Therapeutic applications of CD4+ T cells specific for oncogenic driver mutations
致癌驱动突变特异性 CD4 T 细胞的治疗应用
基本信息
- 批准号:10640078
- 负责人:
- 金额:$ 19.41万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-03-04 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:AddressAdoptive Cell TransfersAdoptive ImmunotherapyAdoptive TransferAllelesAmino AcidsAntigen PresentationAntigen-Presenting CellsAntigensAutologousBRAF geneBiopsyCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCancer PatientCell physiologyCellsClinicalClinical TrialsCorrelative StudyEpidermal Growth Factor ReceptorFrequenciesHLA AntigensHeterogeneityHistocompatibility Antigens Class IIHumanImmuneImmune responseImmune systemImmunologicsImmunotherapyInfiltrationInflammationKRAS2 geneKnowledgeLearningMajor Histocompatibility ComplexMalignant NeoplasmsMeasuresMediatingMinorityMutateMutationOncogenicPatient TransferPatientsPeptidesPhase I Clinical TrialsPhenotypePlayPopulationProcessRNA analysisRecurrenceRoleSafetySamplingSignal TransductionSiteSolid NeoplasmSpecificitySurfaceT cell responseT-Cell ReceptorT-LymphocyteTechniquesTherapeuticTherapeutic EffectTumor AntigensTumor ImmunityTumor-Infiltrating LymphocytesWorkantigen-specific T cellsantitumor effectcancer cellcancer infiltrating T cellscancer therapydimensional analysisdriver mutationengineered T cellsexhaustionexperiencefightingfirst-in-humanhigh dimensionalityimmune activationimmune checkpoint blockadein vivoinsightmelanomamigrationmouse modelneoantigensneoplastic cellprotein complexresponsesingle cell analysissingle-cell RNA sequencingtranscriptometumortumor microenvironment
项目摘要
Abstract
Increasing evidence indicates that clinical responses to immune checkpoint blockade (ICB) in solid tumors are
mediated by T-cell recognition of “neoantigens” created when peptides containing amino acids altered by
cancer specific mutations are presented on major histocompatibility complex (MHC) proteins. Thus, strategies
to augment such T-cell responses independent of, or concurrent with ICB, could be of therapeutic benefit. Prior
work on neoantigen-reactive T cells has focused on CD8+ T cells which directly recognize antigens presented
on class I MHC expressed by tumor cells. However, there is emerging evidence that CD4+ T cell responses
directed against neoantigens presented by class II MHC on professional antigen presenting cells (APC) are
common, contribute to tumor rejection in mouse models, and are effective in cancer patients treated with
adoptively transferred tumor infiltrating lymphocytes. I recently discovered CD4+ T-cells specific for recurrent
driver mutations in BRAF, KRAS, Her2 and EGFR in cancer patients, and have cloned the specific T cell
receptors (TCRs) to use for adoptive immunotherapy of patients that express these mutations and have the
correct MHC alleles. Driver mutations make ideal immunotherapy targets because, unlike most neoantigens
that are random and patient specific, they are positively selected for clonal and homogenous expression and
are found in multiple patients. We and others have shown that driver mutation-specific CD4+ T cell responses
are commonly present, and that these T cells can be expanded locally in tumors, suggesting they recognize
tumor antigens in vivo. In mouse models, tumor antigen-specific CD4+ T cells can mediate tumor rejection
through direct destruction of tumor cells, activation of innate immune cells, and stimulation of CD8+ T cell
responses, but the mechanisms of action by CD4+ T cells in human antitumor immunity are largely unknown.
High dimensional single cell analysis of human tumors has shown heterogeneity of CD4+ T cells with regards
to activation, exhaustion, cytolytic potential, and differentiation states associated with stimulation versus
suppression of cellular immune responses, but which of these populations contain the small subset of
neoantigen specific CD4+ T cells is unknown. In specific aim 1 we will address the frequency, activation, and
differentiation state of neoantigen specific CD4+ T cells in tumors to better understand whether and how these
cells might contribute to antitumor immunity. We will then use our discovery of a TCR that can redirect the
specificity of CD4+ T cell to the common BRAF V600E mutation to ask whether adoptive cell transfer of
neoantigen-specific CD4+ T cells can be safe in a first in human phase I clinical trial in specific aim 2. This
trial will give the opportunity for asking whether adoptively transferred CD4+ T cells can mediate therapeutic
effects and address potential mechanisms for CD4+ T cells to mediate antitumor immunity. If successful, this
approach could be applied to additional targets in larger number of patients.
摘要
项目成果
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Joshua R Veatch其他文献
Joshua R Veatch的其他文献
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{{ truncateString('Joshua R Veatch', 18)}}的其他基金
Therapeutic applications of CD4+ T cells specific for oncogenic driver mutations
致癌驱动突变特异性 CD4 T 细胞的治疗应用
- 批准号:
9977672 - 财政年份:2020
- 资助金额:
$ 19.41万 - 项目类别:
Therapeutic applications of CD4+ T cells specific for oncogenic driver mutations
致癌驱动突变特异性 CD4 T 细胞的治疗应用
- 批准号:
10378482 - 财政年份:2020
- 资助金额:
$ 19.41万 - 项目类别: