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: 10333517
• 负责人: Vinod P Balachandran
• 金额: $ 53.49万
• 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/10333517
• 关键词: 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; 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 and Toxicology; Phenotype; Pre-Clinical Model; Primary Neoplasm; Proteins; Recombinant Interleukins; Recombinants; Reporter; Resistance; Safety; Sampling; Signal Transduction; Site; Skin; Specimen; Survivors; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Tissues; Toxicology; Translating; Translations; Tumor Immunity; Work; anti-PD-1; anti-PD1 antibodies; anti-PD1 therapy; biomarker-driven; cancer immunotherapy; cancer therapy; chemokine; cohort; cytokine; cytotoxicity; density; design; drug mechanism; 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.

项目总结--RP3 免疫疗法可以诱导晚期癌症患者的持久反应，是最令人兴奋的新疗法 癌症治疗。然而，由于目前的免疫疗法直接重振原有的抗肿瘤T细胞， 它们对T细胞缺乏(“冷”)的癌症无效，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。为了确定这样的策略， 我们发现，与大多数T细胞贫乏和“冷”的PDAC相比，富含T细胞的“热”肿瘤 罕见的长期PDAC幸存者被较高密度的第2组固有淋巴样细胞(ILC2s)渗透， 一种新近发现的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激活的细胞因子IL-33的高表达与CD8+T细胞密度的高相关， 在人的PDAC中，T细胞具有更强的杀伤活性，存活时间延长2倍。使用PDAC小鼠模型，我们发现 重组IL33(RIL33)系统输送激活肿瘤ILC2s产生趋化因子CCL5，Recruit 肿瘤内树突状细胞，将肿瘤内CD8+T细胞放大10倍，并限制肿瘤生长。另外，就像 活化的T细胞，rIL33激活的ILC2s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抗体阻断最大限度地限制了肿瘤的生长和延长了生存时间。 因此，我们的实验室研究确定rIL33是一种新的治疗性细胞因子，可以刺激从头开始的抗肿瘤。 PDAC中的免疫作为单用或与PD-1拮抗剂联合治疗。然而，由于有 目前还没有针对IL33-ILC2轴的药物，也没有针对人PDAC肿瘤的免疫学药物 异质、适当的药物传递策略和目标患者队列，以合理地翻译这些 对PDAC患者的发现是未知的。我们将通过三个具体目标来解决这些关键的知识差距 为了确定rIL33在免疫异质性PDAC分子亚型中是否具有抗肿瘤效果(1)， (2)在免疫异质性的PDAC原发肿瘤和转移瘤中，以及(3)作为半衰期延长的临床- 相容的药物。我们将完成这些目标，从而建立将rIL33翻译给患者的原则 对IL33-ILC2轴成分缺陷的原位PDAC小鼠进行机制研究，患者来源 肿瘤免疫微环境的有机模型、配对多基因的细胞和转录分析 现场人类PDAC原发肿瘤和转移，以及启用IND的毒理学研究。通过这些研究， 我们将确定目标患者队列、作用机制和最佳药物，以指导设计 在研究结束时，在PDAC患者中进行第一次人类rIL33临床试验。因此，这项工作将 批判性地扩展我们对新的IL33-ILC2治疗轴的临床前和翻译生物学的知识， 加速将其转化为患者，并解决对有效的PDAC免疫疗法的未得到满足的需求。