TMIC-12. TUMOR-HOMING RNA-NANOPARTICLES REPROGRAM IMMUNE CELLS IN THE BRAIN TUMOR MICROENVIRONMENT

Abstract BACKGROUND While dendritic cell (DC) vaccine therapy has shown considerable promise for glioblastoma (GBM) patients (Mitchell et al. Nature, 2015), their advancement into human clinical trials has been fraught with challenges in the development, manufacturing, and marketing of successful cancer immunotherapies. To circumvent the challenges associated with cell therapy, we have developed a new platform technology consisting of tumor derived mRNA complexed into lipid-nanoparticles (RNA-NPs) for systemic delivery to DCs in vivo and induction of antigen specific T cell immunity against GBM. OBJECTIVES/ METHODS We sought to assess if surface and charge modifications to our custom lipid-NP could facilitate its localization to lymphoid organs and the brain tumor microenvironment. RESULTS We demonstrate that intravenous administration of our unmodified custom RNA-NPs mediate systemic activation of DCs; these include activation of CD11c+ cells in the brains of animals with intact blood brain-barriers (BBBs). RNA-NPs mediate antigen specific T cell immunity and anti-tumor efficacy with increased tumor infiltrating lymphocytes against a NF-1/p53 mutant glioma that recapitulates features of human GBM in immunocompetent mice. Modification of surface charge could direct these RNA-NPs to lymphoid organs (e.g. spleen, lymph nodes) while modification of the lipid backbone (with cholesterol) enhances localization to innate immune cells in NF-1/p53 mutant and GL261 gliomas. We therefore assessed if this customizable lipid-NP could be leveraged for delivery of immune checkpoint inhibitors (ICIs) (i.e. PD-L1 siRNA) to the brain tumor microenvironment. Compared with scrambled siRNA-NPs in combination with ICIs, surface modified siRNA-NPs (antagonizing PD-L1) in combination with ICIs mediated significant antitumor efficacy with 37% long term survivors in an otherwise fatal brain tumor model. CONCLUSION We designed multifunctional RNA-NPs with a simple, scalable synthesis method that enables delivery of nucleic acids to innate immune cells in lymphoid organs and brain tumors.

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475. Emozolomide Inhibits the Migration of Immune Cells into the Brain Tumor Microenvironment and Their Systemic Expansion, but Exerts a Synergistic Anti-Tumor Effect When Combined with Combined Conditional Cytotoxic/Immune-Gene Therapy

Molecular Therapy ◽

10.1016/s1525-0016(16)37916-3 ◽

2010 ◽

Vol 18 ◽

pp. S183

Keyword(s):

Gene Therapy ◽

Brain Tumor ◽

Tumor Microenvironment ◽

Immune Cells ◽

Immune Gene ◽

The Brain

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IMMU-14. REVEALING THE MANY MYELOID STATES IN HUMAN BRAIN TUMORS AND WAYS TO PERTURB THEM

Neuro-Oncology ◽

10.1093/neuonc/noab196.373 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi94-vi95

Author(s):

Tyler Miller ◽

Chadi El Farran ◽

Julia Verga ◽

Charles Couturier ◽

Zeyu Chen ◽

...

Keyword(s):

Brain Tumor ◽

Tumor Microenvironment ◽

Immune Cells ◽

Ex Vivo ◽

Myeloid Cells ◽

Human Tumor ◽

Myeloid Cell ◽

Low Grade ◽

Tumor Patients ◽

The Many

Abstract Recent breakthroughs in immunotherapy have revolutionized treatment for many types of cancer, but unfortunately trials of these therapies have failed to provide meaningful life-prolonging benefit for brain tumor patients, potentially due to abundant immunosuppressive myeloid cells in the tumor. Our ultimate goal is to reprogram immunosuppressive tumor associated myeloid cells to an antitumor state to enable effective immunotherapy. Towards this goal, we have deeply characterized the immune microenvironment of more than 50 primary high and low grade gliomas using high-throughput single-cell RNA-sequencing to reveal recurrent myeloid cell states and immunosuppressive programs across IDH1 wild-type and mutant tumors. We have also established a brain tumor organoid model from primary patient tissue that maintains all of the tumor microenvironment, including myeloid and other immune cells. We utilize the this model to functionally test data-driven reprogramming strategies and understand how they impact the states of tumor and immune cells in the ex vivo human tumor microenvironment.

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Engineering the Brain Tumor Microenvironment Enhances the Efficacy of Dendritic Cell Vaccination: Implications for Clinical Trial Design

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-11-0915 ◽

2011 ◽

Vol 17 (14) ◽

pp. 4705-4718 ◽

Cited By ~ 25

Author(s):

Yohei Mineharu ◽

Gwendalyn D. King ◽

AKM G. Muhammad ◽

Serguei Bannykh ◽

Kurt M. Kroeger ◽

...

Keyword(s):

Clinical Trial ◽

Brain Tumor ◽

Dendritic Cell ◽

Tumor Microenvironment ◽

Trial Design ◽

Clinical Trial Design ◽

Dendritic Cell Vaccination ◽

The Brain

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The CNS and the Brain Tumor Microenvironment: Implications for Glioblastoma Immunotherapy

International Journal of Molecular Sciences ◽

10.3390/ijms21197358 ◽

2020 ◽

Vol 21 (19) ◽

pp. 7358

Author(s):

Fiona A. Desland ◽

Adília Hormigo

Keyword(s):

T Cells ◽

Brain Tumor ◽

Tumor Microenvironment ◽

Immune Modulation ◽

Primary Brain Tumor ◽

Cellular Heterogeneity ◽

Checkpoint Molecule ◽

Engineered T Cells ◽

Immunosuppressive Tumor Microenvironment ◽

The Brain

Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor in adults. Its aggressive nature is attributed partly to its deeply invasive margins, its molecular and cellular heterogeneity, and uniquely tolerant site of origin—the brain. The immunosuppressive central nervous system (CNS) and GBM microenvironments are significant obstacles to generating an effective and long-lasting anti-tumoral response, as evidenced by this tumor’s reduced rate of treatment response and high probability of recurrence. Immunotherapy has revolutionized patients’ outcomes across many cancers and may open new avenues for patients with GBM. There is now a range of immunotherapeutic strategies being tested in patients with GBM that target both the innate and adaptive immune compartment. These strategies include antibodies that re-educate tumor macrophages, vaccines that introduce tumor-specific dendritic cells, checkpoint molecule inhibition, engineered T cells, and proteins that help T cells engage directly with tumor cells. Despite this, there is still much ground to be gained in improving the response rates of the various immunotherapies currently being trialed. Through historical and contemporary studies, we examine the fundamentals of CNS immunity that shape how to approach immune modulation in GBM, including the now revamped concept of CNS privilege. We also discuss the preclinical models used to study GBM progression and immunity. Lastly, we discuss the immunotherapeutic strategies currently being studied to help overcome the hurdles of the blood–brain barrier and the immunosuppressive tumor microenvironment.

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