Antigen Specific T Cells
抗原特异性 T 细胞
基本信息
- 批准号:10197003
- 负责人:
- 金额:$ 20.54万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-05-21 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:AIDS related cancerAML/MDSAcute Lymphocytic LeukemiaAcute Myelocytic LeukemiaAdoptive TransferAllogeneic Bone Marrow TransplantationAllogenicAntigen TargetingAntigensAntiviral AgentsB-Cell Acute Lymphoblastic LeukemiaB-Cell Antigen ReceptorBerlinBiological AssayBloodBlood donorBone Marrow TransplantationCAR T cell therapyCD19 AntigensCD19 geneCell TransplantationCell surfaceCellsChemotherapy and/or radiationClinicalClinical TrialsCytotoxic T-LymphocytesDevelopmentDiseaseDisease remissionDonor personDysmyelopoietic SyndromesEpitope spreadingFlow CytometryFrequenciesHIVHIV AntigensHIV GenomeHIV InfectionsHIV SeronegativityHIV therapyHIV-1Hematologic NeoplasmsHematopoietic stem cellsHigh Dose ChemotherapyHuman Herpesvirus 4ImmuneImmune mediated destructionImmune responseImmune systemImmunityImmunoassayImmunotherapyIn complete remissionIncidenceIndividualInfectionInfusion proceduresInterruptionLengthLifeLymphomaMalignant NeoplasmsMeasuresMutationMyelogenousMyeloproliferative diseaseNatural ResistancePatient-Focused OutcomesPatientsPersonsPhase I Clinical TrialsPhase I/II Clinical TrialPopulationPrognosisProteinsRegimenRegistriesRelapseResidual TumorsResidual stateResistance to infectionRiskSafetySpecificitySurface AntigensSurvivin AntigenT cell receptor repertoire sequencingT cell therapyT-LymphocyteTestingTherapeuticTrainingTreatment-related toxicityTumor AntigensTumor EscapeVariantViralVirusWT1 geneantigen-specific T cellsantiretroviral therapyantiviral immunitycancer testis antigencell killingchimeric antigen receptorchimeric antigen receptor T cellsconditioningdigitaleffective therapyenzyme linked immunospot assayexperiencegraft vs leukemia effecthigh riskhuman diseaseimmune reconstitutionimproved outcomein vivointerestleukemianeoplastic cellnovelnovel strategiesnovel therapeuticspersonalized medicinepost-transplantpreventreceptorreconstitutionresponsesafety and feasibilitysuccesstargeted treatmenttumor
项目摘要
Project 3
Project Summary
Bone Marrow Transplant (BMT) has improved outcomes for patients with high risk or relapsed acute myeloid
leukemia (AML) and Myelodysplastic Syndrome (MDS). This is due to both the ability to give high doses of
chemotherapy and/or radiation to further eradicate residual leukemia and because the donor cells may detect
and lyse residual tumor cells, termed the graft-versus-leukemia (GVL) effect. However, patients with high risk
or persistent disease continue to experience a dismal prognosis despite BMT, ranging from 10-40% survival at
5 years. Thus, developing novel therapeutics for myeloid malignancies is critical. T-cell immunotherapy post
BMT using virus-specific cytotoxic T lymphocytes, has been highly successful for the treatment of virus-
associated diseases (including EBV+ lymphomas) after BMT. However, only limited studies have been
conducted utilizing T-cell therapies targeting non-viral tumor-associated antigens for patients after BMT. The
development of T-cells expressing a chimeric antigen receptor (CAR) for CD19 has shown significant promise
for patients with B-cell acute lymphoblastic leukemia (ALL). However, greater than 40% of the responses are
not durable because the tumor evades the immune system by downregulating or modulating expressed target
antigens. Furthermore, this approach can only target tumor antigens expressed on the cell surface and many
tumor-associated antigens (TAAs) are intracellular. Furthermore, to date, CAR-T-cell therapy has not been as
successful clinically for patients with myeloid malignancies as CD19-CAR T cells have been for patients with
ALL. To extend T cell therapy to patients with AML/MDS post allogeneic BMT, we have developed a novel
strategy to reactivate and expand T cells with specificity for multiple TAAs: Survivin, PRAME and WT1, which
collectively are expressed by >90% of myeloid blasts. We reason that targeting multiple TAAs simultaneously
will minimize tumor immune escape. Interest in BMT is also building as a potential means to clear HIV-1-
infected cells from infected persons and achieve a functional cure of HIV infection. However, interruption of
ART post-transplant is associated with life-threatening HIV rebound. Therefore, we propose that reconstitution
of the immune system early post-BMT with the adoptive transfer of ex vivo expanded TAA and HIV-specific T
cells carrying the CCR5Δ32 mutation would confer protection from relapse AND could reconstitute an effective
HIV cellular immune response to prevent such uncontrolled rebound. Our central hypotheses are: (i) that the
GVL effect post BMT will be enhanced by adoptive transfer of T-cells targeting multiple TAAs and (ii)
that this approach can be applied to HIV-associated malignancies and will be effective for targeting
multiple HIV and tumor associated antigens. We will test these hypotheses in clinical trials proposed for
Aim 1. In we will generate and infuse T-cell products from eligible BMT donors that target multiple TAAs (+/-
HIV) to HIV+ and HIVneg patients with AML/MDS. In Aim 2 we will evaluate the anti tumor and antiviral clinical
and immune responses after T cell infusion. In summary, this approach may enable T-cell immunotherapy to
become more broadly applied to all patients with malignancies after BMT.
