Improving the Efficacy of Allogeneic Cell Therapies of Cancer
提高癌症同种异体细胞疗法的疗效
基本信息
- 批准号:10620375
- 负责人:
- 金额:$ 7.55万
- 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:2022-08-01 至 2026-07-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdoptive Cell TransfersAdoptive TransferAffectAllogenicAntibodiesAutologousBlood CirculationCAR T cell therapyCD19 geneCancer PatientCell TherapyCellsClinicalClinical ResearchComplexDevelopmentEngineeringEvaluationGeneticGoalsHematologic NeoplasmsHematologyImmuneImmune EvasionImmunosuppressionImpairmentIndividualInflammationKnowledgeLiquid substanceLymphocyteMalignant NeoplasmsMediatingMediator of activation proteinModificationMolecularMyeloid-derived suppressor cellsNatural Killer CellsNeoplasm MetastasisNeuroblastomaOX40PatientsPeptidesPerformancePhasePre-Clinical ModelPrimary NeoplasmResearchResearch Project GrantsResistanceRestReverse engineeringRiskSiteSolidSolid NeoplasmStudy modelsSurfaceT cell therapyT-LymphocyteTNFSF5 geneTherapeuticTreatment EfficacyTreatment outcomearmcancer therapycellular targetingchemokinechimeric antigen receptorchimeric antigen receptor T cellsclinical translationcostcytokineexhaustimprovedinflammatory milieuinhibitormacrophagemouse modelnext generationpost-doctoral trainingpreclinical studypreventreceptorresponsetumortumor growthtumor microenvironmenttumor-immune system interactions
项目摘要
PROJECT SUMMARY
While chimeric antigen receptor (CAR) T-cells can be very effective in advanced hematological malignancies,
autologous products often have variable potency and require complex and expensive manufacturing, limiting
their scalability and accessibility. The long-term goal of this proposal is to develop a well-characterized, ‘off-
the-shelf’ (OTS) therapeutic T-cell platform using banked T-cells pre-manufactured from healthy donors, thus
offering immediate availability and high potency at a reduced cost. One major limitation of this approach is
potential immune rejection of infused OTS T-cells by host T- and NK-cells, which would impair persistence and
clinical benefit of the T-cell therapy. Therefore, my graduate dissertation project (Aim 1) focuses on engineering
OTS therapeutic T-cells to resist host immune rejection. I have developed the ‘first-in-class’ chimeric
alloimmune defense receptor (ADR) which enables allogeneic OTS CAR T-cells to defend themselves by
selectively eliminating activated host alloreactive lymphocytes while sparing other resting non-alloreactive cells.
T-cells co-expressing a 4-1BB-directed ADR and a CAR evade immune rejection and produce long-term anti-
tumor activity in mouse models of OTS CAR T-cell therapy for both liquid and solid tumors. We are now
optimizing the 4-1BB-specific ADR for clinical translation and will initiate a Phase I clinical study in our center. I
am also exploring other potential ADR targets, including OX40 and CD40L, to maximize the anti-rejection activity.
In addition to alloimmune rejection, activity of OTS T-cells in solid tumors can be inhibited by the
immunosuppressive tumor microenvironment (TME). Mounting evidence suggests that the inflammatory milieu
created by therapeutic T-cells may elicit reactive changes both locally (in the TME) and systemically (in
circulation) that further inhibit anti-tumor activity of therapeutic T-cells and possibly promote tumor growth and
metastasis. Examples include a surge of immunosuppressive M2-like macrophages in neuroblastoma patients
receiving GD2 CAR T-cells and poor responses to CD19 CAR T-cell therapy in patients with high circulating
myeloid-derived suppressor cells. In addition, preclinical studies indicate that treatment-induced inflammation
enhances pre-metastatic niche (PMN) formation and increases the risk of metastasis. Therefore, during my post-
doctoral training (Aim 2), I will first elucidate the reactive changes (both in TME and in circulation) caused by
therapeutic T-cells and identify cellular/molecular mediators of enhanced immunosuppression at the primary
tumor site. I will also investigate how T-cell therapies may affect PMN formation in solid tumors. I will then further
modify therapeutic T-cells to counteract these unwanted responses by arming them with secreted factors
(antibodies, peptide inhibitors) to block the responsible cytokines / chemokines, or by enabling them to selectively
eliminate inhibitory cellular subsets in the TME.
