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Principal Investigator: Shari Pilon-Thomas
Organization: H. LEE MOFFITT CANCER CTR & RES INST
Fiscal Year: 2024
Award: $452,237
Funding agency: National Cancer Institute
Summary
Bladder cancer is the fourth most common cancer in men and a leading cause of cancer mortality among men
and women with the rates of bladder cancer incidents and bladder cancer-related deaths that have not
decreased over the last 40 years. Therefore, novel more precise treatment strategies are desired. Bladder
cancer has long been recognized as a malignancy that is responsive to immune-based therapy. One of the
novel immunotherapy approaches utilizes the adoptive cell therapy (ACT), where autologous tumor-infiltrating
T lymphocytes (TIL) are expanded and activated ex vivo and then reinfused into the cancer patient. However,
typical systemic administration of ACT-TIL requires prior lymphodepletion and thus TIL are injected
infrequently and in large numbers. Bladder is a specific organ which allows for intravesical delivery by direct
administration of drugs and T cells through a catheter making it amenable to multiple and more frequent
infusions of TIL and other therapeutics, potentially with smaller doses. This gives an unprecedented
opportunity to use mathematical modeling integrated with pre-clinical mouse models to design, optimize and
validate ACT-TIL combination therapies that will maximize tumor response and minimize toxicity. Our methods
include microscopic- and macroscopic-level in silico models supported by in vitro, in vivo and ex vivo
experimental data, defined T cells and a murine models of bladder cancer that mimic clinically-relevant
procedures. In Aim 1, we will develop in silico models to enhance T cell infiltration into the bladder tumors. In
Aim 2, we will optimize T cell properties ex vivo for the most effective T cell-cancer cell interactions. In Aim 3,
we will apply our integrated methodology to design most effective combination therapy protocols to increase
the effectiveness of reinfused TILs. The deliverables of this study will improve our understanding of how the
bladder tumor microenvironment impacts T cell infiltration and T cell-tumor cell interactions and will lead to
strategies that improve bladder cancer treatment by mathematically optimizing treatment schedules.
Terms: <Abscission><Adoptive Cell Transfers><Adoptive Cellular Immunotherapy><Adoptive Immunotherapy><Antigen-Presenting Cells><Autologous><Bladder><Bladder Cancer><Bladder Drug Administration><Bladder Neoplasm><Bladder Tumors><Bladder Urinary System><CD8><CD8B><CD8B1><CD8B1 gene><Calibration><Cancer Cause><Cancer Etiology><Cancer Histology><Cancer Patient><Cancer Treatment><Cancers><Catheters><Cell Communication><Cell Communication and Signaling><Cell Interaction><Cell Signaling><Cell model><Cell-to-Cell Interaction><Cellular model><Cessation of life><Characteristics><Checkpoint inhibitor><Clinical><Clinical Trials><Combined Modality Therapy><Computer software><Data><Death><Dendritic Cells><Disease><Disorder><Dose><Drugs><Effectiveness><Excision><Extirpation><Future><Generations><Histology><Human Characteristics><Human Nature><Immune checkpoint inhibitor><Immune mediated therapy><Immunologically Directed Therapy><Immunologist><Immunotherapy><In Vitro><Infiltration><Infusion><Infusion procedures><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Intravesical Administration><Intravesical Drug Administration><LYT3><Malignant Bladder Neoplasm><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Bladder><Malignant neoplasm of urinary bladder><Math><Math Models><Mathematics><Medication><Metabolic><Methodology><Methods><Microscopic><Modeling><Morphology><Multimodal Therapy><Multimodal Treatment><Organ><PDX model><Patient derived xenograft><Patients><Pharmaceutical Preparations><Phase><Pre-Clinical Model><Preclinical Models><Procedures><Property><Protocol><Protocols documentation><Removal><Research><Resected><Schedule><Signal Transduction><Signal Transduction Systems><Signaling><Software><Stress><Surgical Removal><T cell based therapeutics><T cell based therapy><T cell directed therapies><T cell infiltration><T cell targeted therapeutics><T cell therapy><T-Cells><T-Lymphocyte><T-cell therapeutics><T-cell transfer therapy><Therapeutic><Toxic effect><Toxicities><Treatment Protocols><Treatment Regimen><Treatment Schedule><Tumor Cell><Urinary Bladder Cancer><Urinary Bladder Malignant Tumor><Urinary Bladder Neoplasm><Urinary Bladder Tumor><VAC-TX><Vaccine Therapy><Vaccines><Veiled Cells><Woman><Work><accessory cell><adoptive T cell transfer><adoptive T-cell therapy><adoptive cell immunotherapy><adoptive cell therapy><adoptive cellular therapy><anti-cancer therapy><biological signal transduction><cancer cell><cancer infiltrating T cells><cancer microenvironment><cancer therapy><cancer type><cancer-directed therapy><chemotherapy><clinical relevance><clinically relevant><combination therapy><combined modality treatment><combined treatment><computer based prediction><design><designing><drug/agent><immune check point inhibitor><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><improved><in silico><in vivo><infusions><interventional strategy><intravesical><malignancy><mathematic model><mathematical model><mathematical modeling><men><mortality><mouse model><multi-modal therapy><multi-modal treatment><murine model><neoplasm/cancer><neoplastic cell><novel><patient derived xenograft model><peripheral blood><pre-clinical><preclinical><predictive modeling><resection><response><simulation><success><therapeutic T-cell platform><therapeutic vaccination><therapy optimization><thymus derived lymphocyte><treatment optimization><treatment strategy><tumor><tumor infiltrating T cells><tumor microenvironment><urinary bladder><virtual>