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Principal Investigator: Prabhani Atukorale
Organization: UNIVERSITY OF MASSACHUSETTS AMHERST
Fiscal Year: 2021
Award: $194,524
Funding agency: National Cancer Institute
PROJECT SUMMARY
Despite their transformative promise, traditional cancer vaccines have had poor clinical responses since
vaccine-specific systemic T cells often cannot traffic to immunosuppressed “cold” tumors. Traditional vaccines
generate only a lymph node-derived augmentation or “prime” of systemic CD8+ T cells that are trained to
comprehensively seek and eliminate specific target tumor cells. Traditional strategies, however, have been
short-sighted in that they have failed to develop methods to recruit these T cells to the “cold” tumor
microenvironment (TME) that advances by building a formidable local immunosuppressive barrier driven
largely by dysfunctional innate immune cells. Our strategy seeks to reprogram dysfunctional tumor-resident
innate antigen-presenting cells (APCs), such as dendritic cells (DCs) and macrophages, by driving a local anti-
tumor immune response with a proinflammatory cytokine gradient that reshapes the TME from non-inflamed
and “cold” to inflamed and “hot” to recruit or “pull” systemic T cells in from a “prime”. In our recent Cancer
Research paper (Atukorale et al. 2019) and additional preliminary data, we report on the development of a
“pull” strategy based on a novel immunostimulatory nanoparticle (immuno-NP) that is significant due to key
engineering design features. Immuno-NPs co-encapsulate two synergistic immune agonists on the same
particle, cdGMP, an agonist of the STING pathway, and MPLA, an agonist of the TLR4 pathway, to promote a
robust production of proinflammatory Type I interferon ß in target APCs. Immuno-NPs can be safely delivered
in the systemic blood circulation to achieve widespread and preferential deposition in the tumor perivascular
regions that are rich in their target APCs. Immuno-NPs drive a powerful local self-amplifying anti-tumor
immune response that harnesses otherwise “exhausted” immunosuppressed local CD8+ T cells as the key
effectors of tumor clearance, which suggests highly effective “cold-to-hot” TME reprogramming. Our central
hypothesis is that precise coupling of a standard lymph node-directed CD8+ T cell vaccine “prime” with a
tumor-directed immuno-NP “pull” for a novel “prime-pull” approach can provide the key missing link for effective
cancer vaccination. Specific Aim 1 will identify optimal function of an immuno-NP pull in terms of immuno-NP
design and co-treatment with anti-PD1. Specific Aim 2 will develop a precise “prime-pull” coupling schedule.
Specific Aim 3 will evaluate safety and toxicity for effective dose/scheduling “prime-pull” regimens. Dr.
Atukorale's career goals are to establish a nanomaterials-based cancer immuno-engineering laboratory as an
independent investigator. She will develop immuno-nanomaterials tools that drive, quantify, and interrogate
immunity, specifically in the context of lethal cancers. Dr. Atukorale's strong career development plan includes
significant new research collaborations, a senior advisory committee, research presentations, faculty-level
workshops, and plans for subsequent grant proposals. Her future sponsoring institution will be based in both
Schools of Medicine and Engineering, in direct line with her highly interdisciplinary research interests.
Terms: <Advisory Committees><Agonist><Antigen Targeting><Antigen-Presenting Cells><Antineoplastic Vaccine><Applications Grants><Automobile Driving><Beds><Blood Circulation><Bloodstream><Breast Cancer><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cancer Vaccines><Cancers><Cell Body><Cell Locomotion><Cell Migration><Cell Movement><Cells><Cellular Migration><Cellular Motility><Checkpoint inhibitor><Chemotherapy and Radiation><Chemotherapy and/or radiation><Circulation><Clinical><Collaborations><Combined Modality Therapy><Coupled><Coupling><Cyclicity><Data><Data Reporting><Dendritic Cells><Deposit><Deposition><Development><Development Plans><Dose><Educational workshop><Encapsulated><Endogenous Interferon Beta><Engineering><Ensure><Faculty><Fibroblast Interferon><Future><Goals><Grant Proposals><Guanosine Monophosphate><Guanylic Acids><Hepatotoxic effect><Hepatotoxicity><Histopathology><Homolog of Drosophila TOLL><Hydrophobicity><IFN-Beta><IFN-β><IFNb><Immune><Immune Cell Activation><Immune checkpoint inhibitor><Immunes><Immunity><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><In Vitro><Inflammatory><Institution><Interdisciplinary Research><Interdisciplinary Study><Interferon Type I><Interferon-beta><Interferon-β><Investigation><Investigators><Kinetics><Laboratories><Link><Lipid A><Lipids><Liver Toxicity><Longitudinal Studies><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphatic nodes><Macrophage Activation><Malignant Melanoma><Malignant Neoplasms><Malignant Tumor><Memory><Methods><Motility><Multidisciplinary Collaboration><Multidisciplinary Research><Multimodal Therapy><Multimodal Treatment><Mφ><Natural Interferon Beta><Natural human interferon beta><Neoplasm Vaccines><PD-1 inhibitors><PD1 inhibitors><Paper><Pathway interactions><Periodicity><Perivascular Neoplasm><Perivascular Tumor><Production><Public Health><Publishing><Recurrence><Recurrent><Regimen><Research><Research Personnel><Researchers><Rhythmicity><Safety><Schedule><Sight><Stimulator of Interferon Genes><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><TLR4><TLR4 gene><Task Forces><Testing><Toll Homologue><Toxic effect><Toxic effect on liver cells><Toxicities><Training><Treatment Protocols><Treatment Regimen><Treatment Schedule><Tumor Antigens><Tumor Cell><Tumor Vaccines><Tumor-Associated Antigen><Vaccination><Vaccines><Veiled Cells><Vision><Workshop><aPD-1><aPD1><accessory cell><advisory team><anti programmed cell death 1><anti programmed cell death protein 1 inhibitor><anti-PD-1><anti-PD-1 inhibitors><anti-PD1><anti-PD1 inhibitors><anti-cancer research><anti-programmed cell death protein 1><anti-tumor immune response><anti-tumor vaccine><antiPD-1><antiPD1><anticancer research><antitumor immune response><antitumor vaccine><base><cGAMP STING><cGAMP-STING><cGAMP/STING><cGAS/STING><cancer antigens><cancer microenvironment><cancer research><cancer vaccination><career><career development><cell motility><combination therapy><combined modality treatment><combined treatment><cytokine><data representation><design><designing><developmental><driving><engineered immune system><engineering design><exhaust><hepatic toxicity><hepatoxicity><hydrophilicity><immune activation><immune check point inhibitor><immune engineering><immune suppression><immunoengineering><immunosuppressed><in vivo><innovate><innovation><innovative><interest><long-term study><longitudinal outcome studies><longterm study><lymph gland><lymph nodes><lymphnodes><macrophage><malignancy><malignant breast neoplasm><malignant breast tumor><medical college><medical schools><melanoma><mouse model><multi-modal therapy><multi-modal treatment><murine model><nano materials><nano particle><nano-sized particle><nanomaterials><nanoparticle><nanosized particle><neoplasm/cancer><neoplastic cell><novel><particle><pathway><pre-clinical><preclinical><recruit><response><school of medicine><success><surface coating><thymus derived lymphocyte><toll-like receptor 4><tool><tumor><tumor microenvironment><tumor vaccination><tumor-specific antigen><vaccination strategy><vaccine for cancer><visual function><αPD-1><αPD1>