Gene Edited and Engineered Tumor Cell Therapeutics for Cancer
基因编辑和工程化肿瘤细胞治疗癌症
基本信息
- 批准号:10589097
- 负责人:
- 金额:$ 44.23万
- 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:2021-04-15 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:Active immunityAnimalsAutologousBackBehaviorBostonBrain NeoplasmsCD8-Positive T-LymphocytesCRISPR/Cas technologyCell LineCell TherapyCellsCirculationClinicalCollaborationsCytotoxic agentDataEncapsulatedEngineered GeneEngineeringEnsureExcisionExhibitsExtracellular MatrixGenesGenetic EngineeringGlioblastomaGliomaGoalsHomeHoming BehaviorHumanImmuneImmunityImmunizationImmunocompetentImmunomodulatorsImmunosuppressionImmunotherapyInterferon-betaKnock-outLigandsMacrophageMalignant NeoplasmsMalignant neoplasm of brainMetastatic/RecurrentModalityModelingMusNatural ImmunityNeoplasm MetastasisPatientsPositron-Emission TomographyPre-Clinical ModelPrimary NeoplasmProteinsPublishingRecurrenceRecurrent tumorResectedResidual NeoplasmResidual stateResistanceSafetyScienceSiteSolid NeoplasmSurgically-Created Resection CavityTestingTherapeuticTranslatingTreatment EfficacyTumor ImmunityTumor Stem Cellsadaptive immunityanti-tumor immune responsecancer cellcancer therapycancer typecell killingclinical translationcytotoxicdesignefficacy evaluationevidence basegranulocytehumanized mouseimaging agentimaging biomarkerimmune modulating agentsimmunoregulationin vivomouse modelneoplastic cellnovel therapeutic interventionnovel therapeuticspatient prognosispre-clinicalpreventreceptorrecruitstem cellstemozolomidetherapeutic genome editingtumortumor growthtumor microenvironmentvaccination strategy
项目摘要
SUMMARY
Despite recent advances in therapeutic strategies, the prognosis for patients with highly malignant brain tumors,
glioblastomas (GBM) remains poor, with a median survival of 12-19 months. Immunotherapy has emerged as a
promising approach for different cancer types. However, its efficacy in GBM has been limited primarily by overall
systemic immune suppression and the immune-suppressive tumor micro-environment. Recently, we have shown
CRISPR/Cas9 engineered self-targeting re-purposed cancer cells specifically home to tumor cells and release
targeted ligands that induce tumor cell killing which translates into survival benefits in mouse models of primary
and metastatic tumors. Based on our exciting studies, we have gene edited and subsequently engineered
syngeneic immunosuppressive GBM to express bi-functional immunomodulatory and cytotoxic protein, interferon
(IFN)β and granulocyte macrophage stimulating factor (GMCSF), which is known to induce both innate and
adaptive immunity. Our preliminary data reveal that repurposed immunosuppressive GBM cells do not proliferate
in vivo and elicit an active immunity which prevents tumor recurrence. These results although promising, have
raised fundamental questions for our tumor cell based gene edited therapy strategy to be characterized and
tested extensively in immunocompetent mouse tumor models that mimic clinical settings of immunosuppressive,
resected and recurrent immune-profiled GBM tumors. In this proposal, we will first develop and extensively
characterize a platform of gene edited and engineered syngeneic immunosuppressive and active GBM
therapeutic tumor cells (ThTC) and assess them for their mechanism based direct killing of parental GBM cells
and their ability to elicit active anti-tumor immunity in primary and recurrent mouse GBMs. Based on our previous
findings that GBM tumor resection promotes the recruitment of CD4/CD8 T cells and local delivery of synthetic
extracellular matrix (sECM) encapsulated immunomodulators has therapeutic efficacy, we will test sECM-ThTC
for their therapeutic efficacy in resected GBM mouse tumor models. We hypothesize that ThTC will lead to
specific killing of residual GBM cells in the tumor resection cavity of primary and recurrent GBMs and elicit active
immunity. To ease clinical translation, we will ultimately CRISPR/Cas9 gene edit and subsequently engineer
patient derived resected primary tumor cells (hTC) to express human IFN and GMCSF (hThTC). These hThTC
will be tested in recurrent GBM models generated from glioma stem cell (GSC) lines in humanized mice. The
integration of the safety kill switch, HSV-TK in ThTC will ensure safety in our approach and the incorporation of
genetically engineered imaging markers into both ThTC and GBMs will allow us to follow fate and efficacy in vivo
and thus to fine tune the proposed approaches. We anticipate that our findings will have a major contribution
towards developing novel ThTC based therapies for GBM and are likely to define a new treatment paradigm for
patients with other cancers.
