Proj 4 - Enhancing the Potency and Durability of Immunotherapies
项目 4 - 增强免疫疗法的效力和持久性
基本信息
- 批准号:10265479
- 负责人:
- 金额:$ 12.22万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-18 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:Activated Natural Killer CellAdoptive Cell TransfersAdoptive ImmunotherapyAntibodiesAntigensAutologousCD276 geneCSF1R geneCell CountCell LineCell TherapyCell surfaceCellsChemoresistanceChildChildhood Acute Lymphocytic LeukemiaClinicalClinical TrialsCollaborationsConduct Clinical TrialsCredentialingDataDiseaseDisease ProgressionDisease-Free SurvivalENG geneEndothelial CellsFDA approvedFramework RegionsGleanHematopoietic Stem Cell TransplantationHumanImmuneImmune TargetingImmune systemImmunosuppressionImmunotherapyInterleukin-15LaboratoriesMalignant NeoplasmsMediatingMesenchymalModalityMonoclonal AntibodiesMusMutagenesisMutationNK cell therapyNatural Killer CellsNeuroblastomaNormal tissue morphologyOutcomePD-1 blockadePTK2 genePatientsPharmaceutical PreparationsPhenotypePlayRandomizedRegimenRelapseReportingResearchResearch PersonnelResistanceRoleSeminalSignal TransductionSiteSolidSolid NeoplasmSpecificityT cell therapyT-LymphocyteTGFB1 geneTGFBR1 geneTestingTherapeuticToxic effectTranslationsTumor-infiltrating immune cellsXenograft Modelanti-PD1 antibodiesantibody-dependent cell cytotoxicityanticancer treatmentbasecheckpoint inhibitionchimeric antigen receptorchimeric antigen receptor T cellsexhaustiongenetic approachgenetically modified cellshigh riskimmunogenicityimmunotherapy trialsimprovedimproved outcomeinhibitor/antagonistinsightlenalidomidemedulloblastomaneoplastic cellneuroblastoma cellnovelnovel strategiesosteosarcomapatient derived xenograft modelphase III trialpreventprogramsrelapse patientsresearch clinical testingsialogangliosidestooltraffickingtumor growthtumor microenvironmenttumor-immune system interactions
项目摘要
Recent advances have credentialed immunotherapy as a potent anti-cancer treatment modality. However, with
exception of high-risk neuroblastoma (NB), immunotherapy has not yet been shown to improve outcomes for
children with solid tumors. For patients with NB undergoing myeloablative therapy and autologous
hematopoietic stem cell transplantation, subsequent treatment with dinutuximab, which targets
disialoganglioside (GD2) on NB cells, improves 2-year event-free survival from 46±5% to 66±5%. However,
40% of patients relapse during or after receiving dinutuximab; regimen-related toxicity is high; and 15% of
patients have early disease progression and do not receive this therapy. Other immunotherapies include
adoptive cell therapy with chimeric antigen receptor (CAR) modified T cells and checkpoint inhibition with
monoclonal antibodies (mAbs). CAR T cells have potent activity against pediatric acute lymphoblastic
leukemia but have not yet demonstrated activity against solid tumors. Checkpoint inhibition alone (e.g., anti-
PD-1 mAb) may not have significant anti-NB activity due to its efficacy correlating with the frequent tumor cell
mutations and to the paucity of mutations in NB. Our strategy focuses on cell and mAb based
immunotherapies for NB that does not require high-level inherent immunogenicity and builds upon recent
advances in our understanding of the tumor cell:immune system interface. We hypothesize that therapeutic
gains will be greatest if strategies both enhance cell intrinsic functions of CAR T cells and activated NK (aNK)
cells, and overcome cell extrinsic immunosuppression in the tumor microenvironment (TME). Our Specific
Aims are to enhance the potency and durability of CAR T cells and aNK cells and to develop regimens that
combine enhanced cell therapies with modulation of the immunosuppressive TME. Our Research
Strategy/Approach is 1) to enhance the potency and durability of GD2-CARs using targeted mutagenesis of the
scFv to prevent antigen-independent tonic signaling and exhaustion originating from the scFv; to test a novel
B7-H3-CAR with demonstrated activity; and to add PD-1 blockade to enhance potency and limit exhaustion; 2)
to increase trafficking, persistence and potency of aNK cells by combining them with anti-GD2 and anti-B7-H3
mAbs and with a superagonist IL-15; and 3) to overcome immune suppression in the TME with an anti-CD105
mAb to suppress/eliminate mesenchymal stroma and endothelial cells, with a CSF1R inhibitor to eliminate
suppressive MDSC and TAMs (collaboration with Project 4), with a TGFBR1 inhibitor to prevent suppression by
TGFβ1, and with a FAK/ALK inhibitor to overcome FAK-based induction of T cell suppression and exhaustion
(collaboration with Project 1). In summary, novel approaches to enhance the potency and durability of
adoptive T cell and NK cell therapies will be developed for translation into clinical trials conducted by Core B
(NANT consortium) for patients with high-risk NB.
最近的进展已经证明免疫疗法是一种有效的抗癌治疗方式。然而,随着
项目成果
期刊论文数量(0)
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CRYSTAL L MACKALL其他文献
CRYSTAL L MACKALL的其他文献
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{{ truncateString('CRYSTAL L MACKALL', 18)}}的其他基金
Proj 4 - Enhancing the Potency and Durability of Immunotherapies
项目 4 - 增强免疫疗法的效力和持久性
- 批准号:
10264492 - 财政年份:2017
- 资助金额:
$ 12.22万 - 项目类别:
DIRECTING T CELL RESPONSES DURING IMMUNE RECONSTITUTION
在免疫重建过程中指导 T 细胞反应
- 批准号:
6290854 - 财政年份:
- 资助金额:
$ 12.22万 - 项目类别:
Directing T Cell Responses during Immune Reconstitution
在免疫重建过程中指导 T 细胞反应
- 批准号:
6758284 - 财政年份:
- 资助金额:
$ 12.22万 - 项目类别:
Directing T Cell Responses during Immune Reconstitution
在免疫重建过程中指导 T 细胞反应
- 批准号:
6433436 - 财政年份:
- 资助金额:
$ 12.22万 - 项目类别:
Directing T Cell Responses during Immune Reconstitution
在免疫重建过程中指导 T 细胞反应
- 批准号:
6558707 - 财政年份:
- 资助金额:
$ 12.22万 - 项目类别: