Repolarizing the Tumor and Metastatic Microenvironments to Treat Patients with Pancreatic Cancer
重新极化肿瘤和转移性微环境来治疗胰腺癌患者
基本信息
- 批准号:10278557
- 负责人:
- 金额:$ 51.6万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-02 至 2026-07-31
- 项目状态:未结题
- 来源:
- 关键词:AddressBiopsyBlood specimenCD8-Positive T-LymphocytesCancer EtiologyCancer ModelCellsCessation of lifeClinicClinical TrialsCombination immunotherapyCombined Modality TherapyCytotoxic T-LymphocytesDataDiagnosisDiseaseDistalEncapsulatedEnrollmentExcisionExhibitsFutureGenetically Engineered MouseHumanImmuneImmune responseImmune systemImmunologicsImmunotherapeutic agentImmunotherapyInjectionsInnate Immune SystemInnovative TherapyInterferon Type IIInterleukin-12LeadMalignant NeoplasmsMediatingMetastatic Neoplasm to the LiverMetastatic/RecurrentMicrospheresMusMyeloid CellsMyeloid-derived suppressor cellsNeoplasm MetastasisOperative Surgical ProceduresOutcomePancreasPancreatic Ductal AdenocarcinomaPatientsPeptide HydrolasesPharmacologic SubstancePolymersPre-Clinical ModelPrimary NeoplasmProductionPrognosisProgression-Free SurvivalsPublishingRadiation Dose UnitRadiation therapyResearch PersonnelResectableSafetySamplingScheduleTechnologyTestingTherapeuticTherapeutic EffectTranslatingUltrasonographyUnited StatesUnresectableWorkadaptive immune responseadvanced pancreatic cancerarmbench to bedsidecancer typeclinical applicationclinically relevantcytokineeffective therapyeffector T cellefficacy evaluationfirst-in-humanimmunoregulationimprovedinnovationirradiationmultiple sclerosis treatmentnovelpancreatic cancer cellspancreatic cancer patientspancreatic neoplasmperipheral bloodpre-clinicalprotein degradationresponsesuccesssystemic toxicitytooltreatment optimizationtreatment strategytumortumor microenvironmenttumor-immune system interactions
项目摘要
Pancreatic ductal adenocarcinoma cancer (PDAC) is the 3rd most common cause of cancer deaths in the United
States with a dismal 5-year overall survival of 9%. Surgical intervention is currently the only cure for PDAC,
however, 80% of patients are deemed unresectable at presentation due to locally advanced and/or metastatic
disease. Existing therapies are often unable to downsize locally advanced PDAC (LAPC) for surgical candidacy,
and are also ineffective at providing distal tumor control. Therapeutic approaches capable of both local
downstaging and recurrent/metastatic tumor control are desperately needed to improve resectability rates. This
application will address the unmet need by translating an innovative combination immunotherapy to the clinic
and exploring its effects on LAPC in humans. Our recently published work demonstrated that stereotactic body
radiotherapy (SBRT), a less toxic, more effective strategy that focuses higher dose radiation precisely to the
tumor, combined with the potent immune cell–stimulating cytokine interleukin-12 (IL-12) encapsulated in polymer
microspheres (IL-12MS) resulted in remarkable tumor control and durable cure in preclinical models.
Microsphere technology represents an innovative tool that provides a slow, continuous release of cytokine
intratumorally while also protecting the labile IL-12 protein from degradation by proteases. The combination of
SBRT with IL-12MS not only strongly stimulated the adaptive arm of the immune system including cytotoxic T
cells to destroy pancreatic tumor cells, but also had a repolarizing effect on cells of innate immune system
converting typically immunosuppressive myeloid cells into ones with immunostimulatory potential. Moving this
promising therapy into the clinic, we hypothesize that combined SBRT/IL-12MS therapy is safe and
tolerable, and will improve progression-free survival and tumor downstaging to enable resection in
LAPC. In Aim 1, we will establish a clinical trial exploring the first-in-human use of SBRT followed by ultrasound-
guided IL-12MS delivery in patients with unresectable LAPC. The main objective is to evaluate safety and
tolerability, and the secondary objective is to evaluate efficacy and overall outcome. Aim 2 will perform corollary
studies on peripheral blood along with baseline and on-study tumor biopsies collected from enrolled patients.
These data will address whether SBRT/IL-12MS repolarizes the tumor microenvironment (TME) from an
immunologically “cold” tumor to one that is immunologically “hot”. Aim 3 will utilize preclinical modelling to
develop a strategy to treat metastatic PDAC using SBRT/IL-12MS therapy. These results are essential in order
to expand this therapy into metastatic patients where there are little to no effective treatments. Overall, our
proposed application builds on promising preclinical data showing the potential efficacy of combined SBRT/IL-
12MS therapy for patients with LAPC/metastatic lesions. This technologically innovative strategy utilizes a unique
strategy of repolarizing the TME to treat this recalcitrant malignancy for which there are few effective therapies.
在美国,胰腺导管腺癌是导致癌症死亡的第三大常见原因。
令人沮丧的5年总体存活率为9%的州。手术治疗是目前治疗PDAC的唯一方法,
然而,80%的患者在就诊时由于局部晚期和/或转移而被认为不能切除。
疾病。现有的治疗方法通常不能缩小局部晚期PDAC(LAPC)的手术候选范围,
并且在提供远端肿瘤控制方面也是无效的。两种局部治疗方法都能
降低分期和控制复发/转移肿瘤是提高切除率的迫切需要。这
应用程序将通过将创新的联合免疫疗法转化为临床来解决未得到满足的需求
并探索其对人类LAPC的影响。我们最近发表的研究表明,立体定向体
放射治疗(SBRT),一种毒性较小、更有效的策略,将更高剂量的辐射精确地聚焦到
肿瘤,结合聚合物包裹的强大的免疫细胞刺激细胞因子白介素12(IL-12)
在临床前模型中,微球(IL-12MS)具有显著的肿瘤控制和持久治愈作用。
微球技术代表了一种创新的工具,它提供了缓慢、连续的细胞因子释放
同时保护不稳定的IL-12蛋白不被蛋白酶降解。这两种技术的结合
使用IL-12MS的SBRT不仅强烈刺激包括细胞毒T细胞在内的免疫系统的适应性臂
细胞破坏胰腺肿瘤细胞,也对细胞的先天免疫系统有复极化作用
将典型的免疫抑制髓系细胞转化为具有免疫刺激潜力的细胞。把这个搬到
我们假设SBRT/IL-12MS联合治疗是安全的和
可耐受,并将改善无进展生存率和肿瘤降期,使手术切除成为可能
LAPC。在目标1中,我们将建立一项临床试验,探索SBRT在人类中的第一次使用,然后是超声波-
IL-12MS在不能切除的LAPC患者中的应用主要目标是评估安全性和
耐受性,次要目标是评估疗效和总体结果。目标2将执行推论
外周血研究以及从登记患者收集的基线和研究中的肿瘤活检。
这些数据将解决SBRT/IL-12MS是否会使肿瘤微环境(TME)从
从免疫“冷”瘤到免疫“热”瘤。目标3将利用临床前建模来
开发一种使用SBRT/IL-12MS治疗转移性PDAC的策略。这些结果在顺序上是必不可少的
将这种疗法推广到几乎没有有效治疗方法的转移性患者。总的来说,我们的
拟议的应用建立在前景看好的临床前数据的基础上,显示了SBRT/IL-1联合治疗的潜在疗效。
12MS治疗LAPC/转移性病变。这一技术创新战略利用了一种独特的
重新极化TME的策略来治疗这种几乎没有有效治疗方法的顽固性恶性肿瘤。
项目成果
期刊论文数量(0)
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Scott Andrew Gerber其他文献
Scott Andrew Gerber的其他文献
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{{ truncateString('Scott Andrew Gerber', 18)}}的其他基金
Repolarizing the Tumor and Metastatic Microenvironments to Treat Patients with Pancreatic Cancer
重新极化肿瘤和转移性微环境来治疗胰腺癌患者
- 批准号:
10460543 - 财政年份:2021
- 资助金额:
$ 51.6万 - 项目类别:
Targeting adrenergic stress pathways to Increase tumor sensitivity to radiation and promote development of an anti-tumor immune response
针对肾上腺素能应激途径,提高肿瘤对辐射的敏感性并促进抗肿瘤免疫反应的发展
- 批准号:
10331775 - 财政年份:2019
- 资助金额:
$ 51.6万 - 项目类别:
Targeting adrenergic stress pathways to Increase tumor sensitivity to radiation and promote development of an anti-tumor immune response
针对肾上腺素能应激途径,提高肿瘤对辐射的敏感性并促进抗肿瘤免疫反应的发展
- 批准号:
10083200 - 财政年份:2019
- 资助金额:
$ 51.6万 - 项目类别:
Development of a New Strategy to Treat Locally Advanced Pancreatic Cancer
开发治疗局部晚期胰腺癌的新策略
- 批准号:
10377966 - 财政年份:2019
- 资助金额:
$ 51.6万 - 项目类别:
Development of a New Strategy to Treat Locally Advanced Pancreatic Cancer
开发治疗局部晚期胰腺癌的新策略
- 批准号:
9918927 - 财政年份:2019
- 资助金额:
$ 51.6万 - 项目类别:
Development of a New Strategy to Treat Locally Advanced Pancreatic Cancer
开发治疗局部晚期胰腺癌的新策略
- 批准号:
10610324 - 财政年份:2019
- 资助金额:
$ 51.6万 - 项目类别:
Targeting adrenergic stress pathways to Increase tumor sensitivity to radiation and promote development of an anti-tumor immune response
针对肾上腺素能应激途径,提高肿瘤对辐射的敏感性并促进抗肿瘤免疫反应的发展
- 批准号:
10559547 - 财政年份:2019
- 资助金额:
$ 51.6万 - 项目类别:
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