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Principal Investigator: Gordon Parry
Organization: AMPEDRNA BIOSCIENCES LLC
Fiscal Year: 2024
Award: $398,823
Funding agency: National Cancer Institute
Human papillomavirus (HPV) is responsible for a large proportion of global cancer cases, including head and
neck, cervical and anal cancers, among others. HPV-related cancers are caused by certain high-risk strains of
the virus, which can cause long-lasting infections that eventually lead to the development of cancerous changes.
The mainstay for addressing HPV-related cancer is prevention, particularly through prophylactic vaccination and
screening, and definitive treatment of early pre-cancerous lesions. Despite the success of prevention efforts, the
prevalence of early and late-stage HPV-related cancers is still staggering, with over 18,000 deaths annually in
the US. One promising new treatment approach is immunotherapy, in particular immune checkpoint inhibition
(ICI). However, only 15-30% of patients respond to ICI treatment, highlighting the need for new techniques to
boost efficacy. Although ex vivo adoptive T cell immunotherapies, in which human T cells are genetically modified
outside the body to target cancer cells, are promising, they have significant limitations due to complexity, cost,
and the need for myeloablative lymphodepletion. Effective therapeutic cancer vaccines have long been the holy
grail as potentially safe and cost-effective in vivo-elicited T cell therapies that could be used in all stages of
disease to boost cancer immunotherapy without the challenges and risks of ex vivo adoptive T cell therapies.
While conventional vaccines largely have not been effective, newer highly immunogenic mRNA cancer vaccines
have demonstrated clear evidence of efficacy with a reduction in recurrence and death in late-stage melanoma
and strong anti-tumor responses in pancreatic cancer. Mini-circular RNA (mcRNA) is a highly biostable
therapeutic cancer vaccine platform that can elicit robust activation and expansion of long-lasting antigen-specific
T cells, achieving breakthrough levels up to 8-fold higher than state-of-the-art mRNA vaccines with, surprisingly,
improved safety and tolerability. Our goal is to develop a highly immunogenic HPV E6 and E7 mcRNA vaccine
that could be used as an off-the-shelf HLA-agnostic product or as part of a personalized HLA-specific cancer
vaccine. In this proposal, we plan to build on a significant body of highly encouraging in vitro and in vivo data to
facilitate rapid development of the mcRNA therapeutic vaccine platform with a highly immunogenic vaccine for
HPV-related cancers. Key results from the proposed investigational studies will demonstrate the superior efficacy
of a LNP-encapsulated multivalent mcRNA HPV16 E6/E7 vaccine compared to a N1-methylΨ mRNA vaccine.
In Aim 1, we will show that a multivalent HPV mcRNA vaccine can sustain the expression of long concatemers
of encoded HPV E6/E7 epitopes that are processed and presented to elicit highly potent and durable T cell
responses that can yield a robust immunotherapy in combination with ICI for HPV-related cancer in mice. In Aim
2, we will characterize the immunogenicity of 5 epitope clusters encoding all of the top human MHC-binding
epitopes of HPV16 E6 and E7 in PBMCs collected from human subjects, and assess the immunogenicity of a
multivalent HPV16 epitope cluster vaccine compared to a benchmark HPV16 mRNA vaccine.
Terms: <Address><Anal Cancer><Anal Cancers><Antigenic Determinants><Antineoplastic Vaccine><Antitumor Response><Anus Cancer><Benchmarking><Best Practice Analysis><Binding><Binding Determinants><Blood monocyte><C57BL/6 Mouse><CD14><CD14 gene><CD44><CD44 gene><CD62L><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cancer Cause><Cancer Etiology><Cancer Treatment><Cancer Vaccines><Cancerous><Cancers><Cell Body><Cells><Cervical Cancer><Cervix Cancer><Cessation of life><Checkpoint inhibitor><Clinical><Clinical Trials><Closure by Ligation><Co-Stimulator><Co-culture><Cocultivation><Coculture><Coculture Techniques><Codon><Codon Nucleotides><Collecting Cell><Combination immunotherapy><Costimulator><Cryofixation><Cryopreservation><Data><Death><Dendritic Cells><Development><Disease><Disorder><Dose><Double-Stranded RNA><Early treatment><Encapsulated><Epidermal Thymocyte Activating Factor><Epitopes><Goals><HLHRC><HPV><HPV 16><HPV E6><HPV E7><HPV Vaccine><HPV induced cancer><HPV malignancy><HPV+ cancer><HPV-16><HPV-Related Malignancy><HPV-associated cancer><HPV-associated malignancy><HPV-related cancer><HPV16><Haplotypes><Head and Neck Cancer><Head and Neck Carcinoma><Human><Human Papilloma Virus><Human Papilloma Virus Vaccine><Human Papilloma Virus-Related Malignancy><Human Papilloma Virus-Related Malignant Neoplasm><Human Papilloma Virus-associated cancer><Human Papilloma Virus-associated malignancy><Human Papilloma Virus-related cancer><Human Papillomavirus><Human papilloma virus type 16><Human papillomavirus 16><Human papillomavirus Vaccine><Human papillomavirus cancer><Human papillomavirus induced cancer><Human papillomavirus malignancy><Human papillomavirus type 16><Human papillomavirus-Related Malignancy><Human papillomavirus-Related Malignant Neoplasm><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><IL-2><IL2 Protein><Immune><Immune Interferon><Immune checkpoint inhibitor><Immune mediated therapy><Immune system><Immunes><Immunocompetent><Immunologically Directed Therapy><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapy><In Vitro><Infection><Infectious Human Wart Virus><Interferon Gamma><Interferon Type II><Interleukin 2><Interleukin 2 Precursor><Interleukin II><Interleukin-2><Interleukine 2><Interleukine 2 Precursor><Interleukine II><Kinetics><LAM-1 gene><LECAM1><LNHR><LSEL><LYAM-1><LYAM1><Length><Lesion><Ligation><Lymphocyte Mitogenic Factor><MDU3><Malignant Anal Neoplasm><Malignant Anal Tumor><Malignant Cell><Malignant Cervical Neoplasm><Malignant Cervical Tumor><Malignant Head and Neck Neoplasm><Malignant Melanoma><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasm of the Cervix><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant Tumor of the Anus><Malignant Tumor of the Cervix><Malignant Tumor of the Cervix Uteri><Malignant Uterine Cervix Neoplasm><Malignant Uterine Cervix Tumor><Malignant neoplasm of anus><Malignant neoplasm of cervix uteri><Malignant neoplasm of pancreas><Marrow monocyte><Melanoma><Messenger RNA><Mice><Mice Mammals><Mitogenic Factor><Modeling><Modern Man><Molecular Interaction><Monitor><Murine><Mus><Neoplasm Vaccines><Non-Polyadenylated RNA><Oligo><Oligonucleotides><PBMC><Pancreas Cancer><Pancreatic Cancer><Papillomavirus Transforming Protein E6><Patients><Peptides><Peripheral><Peripheral Blood Mononuclear Cell><Pgp1><Pilot Projects><Prevalence><Preventative Immunization><Preventative vaccination><Prevention><Preventive Immunization><Preventive vaccination><Process><Prophylactic immunization><Prophylactic vaccination><Protein Inhibition><Proteins><Pseudouridine><RNA><RNA Gene Products><RNA chemical synthesis><RNA synthesis><RNA vaccine><RNA-based vaccine><Receptor Protein><Recurrence><Recurrent><Ribonucleic Acid><Risk><SELL gene><Safety><Sampling><Selectin L Gene><Solid Neoplasm><Solid Tumor><Staining method><Stains><Structure><T cell based therapeutics><T cell based therapy><T cell directed therapies><T cell growth factor><T cell response><T cell targeted therapeutics><T cell therapy><T memory cell><T-Cell Activation><T-Cell Growth Factor><T-Cell Stimulating Factor><T-Cells><T-Lymphocyte><T-cell therapeutics><T-cell transfer therapy><T8 Cells><T8 Lymphocytes><TQ-1><Techniques><Therapeutic><Thymocyte Stimulating Factor><Time><Toxicology><Transfection><Translations><Treatment Efficacy><Tumor Cell><Tumor Expansion><Tumor Vaccines><Uterine Cervix Cancer><Vaccines><Veiled Cells><Viral Protein E6><Viral Vector><Virus><aPD-1><aPD1><activate T cells><adoptive T cell transfer><adoptive T-cell therapy><anal squamous cell carcinoma><anti programmed cell death 1><anti-PD-1><anti-PD1><anti-cancer immunotherapy><anti-cancer therapy><anti-programmed cell death protein 1><anti-tumor immune therapy><anti-tumor immunotherapy><anti-tumor response><anti-tumor vaccine><anti-viral immunity><antiPD-1><antiPD1><antibody inhibitor><anticancer immunotherapy><antigen-specific T cells><antiviral immunity><benchmark><biobank><biorepository><cancer cell><cancer immunotherapy><cancer therapy><cancer-directed therapy><check point inhibition><checkpoint inhibition><circular RNA><clinical development><closed circular RNA><cold preservation><cold storage><combinatorial immunotherapy><cost><cost effective><cytokine><determine efficacy><developmental><dsRNA><dual immunotherapy><early therapy><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><efficacy study><evaluate efficacy><examine efficacy><exhaust><genetically engineered cells><genetically modified cells><head/neck cancer><high risk><human papilloma virus 16><human papilloma virus E7><human papillomavirus E6 oncoprotein><human papillomavirus E7><human papillomavirus associated malignancy><human papillomavirus-associated cancer><human papillomavirus-related cancer><human subject><immune check point inhibition><immune check point inhibitor><immune checkpoint inhibition><immune competent><immune suppression><immune suppressive activity><immune suppressive function><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapies><immune-based treatments><immuno therapy><immunogenic><immunogenicity><immunosuppressive activity><immunosuppressive function><immunosuppressive response><immunotherapy for cancer><immunotherapy of cancer><improved><in silico><in vivo><inhibit protein><inhibit proteins><innovate><innovation><innovative><intervention efficacy><lFN-Gamma><mRNA><mRNA vaccine><mRNA-based vaccine><malignancy><malignant head and neck tumor><memory T lymphocyte><monocyte><neoplasm immunotherapy><neoplasm/cancer><neoplastic cell><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><oligos><pancreatic malignancy><papilloma virus Transforming Protein E6><pilot study><precancer><precancerous><premalignant><protein activation><protein inhibitions><protein kinase R><receptor><response><response to therapy><response to treatment><screening><screenings><success><systemic toxicity><therapeutic T-cell platform><therapeutic efficacy><therapeutic response><therapeutic vaccine><therapeutically effective><therapy efficacy><therapy response><thymus derived lymphocyte><translation><treatment response><treatment responsiveness><treatment vaccines><tumor><tumor growth><tumor immune therapy><tumor immunotherapy><type 16 Human papilloma virus><type 16 Human papillomavirus><vaccine for cancer><vaccine for the treatment><vaccine for treatment><vaccine platform><wart virus><αPD-1><αPD1>