Recombinant Interleukin-33 Immunotherapy for Pancreatic Cancer

项目总结-RP 3 免疫疗法可以在晚期癌症患者中诱导持久的反应，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先前存在的抗肿瘤T细胞， 它们在T细胞贫乏（“冷”）癌症如胰腺导管腺癌（PDAC）中无效。新 因此，PDAC需要刺激从头免疫的免疫疗法。为了确定这些战略， 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存活者的细胞被较高密度的第2组先天淋巴样细胞（ILC 2）浸润， 最近发现的具有组织特异性抗肿瘤功能的淋巴细胞。肿瘤ILC 2密度较高， ILC 2激活细胞因子白细胞介素-33（IL 33）的较高表达与较高的CD 8 + T细胞密度相关， 更大的T细胞溶细胞活性，以及在人PDAC中2倍长的存活。使用PDAC小鼠模型，我们发现 重组IL-33（rIL-33）的全身递送激活肿瘤IL-2以产生趋化因子Cc 1 - 5， 肿瘤内树突状细胞，扩增肿瘤内CD 8 + T细胞10倍，并限制肿瘤生长。另外像 活化的T细胞，rIL 33活化的ILC 2上调抑制性免疫检查点PD-1，并且结合rIL 33 PD-I抗体阻断最大限度地限制了肿瘤生长并延长了PDAC小鼠模型中的存活。 因此，我们的实验室研究将rIL 33鉴定为一种新的治疗性细胞因子，其刺激从头抗肿瘤作用。 作为单一疗法和作为与PD-1阻断剂的组合疗法，PDAC中的免疫力。然而，由于有 目前没有靶向IL 33-ILC 2轴的药物，并且由于人PDAC肿瘤在免疫学上是 异质性，适当的药物递送策略和目标患者队列，以合理地转化这些 对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的知识差距 为了确定rIL 33是否具有抗肿瘤功效（1）在免疫异质性PDAC分子亚型中， (2)在免疫异质性PDAC原发性肿瘤和转移瘤中，和（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rIL 33翻译给患者的原则 使用IL 33-ILC 2轴组分缺陷的原位PDAC小鼠的机制研究，患者来源的 肿瘤免疫微环境的类器官模型，匹配的多个细胞的细胞和转录分析， 研究中心人PDAC原发性肿瘤和转移瘤，以及IND启用毒理学研究。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，以告知设计 在研究期结束时，在PDAC患者中进行首次人体rIL 33临床试验。这项工作将 批判性地扩展了我们对新型IL 33-ILC 2治疗轴的临床前和转化生物学的知识， 加速其向患者的转化，并解决有效PDAC免疫疗法的未满足需求。

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.