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Principal Investigator: Xiang-Yang Shawn Wang
Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2024
Award: $577,293
Funding agency: National Cancer Institute
Abstract
Melanoma is the most serious type of skin cancer. Although immune checkpoint blockade (ICB) therapy has
benefited many melanoma patients, most patients do not respond to current ICB. Vaccines can promote ICB
therapeutic efficacy by generating or amplifying tumor-reactive T cells. Conventional vaccines are associated
with limitations such as low stability and bioavailability, preexisting anti-viral-vector immunity, weak antigenicity,
or concerns over genomic integration or virulent reversion. mRNA vaccines hold a great potential for cancer
immunotherapy. Yet, current linear mRNA vaccines are still associated with 1) limited biostability, despite
structural and nucleoside modifications, and the resulting limited shelf-life and moderate antigen translation
efficiency, 2) complicated, time-consuming, and error-prone enzymatic mRNA production, 3) limited loading
capacity in nanocarriers, and 4) short immune memory. To address these limitations, we propose developing
novel, highly stable, modification-free multivalent small circular mRNA (circRNA) to elicit potent and durable
antitumor immunity for ICB combination immunotherapy of melanoma. Small circRNA is comprised of minimal
RNA elements to translate peptide antigens. We showed that 1) small circRNA has high loading capacity in
nanocarriers and efficiently accumulates in lymph nodes and antigen-presenting cells; 2) terminus-free small
circRNA, either free or loaded in nanoparticles, are highly stable relative to current state-of-the-art modified
mRNA vaccine; 3) circRNA vaccines are self-adjuvanted due to intrinsic activation of intracellular pattern
recognition receptors; 4) circRNA prolong antigen translation accompanied by innate immunostimulation, which
promotes T cell responses; 5) circRNA may produce concatemeric long peptide antigens that, relative to minimal
antigens, undergo proteolytic processing for optimal antitumor T cell responses; and 6) low-dose small circRNA
vaccines outperform several current state-of-the-art modified mRNA vaccines to generate potent and durable T
cell immunity. Further, a multivalent circRNA vaccine elicited significantly potentiated ICB therapeutic efficacy of
melanoma in mice. The objective of this project is to develop and test multivalent melanoma circRNA to elicit
multivalent antimelanoma T cell responses and reduce melanoma tumor immunosuppression, elucidate their
molecular and cellular mechanisms to elicit innate and adaptive antitumor immunity, and assess their melanoma
therapeutic efficacies and toxicity in mice. Our highly collaborative team has complementary expertise in circRNA
vaccine, melanoma vaccinology, and clinical melanoma immunotherapy for accomplishing our scientific goals.
If successful, a significant deliverable from this study is to establish a scientific framework for using this novel
mRNA vaccines in melanoma combination immunotherapy.
Terms: <AGRP protein><ART protein><Address><Adjuvant><Antigen Presentation><Antigen-Presenting Cells><Antigens><Bioavailability><Biodistribution><Biological Availability><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cancers><Clinical><Cold Chains><Combination immunotherapy><Complex><Consumption><DNA><Deoxyribonucleic Acid><Dose><Double-Stranded RNA><Elements><Engineering><Evaluation><Gene Transcription><Genetic Transcription><Genomics><Goals><Guidelines><HL-A Antigens><HLA Antigens><Heterograft><Heterologous Transplantation><Human><Human Leukocyte Antigens><IRES><Immune><Immune Cell Activation><Immune mediated therapy><Immune memory><Immune response><Immunes><Immunity><Immunologic Memory><Immunologic Sensitization><Immunologic Stimulation><Immunological Memory><Immunological Sensitization><Immunological Stimulation><Immunological response><Immunologically Directed Therapy><Immunomodulation><Immunostimulation><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapy><In Vitro><Inflammation><Innate Immune Response><Innate Immunity><Internal Ribosome Entry Segment><Internal Ribosome Entry Site><Lead><Leukocyte Antigens><Life><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphatic nodes><MEL><MEL Gene><MEL Transforming Oncogene Homolog><Malignant Melanoma><Malignant Neoplasms><Malignant Skin Neoplasm><Malignant Tumor><Melanocyte Transforming Oncogene Homolog><Melanoma><Melanoma Tumor><Melanoma Vaccine><Melanoma patient><Messenger RNA><Mice><Mice Mammals><Modern Man><Modification><Molecular><Murine><Mus><Native Immunity><Natural Immunity><Non-Polyadenylated RNA><Non-Specific Immunity><Nonspecific Immunity><Nucleosides><Nucleotides><Oligo><Oligonucleotides><Outcome><Patients><Pattern recognition receptor><Pb element><Peptides><Physiologic Availability><Process><Production><Prognosis><Proteolytic Clipping><Proteolytic Processing><RAB8><RAB8 Homolog><RNA><RNA Expression><RNA Gene Products><RNA vaccine><RNA-based vaccine><Ribonucleic Acid><Ribosome Entry Site><Role><Safety><Scheme><Skin Cancer><Structure><T cell based therapeutics><T cell based therapy><T cell directed therapies><T cell response><T cell targeted therapeutics><T cell therapy><T memory cell><T-Cells><T-Lymphocyte><T-cell therapeutics><T-cell transfer therapy><T8 Cells><T8 Lymphocytes><Testing><Time><Toxicology><Transcription><Transgenic Organisms><Translating><Translations><Transportation><Treatment Efficacy><Treatment-related toxicity><Tumor Antigens><Tumor Immunity><Tumor growth in melanoma><Tumor-Associated Antigen><Tumor-infiltrating immune cells><Vaccines><Viral Vector><Virulent><Xenograft><Xenograft procedure><Xenotransplantation><accessory cell><adaptive immune response><adoptive T cell transfer><adoptive T-cell therapy><adult youth><aged mice><aged mouse><agouti-related protein><anamnestic reaction><anti-cancer immunotherapy><anti-tumor immune therapy><anti-tumor immunity><anti-tumor immunotherapy><anticancer immunotherapy><antitumor immunity><cancer antigens><cancer immunity><cancer immunotherapy><check point blockade><checkpoint blockade><circular RNA><clinical practice><closed circular RNA><combinatorial immunotherapy><design><designing><dsRNA><dual immunotherapy><elderly mice><heavy metal Pb><heavy metal lead><host response><humanized mice><humanized mouse><immune activation><immune cell infiltration of tumors><immune cells infiltrating the tumor><immune cells that infiltrate the tumor><immune check point><immune check point blockade><immune checkpoint><immune checkpoint blockade><immune microenvironment><immune modulation><immune regulation><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapies><immune-based treatments><immunecheckpoint><immuno therapy><immunogen><immunogenic><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><immunosuppressive activity><immunosuppressive function><immunosuppressive microenvironment><immunosuppressive response><immunosuppressive tumor microenvironment><immunotherapy for cancer><immunotherapy of cancer><improved><infiltration of tumors by immune cells><innovate><innovation><innovative><intervention efficacy><intratumoral immune cell><intratumoral immune infiltrate><lipid based nanoparticle><lipid nanoparticle><lymph gland><lymph nodes><lymphnodes><mRNA><mRNA vaccine><mRNA-based vaccine><malignancy><malignant skin tumor><manufacture><memory T lymphocyte><nano particle><nano-sized particle><nanocarrier><nanoparticle><nanosized particle><nanovessel><neo-antigen><neo-epitopes><neoantigens><neoepitopes><neoplasm immunotherapy><neoplasm/cancer><new vaccines><next generation vaccines><novel><novel vaccines><old mice><oligos><pre-clinical><preclinical><protein kinase R><secondary immune response><social role><therapeutic T-cell platform><therapeutic efficacy><therapeutic toxicity><therapy associated toxicity><therapy efficacy><therapy related toxicity><therapy toxicity><thermolability><thermostability><thymus derived lymphocyte><transgenic><translation><treatment toxicity><treatment-associated toxicity><tumor><tumor immune cell><tumor immune infiltrate><tumor immune microenvironment><tumor immune therapy><tumor immunotherapy><tumor infiltration of immune cells><tumor-immune system interactions><tumor-specific antigen><uptake><vaccinology><xeno-transplant><xeno-transplantation><young adult><young adulthood>