Harnessing the thymus for long-term tumor control with hematopoietic stem cell-derived naive CAR T cells
利用造血干细胞衍生的初始 CAR T 细胞利用胸腺来长期控制肿瘤
基本信息
- 批准号:10365031
- 负责人:
- 金额:$ 59.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-03-01 至 2027-01-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdoptive Cell TransfersAffectAffinityAllogenicAntigen ReceptorsAntineoplastic AgentsAreaB-LymphocytesBiologicalBiological AssayBiological ModelsBiologyBioreactorsBone MarrowBypassCD19 geneCD28 geneCancer PatientCause of DeathCell LineageCell MaintenanceCellsChildhoodChildhood Acute Lymphocytic LeukemiaClinicalConsolidation TherapyDataDevelopmentDisease remissionEngraftmentEpithelialGene ExpressionGene TransferGenerationsGoalsGoldHematopoietic stem cellsHomingHumanHuman ActivitiesImmunityImmunologic SurveillanceImmunologyImmunotherapeutic agentIn VitroInjectionsIntravenousLaboratoriesLifeLongitudinal StudiesMaintenanceMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of thymusMediatingMethodsModalityModelingModern MedicineMolecularMusOutcomePathway interactionsPatientsPeripheralPhenotypePre-B Acute Lymphoblastic LeukemiaProceduresProductionProtocols documentationPublishingRelapseResearchSignal TransductionSpecificitySumSystemT cell differentiationT cell reconstitutionT cell therapyT-Cell DevelopmentT-Cell ReceptorT-LymphocyteTechnologyTestingThymus GlandTimeTumor AntigensTumor BurdenVariantantigen-specific T cellsbasecancer immunotherapycancer therapycell transformationcellular engineeringcellular transductionchemotherapyclinical applicationclinically relevantconditioningcytokine release syndromedesigndisorder controlengineered stem cellsexhaustiongenetic manipulationhematopoietic engraftmenthigh riskhumanized mouseimage guidedimprovedin vivoinnovationirradiationleukemia/lymphomaminimally invasivemolecular targeted therapiesmouse modelneoplastic cellnoveloverexpressionpatient derived xenograft modelpatient populationpre-clinicalpreclinical efficacypreservationpreventrational designreceptorrelapse risksecondary lymphoid organself-renewalsingle-cell RNA sequencingtransgene expressiontranslational studytumortumor specificityyoung adult
项目摘要
PROJECT SUMMARY
Chimeric receptor antigen (CAR) T cells are transforming cancer treatment by providing tumor-specific,
molecularly targeted therapies. However, even though current clinical applications of CAR T cell-based cancer
immunotherapies such as Kymriah or Yescarta induce remission in most cases, long-term disease control, which
is especially needed in pediatric and young adult cancer patients with high-risk malignancies, remains a major
clinical challenge. In fact, malignant relapse continues to be the leading cause of death post CAR T cell therapy.
Insufficient CAR T cell persistence in vivo is a major obstacle to reducing the risk of relapse and improving
survival. We have developed a novel platform for long-lasting tumor immunosurveillance based on continuous
in vivo generation of naïve CAR T cells. This proposal is driven by the hypothesis, based on our published and
unpublished data, that after the completion of the initial course of intensive chemotherapy long-lasting T cell
immunity to cancer antigens can be established by using hematopoietic stem and progenitor cells (HSPCs)
engineered to express a tumor cell-targeting CAR and delivered into the patient’s thymus. Image-guided
intrathymic injection is a minimally invasive procedure that harnesses the thymus of cancer patients as an in vivo
bioreactor, thus offering an innovative and also relatively simple and low-toxic clinical method for sustainable
production of highly potent naïve designer T cells from genetically manipulated HSPCs. Direct thymic
engraftment of HSPCs (bypassing the bone marrow) eliminates the need for myelo-ablative conditioning while
preserving the desired outcome, i.e., long-term generation of naïve antigen-specific T cells. Thymic engraftment
will be facilitated by thymic irradiation combined with either cell delivery to the thymus by intrathymic injection or
by enhancing the thymic homing capacity of intravenously administered HSPCs by overexpression of thymus-
specific homing molecules. We will focus on CD19 CARs as a model system to establish proof of concept of our
approach because CD19 CARs have become the gold standard for evaluating novel CAR technologies. Our
experimental approaches include strategies designed to allow successful thymic negative selection of CD19
CAR-transduced HSPCs. Over time the project is expected to expand to include a variety of CAR specificities.