项目3
项目概要
骨髓移植 (BMT) 改善了高危或复发性急性髓系白血病患者的预后
白血病 (AML) 和骨髓增生异常综合征 (MDS) 这是由于给予高剂量的能力所致。
化疗和/或放疗以进一步根除残留的白血病,并且因为供体细胞可能检测到
并裂解残留的肿瘤细胞,称为移植物抗白血病(GVL)效应,但对高危患者。
尽管进行 BMT,但持续性疾病仍继续经历令人沮丧的预后,生存率在 10-40% 之间
因此,开发新的 T 细胞免疫疗法至关重要。
BMT 使用病毒特异性细胞毒性 T 淋巴细胞,在治疗病毒感染方面取得了巨大成功。
BMT 后的相关疾病(包括 EBV+ 淋巴瘤)然而,只有有限的研究。
利用针对 BMT 后患者的非病毒肿瘤相关抗原的 T 细胞疗法进行治疗。
表达 CD19 嵌合抗原受体 (CAR) 的 T 细胞的开发已显示出巨大的前景
然而,对于 B 细胞急性淋巴细胞白血病 (ALL) 患者,超过 40% 的缓解是这样的。
不持久,因为肿瘤通过下调或调节表达的靶标来逃避免疫系统
此外,对于肿瘤抗原,这种方法只能针对细胞表面表达的抗原和许多抗原。
此外,迄今为止,CAR-T 细胞疗法还没有达到肿瘤相关抗原 (TAA) 的水平。
CD19-CAR T 细胞已在治疗骨髓恶性肿瘤患者中取得了临床成功
为了将 T 细胞疗法扩展到同种异体 BMT 后的 AML/MDS 患者,我们开发了一种新型疗法。
重新激活和扩增 T 细胞的策略,对多种 TAA 具有特异性:Survivin、PRAME 和 WT1,其中
总体而言,>90% 的髓系母细胞均表达,我们推断同时靶向多个 TAA。
将最大限度地减少肿瘤免疫逃逸,人们对 BMT 作为清除 HIV-1- 的潜在手段也产生了兴趣。
然而,从感染者身上提取感染细胞并实现治愈HIV感染的功能。
移植后 ART 与危及生命的 HIV 反弹有关,因此,我们建议进行重建。
BMT 后早期的免疫系统通过过继转移体外扩增的 TAA 和 HIV 特异性 T
携带 CCR5Δ32 突变的细胞将提供防止复发的保护,并且可以重建有效的
HIV 细胞免疫反应可防止这种不受控制的反弹。我们的中心假设是:(i)
BMT 后的 GVL 效应将通过靶向多个 TAA 的 T 细胞过继转移得到增强,并且 (ii)
这种方法可以应用于与艾滋病毒相关的恶性肿瘤,并且可以有效地靶向治疗
我们将在提出的临床试验中测试这些假设。
目标 1. 我们将从合格的 BMT 捐赠者那里生成并注入 T 细胞产品,这些产品针对多个 TAA(+/-
HIV)对患有 AML/MDS 的 HIV+ 和 HIVneg 患者的影响 在目标 2 中,我们将评估抗肿瘤和抗病毒临床。
总之,这种方法可能使 T 细胞免疫疗法能够
更广泛地应用于 BMT 后的所有恶性肿瘤患者。
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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Catherine M. Bollard其他文献
The IPTA Nashville consensus conference on post-transplant lymphoproliferative disorders after solid organ transplantation in children: IV-consensus guidelines for the management of post-transplant lymphoproliferative disorders in children and adolescents.
