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Principal Investigator: JODI Kathleen MARANCHIE
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $438,296
Funding agency: National Cancer Institute
ABSTRACT
Although RCC is typically classified as an immunogenic tumor, recent profiling studies instead suggest that
presence of CD8+ TIL in this form of cancer is an indicator of poor prognosis. These findings emphasize the
importance of appreciating immune context/immune cell networking in the tumor microenvironment when
interpreting the operational status of tumor immunity and its likely impact on disease progression and response
to interventional therapy. Indeed, if one instead considers organized clusters of CD8+ T cells and mature DC-
LAMP+ dendritic cells (DC) within tertiary lymphoid structures (TLS) in tumors, these lymphoid “organs” are
positive prognostic indicators for overall survival/PFS in RCC patients. Tumor-associated TLS have been
suggested to serve as an immune “oasis” for infiltrating lymphocytes exhibiting less-exhausted phenotypes, and
as sites for in situ DC-mediated cross-priming of a diversified therapeutic CD8+ T cell repertoire. We have
recently shown that vaccination against tumor-associated blood vessel antigens (TBVA) results in vascular
normalization (VN; i.e. vascular trimming, reduced vascular leak/hypoxia/interstitial fluid pressure) and the de
novo development of TLS within tumors in mice and humans responding to interventional vaccine-based
immunotherapy. Remarkably, we have also observed that the anti-tumor efficacy of these vaccines exhibits
profound gender/sexual dimorphism, with higher response rates in females (or castrated males) vs. intact males,
suggesting a regulatory role for sex steroids and their receptors. Our central hypotheses are that: i.)
combination immunotherapy promoting VN in RCC will enhance TLS development and the generation of a
broadly-reactive therapeutic CD8+ T cell repertoire exhibiting superior “fitness” and anti-tumor efficacy, and ii.)
gender dimorphic response to vaccination can be circumvented by co-administration of androgen synthesis/AR
antagonists. Given a 2:1 male:female incidence of ccRCC, these latter studies are expected to dramatically
expand the therapeutic utility of TBVA-targeted vaccines against RCC. We will initially perform an exploratory
clinical trial to determine the impact of an autologous αDC1/peptide vaccine targeting TBVA + oral low-dose
cabozantinib on VN, TLS formation and tumor-infiltrating T cell fitness in patients with recently-diagnosed primary
ccRCC prior to planned surgical resection (Aim 1), before then pursuing animal models to test the hypotheses
that i.) agents capable of promoting VN in murine RCC (RENCA, RENCA.VHL-/-) tumors will synergize with
vaccines targeting RCC and/or TBVA antigens +/- checkpoint blockade in promoting the development of TLS,
improved tumor-infiltrating T cell (TIL) fitness, an expanded TIL repertoire and superior therapeutic benefit (Aim
2) and ii.) agents capable of interrupting androgen synthesis/androgen receptor-signaling will improve
therapeutic efficacy of VN-inducing immunotherapies in male/female BALB/c mice bearing RCC tumors (Aim 3).
Terms: <Abbreviations><Abscission><Adventitial Cell><Androgen Receptor><Androgenic Agents><Androgenic Compounds><Androgens><Angiogenesis Antagonists><Angiogenesis Blockers><Angiogenesis Inhibitors><Angiogenetic Antagonists><Angiogenetic Inhibitors><Angiogenic Antagonists><Angiogenic Inhibitors><Angiostatic Agents><Animal Model><Animal Models and Related Studies><Anti-Angiogenetic Agents><Anti-Angiogenic Agents><Anti-Angiogenic Drugs><Antiangiogenesis Agents><Antiangiogenic Agents><Antiangiogenic Drugs><Antigen Targeting><Antigenic Determinants><Antigens><Apoptosis><Apoptosis Pathway><Assay><Attention><Autologous><Autologous Dendritic Cells><BALB C Mouse><BALB/c><Binding Determinants><Bioassay><Biological Assay><Blood><Blood Reticuloendothelial System><Blood Vessel Tumor><Blood Vessels><Blood flow><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><Cancers><Cell Body><Cells><Checkpoint inhibitor><Classification><Clear cell renal cell carcinoma><Clinic><Clinical><Clinical Trials><Co-Stimulator><Combination immunotherapy><Costimulator><Cross-Priming><Dendritic Cells><Development><Diagnosis><Disease Progression><Dose><ELISPOT><Ectopic lymphoid organ><Ectopic lymphoid structure><Epidermal Thymocyte Activating Factor><Epitopes><Excision><Exhibits><Extirpation><Female><Fostering><Future><Gender><Gender Issues><Gene Transcription><Generations><Genetic Transcription><Gonadal Steroid Hormones><Grawitz Tumor><HLA Class I Histocompatibility Antigen, A-2 Alpha Chain><HLA-A Class I Antigen 2><HLA-A Histocompatibility Type Antigen 2><HLA-A2><HLA-A2 Antigen><Human><Hypernephroid Carcinoma><Hypernephroma><Hypoxia><Hypoxic><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><IL-2><IL2 Protein><Immune><Immune Interferon><Immune checkpoint inhibitor><Immune infiltrates><Immune mediated therapy><Immunes><Immunity><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologically Directed Therapy><Immunologics><Immunotherapy><In Situ><Inbred BALB C Mice><Incidence><Infiltration><Inflammation><Inflammatory><Intercellular Fluid><Interferon Gamma><Interferon Type II><Interleukin 2><Interleukin 2 Precursor><Interleukin II><Interleukin-2><Interleukine 2><Interleukine 2 Precursor><Interleukine II><Interruption><Interstitial Fluids><Intervention><Intervention Strategies><LYT3><Lymphatic cell><Lymphocyte><Lymphocyte Mitogenic Factor><Lymphocytic><Lymphoid><Maintenance><Major Histocompatibility Complex, Class I, A2 Antigen><Male Castration><Malignant Neoplasms><Malignant Tumor><Mediating><Melanoma patient><Mice><Mice Mammals><Mitogenic Factor><Modern Man><Murine><Mus><Neoplasms in Vascular Tissue><Neovascularization Inhibitors><Nephroid Carcinoma><Operative Procedures><Operative Surgical Procedures><Oral><Oxygen Deficiency><Patients><Peptide Vaccines><Peptides><Perfusion><Pericapillary Cell><Pericytes><Perivascular Cell><Phase><Phase 2 Clinical Trials><Phase II Clinical Trials><Phenotype><Prognosis><Programmed Cell Death><RNA Expression><Receptor Protein><Receptor Signaling><Removal><Renal Adenocarcinoma><Renal Cell Adenocarcinoma><Renal Cell Cancer><Renal Cell Carcinoma><Resistance><Role><Rouget Cells><Sex Hormones><Sex Steroid Hormones><Site><Sterility><Structure><Surgical><Surgical Interventions><Surgical Procedure><Surgical Removal><Systematics><Systems Biology><T cell based therapeutics><T cell based therapy><T cell directed therapies><T cell growth factor><T cell infiltration><T cell receptor repertoire sequencing><T cell receptor sequencing><T cell response><T cell targeted therapeutics><T cell therapy><T-Cell Growth Factor><T-Cell Stimulating Factor><T-Cells><T-Lymphocyte><T-cell therapeutics><T-cell transfer therapy><T8 Cells><T8 Lymphocytes><TCR repertoire sequencing><TCR sequencing><TCR-seq><TCRseq><Tertiary lymphoid structure><Testing><Therapeutic><Therapeutic Androgen><Therapeutic Intervention><Thymocyte Stimulating Factor><Transcription><Translations><Treatment Efficacy><Tumor Expansion><Tumor Immunity><Tumor Tissue><Vaccination><Vaccine Antigen><Vaccines><Vascular Endothelial Cell><Vascular Neoplasms><Vascular Tissue Tumor><Vascular Tumor><Veiled Cells><adoptive T cell transfer><adoptive T-cell therapy><antagonism><antagonist><anti-tumor immunity><antiangiogenic><antitumor immunity><biosignature><blood vessel neoplasm><cancer immunity><cancer infiltrating T cells><cancer microenvironment><cancer progression><ccRCC><check point blockade><checkpoint blockade><combinatorial immunotherapy><cytokine><design><designing><developmental><dimorphism><dual immunotherapy><effective therapy><effective treatment><enzyme linked immunospot assay><exhaust><female treatment><fitness><gonadal steroids><immune cell infiltrate><immune check point blockade><immune check point inhibitor><immune checkpoint blockade><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunogenic><immunogenic apoptosis><immunogenic cell death><immunogenicity><improved><in vivo><inhibitor><intervention efficacy><intervention therapy><interventional strategy><kidney adenocarcinoma><lFN-Gamma><lymph cell><lymph organ><lymphatic organ><lymphoid organ><male><malignancy><model of animal><necrotic tissue><neoplasm progression><neoplasm/cancer><neoplastic progression><novel><patient response><patient specific response><phase II protocol><pressure><prognostic indicator><receptor><recruit><resection><resistant><response><response to therapy><response to treatment><responsive patient><sex dimorphism><sex steroid><sexual dimorphism><sexually dimorphic><social role><sterile><surgery><synergism><tertiary lymphoid organ><therapeutic T-cell platform><therapeutic efficacy><therapeutic outcome><therapeutic response><therapy efficacy><therapy outcome><therapy response><thymus derived lymphocyte><tissue necrosis><translation><treat females><treat women><treatment among females><treatment among women><treatment in females><treatment in women><treatment response><treatment responsiveness><tumor><tumor infiltrating T cells><tumor microenvironment><tumor progression><vaccine efficacy><vaccine for immunotherapy><vaccine immunotherapy><vaccine-based immunotherapy><vascular><women's treatment>