Development of a tumor-activated IL12 prodrug to treat solid tumors
Development of a tumor-activated IL12 prodrug to treat solid tumors
批准号:
10152759
负责人:
Benjamin Moon
金额:
$3.65万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-02-01 至 2025-01-31
关键词:
AccountingAcidityAddressAdoptive TransferAdverse effectsAffinityAntibodiesAntitumor ResponseBindingBiodistributionBiological AssayBiological MarkersBloodBody WeightBody Weight decreasedBody Weights and MeasuresC57BL/6 MouseCD8-Positive T-LymphocytesCD8B1 geneCause of DeathCell Differentiation processCellsCellular ImmunityCessation of lifeCleaved cellClinicalClinical TrialsCombined Modality TherapyComplexDataDevelopmentDoseDrug DesignDrug KineticsEffector CellEnzymesExposure toFutureGoalsHistologyHomeostasisHumanHypoxiaImmuneImmune checkpoint inhibitorImmune responseImmunotherapeutic agentImmunotherapyImpairmentInterferon Type IIInterleukin-12KineticsLymphoid CellMC38MMP14 geneMalignant NeoplasmsMeasuresMediatingModalityModelingMolecularMolecular ConformationMonitorMusNatural Killer CellsNear-infrared optical imagingNeoplasm MetastasisPatientsPharmaceutical PreparationsPlayPre-Clinical ModelProdrugsProductionPrognostic MarkerPropertyRefractoryRoleScheduleSerumSignal PathwaySignal TransductionSiteSolid NeoplasmSupporting CellT-LymphocyteTestingTissue SampleToxic effectTumor ImmunityTumor-infiltrating immune cellsType I Epithelial Receptor CellUnited Statesantitumor effectbasecancer immunotherapycell typeclinical developmentconventional therapycytokineflexibilitygenetic signatureimmune checkpointimprovedin vivoinsightneoplastic cellnovelnovel therapeuticsoverexpressionpreclinical studypreclinical trialpreventreceptorresponsesingle-cell RNA sequencingsubcutaneoussuccesssynergismtumortumor microenvironment
中文摘要
项目概要/摘要:
尽管癌症免疫疗法最近取得了进展,但由于肿瘤免疫抑制,实体瘤在很大程度上仍然难以治疗。
肿瘤微环境(TME)破坏免疫稳态。在TME内,
缺氧、酸性、抑制性细胞和免疫检查点导致I型效应细胞分化不良,
阻止了强大免疫反应的发展。IL 12是一种天然产生的细胞因子,
通过先天淋巴细胞(ILC)上的IL 12 R β1/IL 12 R β2复合物诱导I型细胞介导的免疫
和T细胞。IL 12在临床前试验中已经非常成功地对抗实体瘤,但其临床应用还不多见。
由于系统性免疫过度激活而导致的致命毒性损害了发育。我开发了一个
一种新的基于IL-12的前药(proIL-12),其在体内没有明显的毒性,但保持完全的抗肿瘤活性,
功效proIL 12的动力学和细胞机制仍需确定,但初步数据表明,
T细胞起关键作用,IFNγ是诱导的主要细胞因子。因此,我假设proIL 12在体内循环
以惰性前药形式存在,直到被肿瘤特异性酶激活,此时它直接通过
IL-12受体介导,IFN-γ介导。为了验证我的假设,我将首先验证proIL 12的药物
通过确定最佳给药方案、监测肿瘤特异性活化和测量毒性来确定肿瘤特征。
然后,我将探索ILC和T细胞中哪些特定的细胞亚型是排斥肿瘤所必需的。最后,
我将独立评估IFNγ在协调proIL 12应答中的下游作用。通过系统地
为了表征proIL 12的物理和机械特性,我不仅将其用于进一步的临床应用,
这些信息不仅可以帮助开发,而且可以为未来的步骤提供信息,例如联合治疗或预后标记物。作为一个整体,我
研究将产生一种能够逆转TME诱导的免疫紊乱的可耐受的免疫抑制剂,
消除实体肿瘤。
英文摘要
Project Summary/Abstract:
Despite recent advances in cancer immunotherapy, solid tumors remain largely refractory to treatment due to
disruption of immune homeostasis by the tumor microenvironment (TME). Within the TME, a combination of
hypoxia, acidity, suppressive cells, and immune checkpoints leads to poor differentiation of type I effector cells,
preventing the development of a robust immune response. IL12 is a naturally produced cytokine that can directly
induce type I, cell-mediated immunity through the IL12Rβ1/IL12Rβ2 complex on innate lymphoid cells (ILCs)
and T cells. IL12 has been remarkably successful against solid tumors in preclinical trials, but its clinical
development has been impaired by lethal toxicity due to systemic immune overactivation. I have developed a
novel IL12-based prodrug (proIL12) that displays no noticeable toxicity in vivo but maintains full antitumor
efficacy. The kinetics and cellular mechanism of proIL12 must still be ascertained, but preliminary data suggests
T cells play a critical role and IFNγ is the main cytokine induced. Therefore, I hypothesize that proIL12 circulates
in inert prodrug form until activated by tumor-specific enzymes, at which point it activates T cells directly through
IL12 receptor and secondarily through IFNγ production. To test my hypothesis, I will first validate proIL12’s drug
profile by determining an optimal dosing schedule, monitoring tumor-specific activation, and measuring toxicity.
Then, I will explore which specific cell subtypes among ILCs and T cells are necessary to reject tumors. Finally,
I will independently assess the downstream role of IFNγ in coordinating the proIL12 response. By systematically
characterizing both physical and mechanistic properties of proIL12, I will not only prepare it for further clinical
development but also inform future steps such as combination therapies or prognostic markers. As a whole, my
study will produce a tolerable immunotherapeutic agent capable of reversing TME-induced immune disarray to
eliminate solid tumors.
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会议论文
Development of a tumor-activated IL12 prodrug to treat solid tumors
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批准号:10558656
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项目类别:
-
资助金额:$4.68万
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财政年份:2021
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负责人:Benjamin Moon
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依托单位:
Development of a tumor-activated IL12 prodrug to treat solid tumors
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批准号:10374765
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项目类别:
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资助金额:$5.18万
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财政年份:2021
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负责人:Benjamin Moon
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依托单位:
海外基金