关于儿童实体器官移植后移植后淋巴细胞增殖性疾病的 IPTA 纳什维尔共识会议:儿童和青少年移植后淋巴细胞增殖性疾病管理 IV 共识指南。
- DOI:
- 发表时间:
2024 - 期刊:
- 影响因子:1.3
- 作者:
Upton D Allen;A. L'Huillier;Catherine M. Bollard;Thomas G Gross;Robert J. Hayashi;B. Höcker;Brtitta Maecker;Stephen D Marks;George V Mazariegos;Françoise Smets;Ralf U Trappe;Gary A. Visner;R. Chinnock;Patrizia Comoli;L. Danziger;Daniel E Dulek;A. Dipchand;Judith A Ferry;Olivia M. Martinez;Diana M Metes;Marian G. Michaels;Jutta Preiksaitis;James E Squires;S. Swerdlow;James D Wilkinson;V. Dharnidharka;Michael Green;Steven A. Webber;Carlos O. Esquivel - 通讯作者:
Carlos O. Esquivel
PR1-specificcytotoxic T lymphocytes are relatively frequent in umbilical cord blood and canbe effectively expanded to target myeloid leukemia
PR1特异性细胞毒性T淋巴细胞在脐带血中相对常见,可有效扩增以靶向髓系白血病
- DOI:
- 发表时间:
2016 - 期刊:
- 影响因子:4.5
- 作者:
Lisa S.St. John;Liping Wan;Hong He;Haven R. Garber;Karen Clise-Dwyer;Gheath Alatrash;Katyoun Rezvani;Elizabeth J.Shpall;Catherine M. Bollard;Qing Ma;Jeffrey J. Molldrem - 通讯作者:
Jeffrey J. Molldrem
Durable immunity to EBV after rituximab and third-party LMP-specific T cells: a Children’s Oncology Group study
使用利妥昔单抗和第三方 LMP 特异性 T 细胞后对 EBV 产生持久免疫力:一项儿童肿瘤学小组研究
- DOI:
10.1182/bloodadvances.2023010832 - 发表时间:
2024-01-01 - 期刊:
- 影响因子:7.5
- 作者:
B. Wistinghausen;K. Toner;D. Barkauskas;Lauren P Jerkins;Hannah Kinoshita;Pamela Chansky;Gloria Pezzella;Lauren Saguilig;Robert J Hayashi;H. Abhyankar;B. Scull;Vivekanudeep Karri;J. Tanna;P. Hanley;M. Hermiston;Carl E. Allen;Catherine M. Bollard - 通讯作者:
Catherine M. Bollard
Limited Immunogenicity of an HLA-A*03:01-restricted Epitope of Erv-k-env in Non-hiv-1 Settings: Implications for Adoptive Cell Therapy in Cancer
非 hiv-1 环境中 Erv-k-env 的 HLA-A*03:01 限制性表位的有限免疫原性:对癌症过继细胞疗法的影响
- DOI:
- 发表时间:
2024 - 期刊:
- 影响因子:0
- 作者:
Erin E. Grundy;Lauren C. Shaw;Loretta Wang;Daniel J. Powell;Mario Ostrowski;R. B. Jones;C. Russell Y. Cruz;Heather Gordish;Catherine M. Bollard;Katherine B. Chiappinelli - 通讯作者:
Katherine B. Chiappinelli
Nasopharyngeal Carcinoma
鼻咽癌
- DOI:
10.1007/978-1-4614-5947-7 - 发表时间:
2024-09-13 - 期刊:
- 影响因子:0
- 作者:
H. Heslop;Cliona M. Rooney;Malcolm K Brenner;S. Gottschalk;Carlos A. Ramos;Catherine M. Bollard;Barbara Savoldo;Gianpetro Dotti;Ann M. Leen;Juan F. Vera;Nabil Ahmed;Claudia Gerken;Matma Kalra;B. Grilley;Bridget Medina;Catherine Perera;Tara Gray - 通讯作者:
Tara Gray
Catherine M. Bollard的其他文献
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{{ truncateString('Catherine M. Bollard', 18)}}的其他基金
HIV-specific ex-vivo expanded T cell therapy (HXTC) to Deplete the Latent Reservoir of Persistent HIV Infection
HIV 特异性体外扩增 T 细胞疗法 (HXTC) 可消除持续性 HIV 感染的潜在储库
- 批准号:
9889986 - 财政年份:2016
- 资助金额:
$ 20.54万 - 项目类别:
Rationale for the Pediatric Hematology and Transfusion Medicine Multidisciplinary Research Training Award (PHTMMRT) at Children?s National
国家儿童医院儿科血液学和输血医学多学科研究培训奖 (PHTMMRT) 的理由
- 批准号:
10360585 - 财政年份:2012
- 资助金额:
$ 20.54万 - 项目类别:
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Specialized Program Of Research Excellence (SPORE) in Leukemia.
白血病专业卓越研究计划 (SPORE)。
- 批准号:
10912197 - 财政年份:2013
- 资助金额:
$ 20.54万 - 项目类别: