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Principal Investigator: Prabhani Atukorale
Organization: UNIVERSITY OF MASSACHUSETTS AMHERST
Fiscal Year: 2023
Award: $237,749
Funding agency: National Institute of Biomedical Imaging and Bioengineering
PROJECT SUMMARY
This proposal seeks to develop a targeted tri-agonist “super adjuvant” nanoparticle platform for in situ cancer
vaccination. Vaccines consist of 2 components: a tumor-specific antigen that is recognized by CD8+ cytotoxic T
cells (CTLs) and an adjuvant that provides the necessary costimulatory cytokine signals to antigen-presenting
cells (APCs) to prime and activate a CTL response. In complex diseases like cancer, however, a single-
adjuvant vaccine may not be fully effective to mitigate the myriad immunosuppressive effects of a
heterogeneous aggressive tumor microenvironment (TME) such as that of triple-negative breast cancer
(TNBC). Co-delivery of multiple adjuvants in a rationally designed “super adjuvant” formulation can harness
multiple pattern recognition receptor pathways simultaneously to drive a proinflammatory synergistic cytokine
response that has both breadth and depth. Further, compared to standard vaccination, where a preselected
antigen and adjuvant are delivered to lymph nodes, in situ vaccination, where only the adjuvant is delivered
directly to the tumor, has clear advantages. In an in situ approach, the tumor itself provides the antigen in the
form of neoantigens shed from dying tumor cells. This approach captures patient heterogeneity on a
personalized basis and does not require prior knowledge of tumor antigens. Current in situ approaches,
including free agonists, free cytokines, and immunogenic viruses, rely heavily on direct intratumoral injection to
minimize off-target toxicity and are cancer type-specific. Intratumoral delivery itself also has serious limitations
in both delivery and efficacy. Supported by our recent publications and additional preliminary data, this high-
risk proposal seeks to address these shortcomings by designing a “super adjuvant” immunomodulatory
nanoparticle (immuno-NP) platform that coencapsulates 3 synergistic Type I interferon-driving innate immune
agonists on the same NP using lipid-based materials and microfluidics. Specifically, 60-nm PEGylated
immuno-NPs will be designed to be delivered safely in the systemic blood circulation to co-deliver agonists of
the STING, TLR4, and TLR9 pathways to tumors. They will also be targeted to multiple specific types of cells in
the TME, including APCs, activated endothelial cells, and tumor cells, to orchestrate a concerted multi-cellular
response that may be necessary to eliminate heterogeneous aggressive tumors. We hypothesize that targeted
tri-agonist “super adjuvant” immuno-NPs will drive a synergistic Type I interferon-mediated APC response that
activates CTLs for tumor clearance in multiple mouse models of TNBC. Specific Aim 1 will identify immuno-NP
design parameters required for optimal function in terms of promoted cytokine breadth and depth. Specific Aim
2 will establish immuno-NP targeting schemes for effective TME homing and therapeutic efficacy. These
studies will effectively address the delivery, efficacy, and safety challenges that severely limit current
approaches. As a platform technology, successful development of this “super adjuvant” immuno-NP also has
wide-ranging applications in standard lymph node-directed vaccination for both cancer and infectious disease.