CAR T cell development from HSPCs will be analyzed both in vitro and in vivo, including assays assessing
thymic hematopoietic stem cell maintenance and T cell differentiation from HSPCs within the thymic epithelial
microenvironment. We will demonstrate in vivo efficacy (B cell depletion and anti-tumor activity) of the most
promising CAR expression system in syngeneic mouse models. Translational studies in humanized mice,
including a patient-derived pediatric acute lymphoblastic leukemia model, will be performed during the final year
of the project. In sum, this research will test the novel paradigm of CAR T cell development in vivo, promising to
make tumor immunosurveillance by CAR T cells broadly available as post-consolidation therapy of high-risk
malignancies in pediatric and young adult patient populations.
项目摘要
嵌合受体抗原(CAR)T细胞通过提供肿瘤特异性,
分子靶向治疗然而,尽管目前基于CAR T细胞的癌症的临床应用
免疫疗法如Kymriah或Yescarta在大多数情况下诱导缓解,长期疾病控制,
尤其需要在儿童和年轻成人癌症患者的高风险恶性肿瘤,仍然是一个主要的
临床挑战事实上,恶性复发仍然是CAR T细胞治疗后死亡的主要原因。
CAR T细胞在体内的持续性不足是降低复发风险和改善预后的主要障碍。
生存我们已经开发了一种基于连续免疫监测的持久肿瘤免疫监测的新平台。
体内产生幼稚CAR T细胞。这一建议是由假设驱动的,基于我们发表的和
未发表的数据表明,在完成强化化疗的初始疗程后,
可以通过使用造血干细胞和祖细胞(HSPC)建立对癌抗原的免疫,
工程化以表达肿瘤细胞靶向CAR并递送到患者的胸腺中。图像引导
胸腺内注射是一种微创手术,
生物反应器,从而提供了一种创新的,也是相对简单和低毒性的临床方法,用于可持续的
从基因操作的HSPC中产生高效的天然设计T细胞。直接胸腺
HSPC的移植(绕过骨髓)消除了对骨髓清除性预处理的需要,
保持期望的结果,即,长期产生幼稚抗原特异性T细胞。胸腺植入
通过胸腺照射结合胸腺内注射细胞递送至胸腺或
通过过表达胸腺-胸腺肽来增强静脉内施用的HSPC的胸腺归巢能力,
特定的归巢分子我们将专注于CD 19汽车作为模型系统,以建立我们的概念验证。
这是因为CD 19汽车已成为评估新型CAR技术的金标准。我们
实验方法包括设计成允许成功的胸腺阴性选择CD 19的策略
CAR转导的HSPC。随着时间的推移,该项目预计将扩大到包括各种CAR特异性。
将在体外和体内分析来自HSPC的CAR T细胞发育,包括评估CAR T细胞的测定。
胸腺造血干细胞维持和胸腺上皮内HSPC的T细胞分化
微环境我们将证明大多数人的体内功效(B细胞耗竭和抗肿瘤活性)。
在同基因小鼠模型中有希望的CAR表达系统。在人源化小鼠中的转化研究,
包括一个病人来源的小儿急性淋巴细胞白血病模型,将在最后一年进行
本项目总之,这项研究将测试体内CAR T细胞发育的新模式,有望
使CAR T细胞的肿瘤免疫监视广泛用作高风险患者的巩固后治疗,
儿童和年轻成人患者人群中的恶性肿瘤。
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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Johannes Zakrzewski其他文献
Johannes Zakrzewski的其他文献
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{{ truncateString('Johannes Zakrzewski', 18)}}的其他基金
Harnessing the thymus for long-term tumor control with hematopoietic stem cell-derived naive CAR T cells
利用造血干细胞衍生的初始 CAR T 细胞利用胸腺来长期控制肿瘤
- 批准号:
10580801 - 财政年份:2022
- 资助金额:
$ 59.26万 - 项目类别:
Strategies to enhance thymus-independent T cell development in cancer patients
增强癌症患者胸腺独立 T 细胞发育的策略
- 批准号:
8318100 - 财政年份:2011
- 资助金额:
$ 59.26万 - 项目类别:
Strategies to enhance thymus-independent T cell development in cancer patients
增强癌症患者胸腺独立 T 细胞发育的策略
- 批准号:
8699163 - 财政年份:2011
- 资助金额:
$ 59.26万 - 项目类别:
Strategies to enhance thymus-independent T cell development in cancer patients
增强癌症患者胸腺独立 T 细胞发育的策略
- 批准号:
8891380 - 财政年份:2011
- 资助金额:
$ 59.26万 - 项目类别:
Strategies to enhance thymus-independent T cell development in cancer patients
增强癌症患者胸腺独立 T 细胞发育的策略
- 批准号:
8517047 - 财政年份:2011
- 资助金额:
$ 59.26万 - 项目类别:
Strategies to enhance thymus-independent T cell development in cancer patients
增强癌症患者胸腺独立 T 细胞发育的策略
- 批准号:
8165831 - 财政年份:2011
- 资助金额:
$ 59.26万 - 项目类别: