Understanding the Behavior of Novel IL13Ralpha2-directed T cell Engager for GBM
Understanding the Behavior of Novel IL13Ralpha2-directed T cell Engager for GBM
批准号:
10604307
负责人:
Irina V Balyasnikova
金额:
$39.38万
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:
2021-04-01 至 2026-03-31
关键词:
AddressAdultAffectAffinityAnimal ModelAnimalsAntibodiesBehaviorBindingBiodistributionBrainCD3 AntigensCancer PatientCell Surface ReceptorsCellsClinical ResearchClinical TrialsCombined Modality TherapyDataDependenceDevelopmentDrug KineticsEffectivenessEngineeringEpidermal Growth Factor ReceptorFailureFlow CytometryFoundationsFutureGeneticGenetic EngineeringGlioblastomaGliomaGranzymeHumanIL13Ralpha2IL2 geneImageImmuneImmune responseImmune systemImmunocompetentImmunotherapyInfiltrationInvestigationKnowledgeKnowledge acquisitionLeadMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of brainMediatingMicroscopyModelingModificationMusNewly DiagnosedOperative Surgical ProceduresOrganPatientsPenetrationPositron-Emission TomographyPre-Clinical ModelPreclinical TestingProcessProteinsProtocols documentationRadiationReagentRecurrenceResearchSolid NeoplasmSpecificitySurvival RateT-Cell ActivationT-LymphocyteTNF geneTestingTestisTissuesTranslatingTreatment ProtocolsTumor AntibodiesTumor Immunityantibody engineeringbi-specific T cell engagerblood-brain tumor barrierbrain cellcancer cellchemotherapychimeric antigen receptor T cellsclinical applicationcytotoxicityepidermal growth factor receptor VIIIhuman modelimmune functionimmunocytochemistryimprovedimproved outcomein vivolongitudinal positron emission tomographymouse modelneoplastic cellnew therapeutic targetnovelperforinphase 1 studypre-clinicalrational designtreatment responsetumortumor microenvironmentuptake
中文摘要
胶质母细胞瘤(GBM)仍然是无法治愈的癌症,尽管有积极的多模式治疗,但生存率很低
包括手术、放疗、化疗和肿瘤治疗领域。未能改善结果,
GBM患者强调迫切需要开发新的靶向治疗。双特异性T细胞增殖剂(BiTEs)
蛋白质通过BiTE结合T细胞和肿瘤促进活化T细胞特异性杀伤癌细胞
细胞因为这种类型的治疗处于实体瘤如GBM的早期发展阶段,我们的研究表明,
肿瘤摄取、药代动力学和作用机制的知识有限,这阻碍了合理的治疗。
用于评价BiTE的临床研究设计。推进BiTE作为治疗GBM的策略,以及其他
在实体瘤中,我们设计并表征了特异性靶向
IL 13 R α2,一种细胞表面受体,在GBM细胞上表达,但在正常脑细胞上不表达。我们已经生成
并测试了靶向人或鼠CD3T细胞的BiTE分子的几种构型。我们的数据显示
IL 13 R α2 BiTE i)特异性结合GBM细胞上的人IL 13 R α2,ii)特异性激活T细胞,
BiTE分子与这些表达IL13Rα2的GBM细胞的接合,iii)介导T细胞依赖性
在pM浓度下杀死GBM细胞,和iv)显著提高携带同基因的小鼠的存活率,
颅内GBM肿瘤成像数据显示,BiTE穿透血液肿瘤屏障,
激活T细胞。初步结果还表明,BiTE的作用机制不仅限于直接杀伤
神经胶质瘤细胞的活化T细胞,但也通过激活额外的宿主影响肿瘤微环境
免疫功能基于我们强大的临床前数据,我们假设(i)全身性GBM通路
递送的BiTE是T细胞依赖性过程,和(ii)BiTE主动调节T细胞以及其他细胞因子。
宿主免疫反应区室,导致临床前的强大抗肿瘤治疗反应。
GBM模型。这一假设将在三个具体目标中得到检验。SA1将调查以下内容的依赖关系
IL 13 R α2 BiTE在T细胞上用于肿瘤进入和保留、肿瘤摄取和生物分布。SA2将研究
IL 13 R α2 BiTE启动宿主免疫系统以产生持久抗肿瘤免疫的机制。
在SA3中,我们将使用GBM的鼠和人模型开发和鉴定BiTE治疗方案,
可以随后转化为对患者的治疗。在成功完成这些研究后,我们
将获得有关影响BiTE抗肿瘤活性的因素的知识。这些研究将提供一个
为IL 13 R α2 BiTE治疗GBM的未来临床应用奠定了坚实的基础,
适用于其他表达IL 13 R α2的恶性肿瘤。
英文摘要
Glioblastoma (GBM) remains incurable cancer with a dismal survival rate despite aggressive multimodal therapy
that can include surgery, radiation, chemotherapy, and tumor-treating fields. The failure to improve outcome in
GBM patients underscores an urgent need to develop new targeted therapies. Bi-specific T cell engager (BiTEs)
proteins promote specific killing of cancer cells by activated T cells via BiTE binding to both T-cells and tumor
cells. Because this type of therapy is at an early stage of development for solid tumors such as GBM, our
knowledge of tumor uptake, pharmacokinetics, and mechanism of action is limited, which hinders the rational
design of clinical studies for evaluating BiTEs. To advance BiTEs as a strategy for treating GBM, as well as other
solid tumors, we have engineered and characterized a single-chain antibody (scFv) that specifically targets
IL13Rα2, a cell surface receptor that is expressed on GBM cells, but not normal brain cells. We have generated
and tested several configurations of BiTE molecules targeting human or murine CD3 T cells. Our data show that
the IL13Rα2 BiTE i) binds specifically to human IL13Rα2 on GBM cells, ii) specifically activates T cells upon
engagement of the BiTE molecule with these IL13Rα2-expressing GBM cells, iii) mediates T-cell dependent
killing of GBM cells at pM concentrations, and iv) significantly improves the survival of mice bearing syngeneic
intracranial GBM tumors. Imaging data show that BiTEs penetrate through the blood-tumor barrier and also
engage T cells. Preliminary results also suggest that the mechanism of BiTE action is not limited to direct killing
of glioma cells by activated T cells but also affects the tumor microenvironment by activating additional host
immune function. Based on our robust preclinical data, we hypothesize that (i) GBM access of systemically
delivered BiTEs is a T-cell-dependent process, and (ii) BiTEs actively modulate T cell as well as other
host immune response compartments, leading to a robust anti-tumor therapeutic response in preclinical
GBM models. This hypothesis will be tested in three Specific Aims. SA1 will investigate the dependencies of
IL13Rα2 BiTE on T cells for tumor access and retention, tumor uptake, and biodistribution. SA2 will study the
mechanism by which IL13Rα2 BiTE primes the host immune system to generate durable anti-tumor immunity.
In SA3, we will develop and identify a BiTE treatment regimen using murine and human models of GBM that
could subsequently be translated into a therapy for patients. Upon successful completion of these studies, we
will acquire knowledge regarding factors that influence BiTE anti-tumor activity. These studies will provide a
strong foundation for future clinical application of IL13Rα2 BiTE for GBM treatment and could be broadly
applicable to other IL13Rα2-expressing malignancies.
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