概括
尽管在理论策略方面取得了最新进展,但对高度恶性脑肿瘤的患者的预后,
胶质母细胞瘤(GBM)仍然很差,中位存活率为12-19个月。免疫疗法已成为
不同癌症类型的有希望的方法。但是,它在GBM中的效率主要受到总体上的限制
全身免疫抑制和免疫抑制肿瘤微环境。最近,我们显示了
CRISPR/CAS9设计的自动靶向重新组合的癌细胞专门用于肿瘤细胞并释放
影响肿瘤细胞杀死的靶向配体,这转化为主要小鼠模型中的生存益处
和转移性肿瘤。基于我们令人兴奋的研究,我们对基因进行了编辑,随后进行了设计
合成性免疫抑制GBM以表达双功能免疫调节和细胞毒性蛋白,干扰素
(IFN)β和粒细胞巨噬细胞刺激因子(GMCSF),已知诱导先天和
自适应免疫。我们的初步数据表明,重新利用的免疫抑制GBM细胞不会增殖
体内并引起活跃的免疫学,可防止肿瘤复发。这些结果虽然很有希望,但
为我们的基于肿瘤细胞的基因编辑疗法策略提出了基本问题,以表征和
在免疫能力的小鼠肿瘤模型中进行了广泛的测试,这些模型模仿了免疫抑制的临床环境
切除并复发性的免疫型GBM肿瘤。在此提案中,我们将首先开发并广泛发展
表征了一个基因的平台编辑和设计的同基因免疫抑制和主动GBM
治疗性肿瘤细胞(THTC),并评估其基于机制的直接杀死父母GBM细胞
以及它们在原发性和复发小鼠GBM中引起主动抗肿瘤免疫的能力。根据我们以前的
GBM肿瘤切除促进CD4/CD8 T细胞的募集和合成的局部递送的发现
细胞外基质(SECM)封装的免疫调节剂具有治疗效率,我们将测试SECM-THTC
在切除的GBM小鼠肿瘤模型中其治疗效率。我们假设THTC会导致
在原发性和复发性GBM的肿瘤切除腔中残留的GBM细胞的特异性杀死并引起主动
免疫。为了简化临床翻译,我们最终将CRISPR/CAS9基因编辑,然后进行工程师
患者衍生的切除的原发性肿瘤细胞(HTC)表达人IFN和GMCSF(HTHTC)。这些HTHTC
将在人源化小鼠中由神经胶质瘤干细胞(GSC)系产生的复发性GBM模型进行测试。这
安全杀死开关的整合,THTC中的HSV-TK将确保我们的方法安全和使用
转基因成像标志物中的THTC和GBM都将使我们能够遵循体内的命运和效率
从而微调提出的方法。我们预计我们的发现将有重大贡献
旨在开发GBM的新型基于THTC的疗法,并可能定义一种新的治疗范式
患有其他癌症的患者。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Khalid A Shah其他文献
Khalid A Shah的其他文献
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{{ truncateString('Khalid A Shah', 18)}}的其他基金
Targeting metastatic tumors with engineered cellular therapies
通过工程细胞疗法靶向转移性肿瘤
- 批准号:
10774430 - 财政年份:2023
- 资助金额:
$ 44.23万 - 项目类别:
Gene Edited and Engineered Tumor Cell Therapeutics for Cancer
基因编辑和工程化肿瘤细胞治疗癌症
- 批准号:
10184164 - 财政年份:2021
- 资助金额:
$ 44.23万 - 项目类别:
Gene Edited and Engineered Tumor Cell Therapeutics for Cancer
基因编辑和工程化肿瘤细胞治疗癌症
- 批准号:
10386860 - 财政年份:2021
- 资助金额:
$ 44.23万 - 项目类别:
Engineered and Encapsulated Stem Cells for Resected Brain Tumors
用于切除脑肿瘤的工程化和封装干细胞
- 批准号:
10578780 - 财政年份:2019
- 资助金额:
$ 44.23万 - 项目类别:
Engineered and Encapsulated Stem Cells for Resected Brain Tumors
用于切除脑肿瘤的工程化和封装干细胞
- 批准号:
10355476 - 财政年份:2019
- 资助金额:
$ 44.23万 - 项目类别:
Fate and efficacy of targeted therapies for metastatic tumors
转移性肿瘤靶向治疗的命运和疗效
- 批准号:
9176644 - 财政年份:2016
- 资助金额:
$ 44.23万 - 项目类别:
Fate and efficacy of targeted therapies for metastatic tumors
转移性肿瘤靶向治疗的命运和疗效
- 批准号:
9428627 - 财政年份:2016
- 资助金额:
$ 44.23万 - 项目类别:
In vivo imaging of encapsulated stem cells in mouse models of tumor resection
肿瘤切除小鼠模型中封装干细胞的体内成像
- 批准号:
8599446 - 财政年份:2013
- 资助金额:
$ 44.23万 - 项目类别:
In vivo imaging of encapsulated stem cells in mouse models of tumor resection
肿瘤切除小鼠模型中封装干细胞的体内成像
- 批准号:
8421265 - 财政年份:2013
- 资助金额:
$ 44.23万 - 项目类别:
In vivo imaging of encapsulated stem cells in mouse models of tumor resection
肿瘤切除小鼠模型中封装干细胞的体内成像
- 批准号:
9405283 - 财政年份:2013
- 资助金额:
$ 44.23万 - 项目类别:
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