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Principal Investigator: Jose R Conejo-Garcia
Organization: DUKE UNIVERSITY
Fiscal Year: 2024
Award: $367,057
Funding agency: National Cancer Institute
Abstract
Aggressive malignant progression and spreading has limited a clear understanding of the
pathophysiology of SCLC. The overarching goal of this “bedside to bench” project is to elucidate
the role of inter-metastatic divergence in therapeutic resistance in small cell lung cancer (SCLC),
with a focus on how antigenic heterogeneity and dominant immunosuppressive butyrophilins
thwart protective adaptive immune responses in this disease, to develop novel interventions to
overcome these hurdles.
We will leverage a Rapid Tissue Donation (RTD) program established at Moofitt Cancer Center,
which provides timely access to the entire repertoire of metastatic lesions in terminal patients,
who generously donate their tissues for this research. Using this resource, plus CDX models
routinely generated for each SCLC patient, we will define barriers that impair the effectiveness of
immunotherapies. During the 5-year tenure of this grant we will generate a rationale for novel
immunotherapeutic trials to overcome overcome these elusive hurdles, with a focus on antigenic
heterogeneity and the role of immunosuppressive butyrophilins.
Based on our expertise on tumor immunology (Dr. Conejo-Garcia) and clinical immunotherapy
(Drs. Perez), as well as access to a Rapid Tissue Donation program, we postulate that the
effectiveness of immunotherapies against small cell lung cancer is thwarted by heterogeneous
immunogenicity across different tumor masses, along with high expression of
immunosuppressive CD277+ butyrophilins. Based on our preliminary results, our central
hypothesis is that pleural effusions and trogocytic tumor-infiltrating T cells could provide a source
of effector lymphocytes for cell therapies that would target multiple tumor masses, in combination
with targeting immunosuppressive BTN3A butyrophilins and/or tumor-derived antibodies. We
propose the following Specific Aims: Aim 1. Define the role of inter-metastatic heterogeneity in
therapeutic resistance in human SCLC. Aim 2. Design novel T cell immunotherapies that
overcome metastatic heterogeneity in SCLC. Aim 3. Determine the potential of antibodies
produced in SCLC to overcome inter-metastatic heterogeneity. These studies will, first, define the
role and heterogeneity of neoantigens and immune cells in SCLC; a poorly characterized disease,
due in part to its aggressiveness. Most importantly, we will provide a mechanistic rationale for
more effective immunotherapies that target the diversity and dominant immunosuppressive
drivers of this human disease, which will target in novel clinical trials at Moffitt.
Terms: <7S Gamma Globulin><Address><Antibodies><Antibody Specificity><Antigen Targeting><Antigens><Area><Autologous><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><B7-H1><B7H1><Biological><Biopsy><Body Tissues><CAR T cells><CAR modified T cells><CAR-T><CAR-Ts><CD274><Cancer Center><Cancer Patient><Cancers><Cell Body><Cell Therapy><Cells><Cessation of life><Class Switching><Class Switchings><Clinical><Clinical Research Protocols><Clinical Trials><Combination immunotherapy><Cryofixation><Cryopreservation><Death><Disease><Disorder><Dysfunction><Effectiveness><Enrollment><Evolution><Functional disorder><Future><Genetic Alteration><Genetic Change><Genetic defect><Goals><Grant><Heterogeneity><Heterograft><Heterologous Transplantation><Human><IgA><IgG><Immune><Immune mediated therapy><Immunes><Immunoglobulin A><Immunoglobulin Class Switching><Immunoglobulin Class Switchings><Immunoglobulin G><Immunologically Directed Therapy><Immunotherapeutic agent><Immunotherapy><Impairment><Individual><Infiltration><Intervention><Intervention Strategies><Isotype Switching><Isotype Switchings><Lymphatic cell><Lymphocyte><Lymphocytic><Lymphocytic Infiltrate><Malignant><Malignant - descriptor><Malignant Neoplasms><Malignant Tumor><Membrane><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Methods><Modeling><Modern Man><Multiple Tumor Masses><Mutation><NSCLC><NSCLC - Non-Small Cell Lung Cancer><Neoplasm Circulating Cells><Neoplasm Metastasis><Newly Diagnosed><Non-Small Cell Lung Cancer><Non-Small-Cell Lung Carcinoma><Oat cell carcinoma><PD-L1><PD-L1 blockade><PDL-1><PDL1><PDL1 blockade><Patients><Phenotype><Physiopathology><Pleural Effusion><Pleural effusion disorder><Process><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Protocol><Protocols documentation><Recurrence><Recurrent><Reporting><Research><Research Resources><Resected><Resistance><Resources><Role><Sampling><Secondary Neoplasm><Secondary Tumor><Small Cell Lung Cancer><Source><T cells for CAR><T-Cells><T-Lymphocyte><T-cell receptor repertoire><TCR repertoire><Tissue Banks><Tissue Collection><Tissue Donations><Tissue repository><Tissues><Tumor-Derived><Work><Xenograft><Xenograft procedure><Xenotransplantation><adaptive immune response><anti-PD-L1 blockade><anti-tumor immune response><bench bed side><bench bedside><bench to bed side><bench to bedside><bench to clinic><bench to clinical practice><biologic><butyrophilin><cancer immunology><cancer infiltrating T cells><cancer metastasis><cell mediated therapies><cell-based therapeutic><cell-based therapy><cellular therapeutic><cellular therapy><check point inhibition><checkpoint inhibition><chemotherapy><chimeric antigen T cell receptor><chimeric antigen receptor (CAR) T cells><chimeric antigen receptor T cells><chimeric antigen receptor fusion protein T-cells><chimeric antigen receptor modified T cells><circulating neoplastic cell><circulating tumor cell><clinical development><cold preservation><cold storage><combinatorial immunotherapy><design><designing><dual immunotherapy><enroll><exosome><genome mutation><human disease><immune check point inhibition><immune checkpoint inhibition><immune drugs><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapeutics><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunogenicity><immunologic therapeutics><immunotherapeutics><immunotherapy agent><interventional strategy><lung oat cell carcinoma><lung small cell neuroendocrine carcinoma><lymph cell><malignancy><membrane structure><neo-antigen><neo-epitopes><neoantigens><neoepitopes><neoplasm immunology><neoplasm/cancer><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><oat cell cancer><overexpress><overexpression><participant enrollment><pathophysiology><patient enrollment><pleural cavity effusion><pressure><prevent><preventing><programmed cell death ligand 1><programmed cell death protein ligand 1><programs><protein death-ligand 1><resistance to therapy><resistant><resistant to therapy><response><small cell lung carcinoma><small cell undifferentiated carcinoma><social role><therapeutic effectiveness><therapeutic resistance><therapy resistant><thymus derived lymphocyte><treatment resistance><tumor><tumor cell metastasis><tumor immunology><tumor infiltrating T cells><xeno-transplant><xeno-transplantation>