Programming Metabolically Fit TILs for Immunotherapy
Programming Metabolically Fit TILs for Immunotherapy
批准号:
10822377
负责人:
Shikhar Mehrotra
金额:
$100.0万
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
项目状态:
未结题
起止时间:
2020-02-15 至 2025-08-31
关键词:
AdoptedAdoptive Cell TransfersAdoptive TransferAffinityAntigensAppearanceB lymphoid malignancyCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCD8B1 geneCancer PatientCell DeathCell Death InductionCellsCellular Metabolic ProcessChronicClinicalCytotoxic T-LymphocytesDataDependenceDoseEngineeringEngraftmentEpitopesExhibitsFOXP3 geneFutureGenerationsGenetic EngineeringGlutamineGoalsHelper-Inducer T-LymphocyteHumanHybridsIL17 geneIL2 geneImmunosuppressionImmunotherapyInfiltrationInfusion proceduresInterferon Type IIInterleukin-15Investigational DrugsInvestigational New Drug ApplicationLeadLogisticsLyticMalignant NeoplasmsMalignant neoplasm of prostateMemoryMetabolicMetabolic stressMetastatic breast cancerMethodologyMethodsMitochondriaMolecular BiologyMutateNutrientPPBP genePathway interactionsPatientsPhasePhase I Clinical TrialsPhase I/II Clinical TrialPhenotypePredispositionPrimary NeoplasmProstatic NeoplasmsProtocols documentationPublicationsPublishingRegulatory T-LymphocyteReportingResearchResourcesSolid NeoplasmT cell therapyT-Cell ReceptorT-LymphocyteT-Lymphocyte SubsetsTC1 CellTNF geneTestingTh1 CellsTimeTumor AntigensTumor EscapeTumor ExpansionTumor SuppressionTumor-Infiltrating LymphocytesUnited States Food and Drug AdministrationVariantViralWomanchimeric antigen receptorcommercializationcostcytokinecytotoxiccytotoxic CD8 T cellsdesigneffector T cellefficacy testingengineered T cellsexhaustionfeasibility testingimmunogenicimmunotherapy clinical trialsimprovedin vivoin vivo Modelinterleukin-21melanomametabolic phenotypeneoantigensneoplastic cellnovelpatient derived xenograft modelphase 1 studypreclinical studyprogramsresponsesenescencestem-like cellstemnesstransdifferentiationtumortumor growthtumor microenvironmenttumor xenograft
中文摘要
摘要
英文摘要
ABSTRACT
Advances in molecular biology and genetic engineering have led to the design and use of modified T cells
recognize tumors to achieve significant tumor control upon adoptive cell transfer (ACT) to patients. These T cells
are either transduced with tumor antigen reactive T cell receptors (TCR), or chimeric antigen receptors (CARs).
Recently, a surge in studies with neo-antigen reactive T cells or T cells recognizing novel mutated antigens has
also shown promise. While the implementation of these studies requires significant technical resources, the
appearance of antigen loss variants also leads to less effective tumor control when using effector T cells reactive
to single tumor antigen or target molecule. Thus, there is a resurgence in using tumor infiltrating lymphocytes
(TILs), which have endogenous T cells reactive to multiple tumor epitopes, for ACT. While most studies have
used the conventional approach to expand TILs using high dose IL2, some recent studies using IL15 or IL21
showed improved tumor control. Preclinical studies have also shown that different subsets of both helper CD4+
T helper (Th) cells and CD8+ T cytotoxic (Tc) cells hold promise for clinical use in ACT protocols. Importantly, T
helper cell subsets with the ability to secrete IL-17 (Th17) have been shown to possess stem cell like phenotype
that attributes to their long-term persistence and leads to improved tumor control tumors as compared to the Th1
subsets (that secrete IFNγ, IL2, TNFα). However, contrary to these observations there are reports that Tc1 cells
exhibit improved tumor control as compared to Tc17 cells. These differences in T cell subsets response to control
tumors, is compounded by the fact that in the suppressive tumor microenvironment a large fraction of these Th
or Tc subsets acquire FoxP3+ regulatory phenotype, become dysfunctional or undergo cell death leading to
tumor reversion. Thus, ex vivo programming conditions that can render a stable phenotype with reduced
‘plasticity’ and not only controls primary tumors, but also results in formation of anti-tumor memory will be of
immense importance in ACT. We have recently established that programming conditions that bring together
‘anti-tumor effector function’ of Th1 cells and ‘stemness’ of Th17 cells lead to a superior hybrid Th1/17 (and
Tc/17) cell exhibiting long-term tumor control. Thus, in the Phase I application we successfully tested the
feasibility of programming metabolically enhanced signature to TILs from melanoma and prostate cancer
patients. For the Phase II application, we hypothesize that ex vivo programming and expansion using hybrid
T1/17 (Th1/17 and Tc1/17) culture conditions will result in a robust anti-tumor control even with fewer adoptively
transferred clinical grade metabolically enhanced TILs (meTILs). Following specific aims are proposed to
establish and develop our approach for commercialization: Specific Aim 1: To generate clinical-grade hybrid
meTILs from melanoma and prostate cancer patients. Specific Aim 2: To establish if clinical grade hybrid meTILs
are superior to conventional TILs in controlling tumor growth in vivo. We believe that this proposal will help adopt
the novel ex vivo programming conditions for generating hybrid meTILs that could be used future in adoptive T-
cell immunotherapy clinical trials.
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