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Principal Investigator: Qizhi C. Yao
Organization: MICHAEL E DEBAKEY VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
As the risk for pancreatic ductal adenocarcinoma (PDAC) has increased to a higher rate
in veterans relative to that in the general population, there is an urgent need to develop effective
therapies to treat PDAC for veterans in the VA system. Recently, cancer immunotherapy has
shown great promise in several cancers, but not in PDAC. Part of the reason for this is the
heterogeneity of PDAC and lack of tailoring of immunotherapy to individual tumor subtypes.
PDAC patient stratification for therapy remains in its infancy, and a reliable method to
deconvolute complex tumor composition to stratify PDAC subtypes has not been recognized.
Recently, we participated in whole genome sequencing of PDAC specimens, which provides the
basis for classifying PDAC into four subtypes based upon patterns of genomic structural
variation (Nature, 2016). Among these, the immunogenic subtype accounts for 30% of 178
PDAC samples in the TCGA database and is characterized by upregulated immune cell
networks, which could indicate differential responses to immunotherapy. In addition, the
Epigenomic Deconvolution (EDec) method, first developed by our co-investigator Dr.
Milosavljevic’s group, provides valuable information about cell type composition of tumors and
cell-type specific gene expression (Cell Rep. 2016). When applied to immunogenic subtype
PDAC tumors, EDec reveals an immunosuppressive microenvironment characterized by the
highest Foxp3 expression among all four subtypes. Cancer cells falling into the immunogenic
subtype also show the highest mesothelin (MSLN) expression. Therefore, we hypothesize that
PDACs with an immunogenic profile could be a target subgroup that is responsive to
immunotherapy either by MSLN virus-like particle (VLP) vaccination or combination therapy of
VLPs and an immune checkpoint inhibitor. We will test our hypothesis in pre-clinical animal
models that best recapitulate human PDAC patient’s response to immunotherapy, including
patient-derived tumor xenografts (PDX) and humanized mouse models. Our preliminary data
have shown that our anti-MSLN VLP vaccine is effective against MSLN-high expressing PDX in
a humanized NSG mouse model (PDX-hu-NSG). Based on our strong preliminary results, we
propose to develop an effective cancer immunotherapeutic approach by combining three highly
synergistic innovations: (1) A novel epigenetic deconvolution method to stratify PDAC tumors;
(2) PDX-hu-NSG models; and (3) Combination therapy of MSLN-VLP vaccine plus anti-PD-1
antibody. We propose two specific aims. In Aim 1, we will determine whether the immunogenic
subtype of PDAC is responsive to MSLN-VLP vaccine in PDX-hu-NSG model. Here, we will
use EDec method to stratify VA PDACs by subtype and then determine MSLN-VLP vaccine
efficacy in specific PDAC subgroups in humanized PDX mouse model. In Aim 2, we will
determine whether combination therapy with anti-PD-1 Ab enhances MSLN VLP vaccine
responses and efficacy in onco-humice model. We will also determine specific tumor infiltrating
subset of cells that are responsible for the effective combination therapy. Furthermore, potential
side-effect of the combination therapy will also be evaluated. Our findings will provide preclinical
evaluation of the therapeutic efficacy of an innovative precision immunotherapy for PDAC in
humanized mice without putting patients at risk. The project will provide understanding of
molecular, cellular, and tissue-level responses to therapy, a key step towards improved
outcomes in PDAC through patient stratification for therapy.
Terms: <Animal Model><Animal Models and Related Studies><Biological Markers><Body Tissues><Cancers><Cell Body><Cells><Checkpoint inhibitor><Classification><Combined Modality Therapy><Complex><Data><Data Bases><Databases><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><FOXP3><FOXP3 gene><Forkhead Box P3><Gene Expression><General Population><General Public><Genomics><Heterogeneity><Human><Immune><Immune checkpoint inhibitor><Immune mediated therapy><Immunes><Immunologically Directed Therapy><Immunotherapy><Individual><Infiltration><Investigators><JM2><Malignant Cell><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Methods><Modeling><Modern Man><Molecular><Multimodal Therapy><Multimodal Treatment><Nature><PD-1 antibody><PD1 antibody><Pancreas Cancer><Pancreas Ductal Adenocarcinoma><Pancreatic Cancer><Pancreatic Ductal Adenocarcinoma><Patients><Pattern><RT-PCR><RTPCR><Research Personnel><Research Specimen><Researchers><Reverse Transcriptase Polymerase Chain Reaction><Risk><SCURFIN><Sampling><Soluble Mpf/Mesothelin-Related Protein><Specimen><Stratification><Subgroup><System><Systematics><TCGA><Testing><The Cancer Genome Atlas><Tissues><Tumor Subtype><Vaccination><Vaccines><Variant><Variation><Veterans><Virus-like particle><anti-PD-1 Ab><anti-PD-1 antibodies><anti-PD-1 monoclonal antibodies><anti-PD1 Ab><anti-PD1 antibodies><anti-PD1 monoclonal antibodies><anti-cancer immunotherapy><anti-programmed cell death protein 1 antibodies><anti-programmed death-1 antibody><anticancer immunotherapy><bio-markers><biologic marker><biomarker><cancer cell><cancer immune therapeutics><cancer immunotherapeutics><cancer immunotherapy><cell type><cohort><combination therapy><combined modality treatment><combined treatment><data base><determine efficacy><effective therapy><effective treatment><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><entire genome><epigenetically><epigenomics><evaluate efficacy><examine efficacy><falls><full genome><genome sequencing><humanized mice><humanized mouse><immune check point inhibitor><immune microenvironment><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapies><immune-based treatments><immuno therapy><immunogenic><immunosuppressive microenvironment><immunosuppressive tumor microenvironment><immunotherapy for cancer><immunotherapy of cancer><improved outcome><infancy><infantile><innovate><innovation><innovative><malignancy><mesothelin><model of animal><mouse model><multi-modal therapy><multi-modal treatment><murine model><nano-string><nanostring><neoplasm/cancer><novel><pancreatic malignancy><patient response><patient specific response><patient stratification><personalized immunotherapy><pre-clinical><pre-clinical evaluation><precision immunotherapy><preclinical><preclinical evaluation><response><response to therapy><response to treatment><responsive patient><reverse transcriptase PCR><side effect><specific biomarkers><stratified patient><therapeutic evaluation><therapeutic response><therapeutic testing><therapy response><treatment response><treatment responsiveness><tumor><tumor immune microenvironment><tumor xenograft><tumor-immune system interactions><vaccine efficacy><vaccine response><vaccine responsiveness><vaccine-induced response><virus-like nanoparticles><viruslike particle><whole genome>