Terms: <1,2-Ethanediol><2-Hydroxyethanol><4T1><Address><Adjuvant><Agonist><Antigen-Presenting Cells><Antigens><Automobile Driving><Basal Transcription Factor><Basal transcription factor genes><Biomedical Engineering><Blood Circulation><Blood Coagulation Factor I><Blood Coagulation Factor One><Blood Factor One><Blood Vessels><Bloodstream><CD62P Antigens><Cancer Biology><Cancers><Cell Body><Cell Line><Cell-Mediated Lympholytic Cells><CellLine><Cells><Chemicals><Coagulation Factor I><Coagulation Factor One><Communicable Diseases><Complex><Cyclicity><Cytokine Signal Transduction><Cytokine Signaling><Cytolytic T-Cell><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><DNA><Data><Dendritic Cells><Deoxyribonucleic Acid><Deposit><Deposition><Development><Diameter><Dihydroxyethanes><Disease><Disorder><EGF Receptor><EGFR><ERBB Protein><Encapsulated><Endothelial Cells><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Ethanediols><Ethylene Glycols><Factor I><Factor One><Fibrin><Fibrinogen><Formulation><GMP-140><General Transcription Factor Gene><General Transcription Factors><Genetic Engineering><Genetic Engineering Biotechnology><Genetic Engineering Molecular Biology><HER1><Harvest><Heterogeneity><Homing><Homolog of Drosophila TOLL><IFN-regulatory factor 3><IRF-3 protein><IRF3><IRF3 gene><Immune><Immune memory><Immune response><Immunes><Immunologic Memory><Immunological Memory><Immunological response><Immunology><Immunomodulation><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><In Situ><In Vitro><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammatory><Injections><Integrins><Integrins Extracellular Matrix><Interferon Regulatory Factor 3><Interferon Type I><Kinetics><Knowledge><LECAM-3><Lipid A><Lipids><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphatic nodes><Macrophage><Malignant Neoplasms><Malignant Tumor><Mediating><Methods><Microfluidics><Monoethylene Glycol><Mφ><P-Selectin><Pathway interactions><Patients><Pattern recognition receptor><Periodicity><Platelet alpha-Granule Membrane Protein><Production><Publications><Qualifying><Recombinant DNA Technology><Rhythmicity><Role><Safety><Scheme><Scientific Publication><Stimulator of Interferon Genes><Strains Cell Lines><T cell response><TGF-alpha Receptor><TLR4><TLR4 gene><TNBC><Temperature><Testing><Toll Homologue><Toxic effect><Toxicities><Transcription Factor Proto-Oncogene><Transcription factor genes><Transforming Growth Factor alpha Receptor><Treatment Efficacy><Tumor Antigens><Tumor Cell><Tumor Immunity><Tumor-Associated Antigen><Urogastrone Receptor><Vaccination><Vaccines><Veiled Cells><Virus><accessory cell><anamnestic reaction><anti-cancer research><anti-tumor immunity><anticancer research><antitumor immunity><bio-engineered><bio-engineers><bioengineering><biological engineering><c-erbB-1><c-erbB-1 Protein><cGAMP STING><cGAMP-STING><cGAMP/STING><cGAS/STING><cancer antigens><cancer immunity><cancer microenvironment><cancer research><cancer type><cell type><cultured cell line><cyclic GMP-AMP synthase/STING><cytokine><cytotoxic CD8 T cells><cytotoxic CD8 T lymphocyte><design><designing><developmental><driving><engineering design><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><ethylene glycol><genetically engineered><high risk><host response><immune modulation><immune regulation><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immunogen><immunogenic><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><immunosuppressive activity><immunosuppressive function><immunosuppressive response><in situ anti-tumor vaccination><in situ antitumor vaccination><in situ cancer vaccination><in situ tumor vaccination><in situ vaccination><in vivo><innovate><innovation><innovative><intervention efficacy><killer T cell><lymph gland><lymph nodes><lymphnodes><malignancy><melting><mouse model><murine model><nano meter scale><nano meter sized><nano particle><nano scale><nano-sized particle><nanometer scale><nanometer sized><nanoparticle><nanoscale><nanosized particle><neo-antigen><neo-epitopes><neoantigens><neoepitopes><neoplasm/cancer><neoplastic cell><pathway><proto-oncogene protein c-erbB-1><rational design><response><secondary immune response><social role><surface coating><synergism><technology platform><technology system><therapeutic efficacy><therapy efficacy><toll-like receptor 4><transcription factor><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor><tumor microenvironment><tumor-specific antigen><uptake><vascular><µfluidic>