotoxicity; design; first-in-human; immune checkpoint; inhibiting antibody; lymph nodes; molecular subtypes; mouse model; neoplastic cell; novel; novel strategies; novel therapeutics; pre-clinical; programmed cell death protein 1; rare cancer; receptor; recruit; refractory cancer; response; transcriptomics; tumor; tumor growth; tumor-immune system interactions

PROJECT SUMMARY – RP3 Immunotherapies can induce durable responses in advanced cancer patients and are the most exciting new cancer treatments. However, as current immunotherapies directly reinvigorate preexisting anti-tumor T cells, they are ineffective in T cell-poor (“cold”) cancers, such as pancreatic ductal adenocarcinoma (PDAC). New immunotherapies that stimulate de novo immunity are therefore needed for PDAC. To identify such strategies, we discovered that compared to the majority of PDACs that are T-cell poor and “cold,” T-cell rich “hot” tumors from rare long-term PDAC survivors are infiltrated by higher densities of group 2 innate lymphoid cells (ILC2s), a recently discovered lymphocyte with tissue-specific anti-tumor function. Higher densities of tumor ILC2s and higher expression of the ILC2-activating cytokine interleukin-33 (IL33) correlated with higher CD8+ T cell density, greater T cell cytolytic activity, and 2-fold longer survival in human PDAC. Using PDAC mouse models, we found that systemic delivery of recombinant IL33 (rIL33) activated tumor ILC2s to produce the chemokine Ccl5, recruit intratumoral dendritic cells, amplify intratumoral CD8+ T cells 10-fold, and restrict tumor growth. In addition, like activated T cells, rIL33-activated ILC2s upregulated the inhibitory immune checkpoint PD-1, and combining rIL33 with PD-1 antibody blockade maximally restricted tumor growth and prolonged survival in PDAC mouse models. Thus, our laboratory studies identify rIL33 as a novel therapeutic cytokine that stimulates de novo anti-tumor immunity in PDAC both as a mono- and as a combination therapy with PD-1 blockade. However, as there are currently no drugs that target the IL33-ILC2 axis, and as human PDAC tumors are immunologically heterogeneous, the appropriate drug delivery strategy and target patient cohorts to rationally translate these findings to PDAC patients are unknown. We will address these key knowledge gaps through three specific aims to determine if rIL33 has anti-tumor efficacy (1) in immunologically heterogeneous PDAC molecular subtypes, (2) in immunologically heterogeneous PDAC primary tumors and metastases, and (3) as half-life extended clinic- compatible drugs. We will complete these aims and thereby establish the principles to translate rIL33 to patients using mechanistic studies in orthotopic PDAC mice deficient in components of the IL33-ILC2 axis, patient-derived organoid models of the tumor immune microenvironment, cellular and transcriptional analyses of matched multi- site human PDAC primary tumors and metastases, and IND-enabling toxicology studies. Through these studies, we will identify the target patient cohorts, the mechanisms of action, and the optimal drug to inform the design of a first-in-human rIL33 clinical trial in PDAC patients by the end of the study period. This work will therefore critically expand our knowledge of preclinical and translational biology of the novel IL33-ILC2 therapeutic axis, accelerate its translation to patients, and address the unmet need for effective PDAC immunotherapy.

项目摘要 – RP3 免疫疗法可以在晚期癌症患者中诱导持久反应，是最令人兴奋的新疗法 癌症治疗。然而，由于当前的免疫疗法直接重振先前存在的抗肿瘤 T 细胞， 它们对缺乏 T 细胞（“冷”）的癌症无效，例如胰腺导管腺癌 (PDAC)。新的 因此，PDAC 需要刺激从头免疫的免疫疗法。为了确定此类策略， 我们发现，与大多数缺乏 T 细胞和“冷”的 PDAC 相比，富含 T 细胞的“热”肿瘤 来自罕见的长期 PDAC 幸存者的细胞被更高密度的第 2 组先天淋巴细胞 (ILC2) 浸润， 最近发现的一种具有组织特异性抗肿瘤功能的淋巴细胞。更高密度的肿瘤 ILC2 和 ILC2 激活细胞因子白细胞介素 33 (IL33) 的较高表达与较高的 CD8+ T 细胞密度相关， 更强的 T 细胞溶细胞活性，以及​​人类 PDAC 中 2 倍的存活时间。使用 PDAC 小鼠模型，我们发现 重组IL33（rIL33）的全身递送激活肿瘤ILC2以产生趋化因子Ccl5，招募 瘤内树突状细胞，将瘤内 CD8+ T 细胞放大 10 倍，并限制肿瘤生长。另外，像 激活的T细胞，rIL33激活的ILC2上调抑制性免疫检查点PD-1，并结合rIL33 在 PDAC 小鼠模型中，PD-1 抗体阻断可最大程度地限制肿瘤生长并延长生存期。 因此，我们的实验室研究将 rIL33 确定为一种新型治疗性细胞因子，可刺激从头抗肿瘤 作为单一疗法和与 PD-1 阻断剂的联合疗法，PDAC 具有免疫性。然而，正如有 目前还没有针对IL33-ILC2轴的药物，并且由于人类PDAC肿瘤是免疫学的 异质性、适当的药物输送策略和目标患者群体，以合理地转化这些 PDAC 患者的研究结果尚不清楚。我们将通过三个具体目标来解决这些关键知识差距 确定 rIL33 是否在免疫异质性 PDAC 分子亚型中具有抗肿瘤功效 (1)， (2) 在免疫异质性 PDAC 原发性肿瘤和转移瘤中，以及 (3) 作为半衰期延长的临床- 兼容药物。我们将完成这些目标，从而确立将 rIL33 转化为患者的原则 对缺乏 IL33-ILC2 轴成分的原位 PDAC 小鼠进行机制研究，源自患者 肿瘤免疫微环境的类器官模型，匹配的多细胞的细胞和转录分析 现场人类 PDAC 原发性肿瘤和转移，以及支持 IND 的毒理学研究。通过这些研究， 我们将确定目标患者群体、作用机制和最佳药物，为设计提供信息 到研究期结束时，将在 PDAC 患者中进行首次人体 rIL33 临床试验。因此这项工作将 批判性地扩展我们对新型 IL33-ILC2 治疗轴的临床前和转化生物学的了解， 加速其向患者的转化，并解决有效 PDAC 免疫疗法未满足的需求。