[R01] CAR neutrophils produced in vivo to remodel tumor microenvironment and treat glioblastoma
Ente: National Cancer Institute
Scadenza: 2030-03-31
Importo max: 641.936 EUR
Paese: US
Descrizione
Project Summary
Glioblastoma (GBM) is the most aggressive type of cancer that occurs in the brain. While functional anti-
cancer therapeutics, such as emerging chimeric antigen receptor (CAR)-T and natural killer (NK) cell therapies,
have been developed to treat various cancers, their therapeutic applications for brain cancers have been
impeded by the blood-brain barrier (BBB) and immunosuppressive tumor microenvironment. Due to their native
ability to cross BBB and penetrate the brain parenchyma, neutrophils have been recently used as carrier cells to
deliver imaging and therapeutic drugs into brain tumors. Recently, the investigators engineered a GBM-targeted
CAR-neutrophils from human pluripotent stem cells (hPSCs) for the first time and demonstrated their superior
antitumor activities in animal models of GBM as compared to CAR-NK cells. However, the limitation of such
approaches is the expensive and strenuous in vitro process required for generating the engineered cells.
Currently, a significant gap remains in our understanding and programming of tumor-associated neutrophils
within the tumor microenvironment (TME) in vivo. In this proposal, the investigators will harness the power of
synthetic biology, unbiased machine learning, next-generation sequencing, murine and canine models to
interrogate tumor-associated neutrophils and develop new strategies to program them towards antitumor effector
cells. Our preliminary data shows that synthetic nucleoside-modified messenger RNA (modRNA) could be
specifically delivered to circulating neutrophils via lipid nanoparticles (LNPs) or exosomes and produce effective
antitumor CAR-neutrophils directly in vivo. The central hypothesis of this proposal is that modRNA CARs specific
for glioma cells will direct neutrophils to remodel TME and extend the lifespan of tumor-bearing animals. To test
this hypothesis, we will first develop and optimize neutrophil-specific CAR constructs with machine learning
algorithms in Aim 1. Then in Aim 2, we will determine the antitumor activities of combinatory CAR-neutrophils
and radiation or CAR-T cell therapy in murine models. In Aim 3, we will evaluate the safety and therapeutic
efficacy of in vivo produced CAR-neutrophils in pet dog patients with spontaneous glioma. It's expected that this
study will lead to the establishment of a novel in vivo neutrophil programming platform, providing proof-of-concept
for modRNA CAR-neutrophil immunotherapy.
Istituzione: PURDUE UNIVERSITY
PI: Xiaoping Bao, Qing Deng, Isabelle Francoise Vanhaezebrouck
Progetto: 5R01CA293514-02
Settori: National Cancer Institute
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