Successful completion of both Aims will ultimately improve the efficacy of OTS T-cell therapies of cancer.
项目总结
虽然嵌合抗原受体(CAR)T细胞在晚期血液系统恶性肿瘤中非常有效,
自体产品的效力往往不同,需要复杂而昂贵的制造,这限制了
它们的可扩展性和可访问性。这项提议的长期目标是开发一种具有良好特点的、
使用来自健康捐赠者的预先制造的银行T细胞的(OTS)治疗性T细胞平台,因此
以更低的成本提供即时可用和高效率。这种方法的一个主要限制是
宿主T细胞和NK细胞对输注的OTS T细胞的潜在免疫排斥反应,这将损害持久性和
T细胞治疗的临床益处。因此,我的毕业论文项目(目标1)的重点是工程学
治疗T细胞以抵抗宿主免疫排斥反应。我研制出了一流的嵌合体
同种异体免疫防御受体(ADR)使同种异体OTS CAR T细胞通过
选择性地清除激活的宿主同种异体反应淋巴细胞,同时保留其他静止的非同种异体反应细胞。
共表达4-1BB导向的ADR和CAR的T细胞逃避免疫排斥反应并产生长期抗
OTS CAR-T细胞治疗液体和固体肿瘤小鼠模型的肿瘤活性。我们现在是
优化用于临床翻译的4-1BB特异性ADR,并将在我们中心启动I期临床研究。我
我还探索了其他潜在的ADR靶点,包括OX40和CD40L,以最大限度地发挥抗排斥活性。
除了同种异体免疫排斥反应外,实体瘤中OTS T细胞的活性还可以被抑制
免疫抑制肿瘤微环境(TME)。越来越多的证据表明,炎症环境
由治疗性T细胞产生的可能引起局部(在TME中)和系统(在
循环),进一步抑制治疗性T细胞的抗肿瘤活性,并可能促进肿瘤生长和
转移。例子包括神经母细胞瘤患者中免疫抑制的M2样巨噬细胞激增
高循环患者接受GD2 CAR T细胞治疗后对CD19 CAR T细胞治疗的不良反应
髓系来源的抑制细胞。此外,临床前研究表明,治疗引起的炎症
促进转移前生态位(PMN)的形成,增加转移的风险。因此,在我任职期间-
博士生培训(目标2),我将首先阐明由以下因素引起的反应性变化(TME和循环)
治疗T细胞和鉴定初级免疫抑制增强的细胞/分子介质
肿瘤部位。我还将研究T细胞疗法如何影响实体瘤中PMN的形成。然后我会更进一步
修饰治疗性T细胞,通过用分泌因子武装它们来抵消这些有害的反应
(抗体、多肽抑制剂)以阻断负责的细胞因子/趋化因子,或通过使它们选择性地
消除TME中的抑制性细胞亚群。
这两个目标的成功实现将最终提高OTS T细胞治疗癌症的疗效。
项目成果
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{{ truncateString('Feiyan Mo', 18)}}的其他基金
Improving the Efficacy of Allogeneic Cell Therapies of Cancer
提高癌症同种异体细胞疗法的疗效
- 批准号:
10686219 - 财政年份:2022
- 资助金额:
$ 7.55万 - 项目类别:
Improving the Efficacy of Allogeneic Cell Therapies of Cancer
提高癌症同种异体细胞疗法的疗效
- 批准号:
10065285 - 财政年份:2020
- 资助金额:
$ 7.55万 - 项目类别:
Improving the Efficacy of Allogeneic Cell Therapies of Cancer
提高癌症同种异体细胞疗法的疗效
- 批准号:
10226318 - 财政年份:2020
- 资助金额:
$ 7.55万 - 项目类别: