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Principal Investigator: Tasuku Kitada
Organization: STRAND THERAPEUTICS INC
Fiscal Year: 2021
Award: $399,725
Funding agency: National Cancer Institute
PROJECT SUMMARY
Triple negative breast cancer (TNBC) has few treatments, and patients have a poor prognosis. Checkpoint
inhibitors (e.g., anti-PD-1 antibodies) represent a promising new therapeutic strategy, and two recent clinical
trials demonstrate that TNBC patients may benefit. However, only a fraction of patients responded indicating that
additional combination therapy with anti-PD-1 is needed. Strand Therapeutics developed a synthetic self-
replicating mRNA (repRNA) for use with anti-PD-1. We achieve tumor-directed expression by encapsulating and
directly injecting the in vitro transcribed repRNA with our fully developed lipid nanoparticle (LNP) into the tumor.
The entire repRNA manufacturing process is done in vitro, giving us advantages over virus-based approaches
that require mammalian cell culture. Once in the tumor microenvironment (TME), the repRNAs express a potent
engineered form of the interleukin 12 (IL-12) fusion protein (IL-12-lumican) to stimulate the anti-tumor activity of
NK cells and CD8 T cells in TNBC lesions. The IL-12-lumican fusion protein reduces the risk of systemic toxicity
and enhanced activity by retaining IL-12 within the TME via a collagen-binding domain (lumican). In addition,
repRNA expression and replication have advantages over the short expression duration of modified RNA
(modRNA), and repRNA stimulates various pattern recognition receptors such as TLRs, RIG-I, and MDA-5 to
upregulate type-I interferon. Furthermore, Strand Therapeutics’ proprietary LNP not only efficiently delivers
mRNA to cells but also uniquely synergizes with the repRNA to induce oncolytic effects (immunogenic cell death).
These additional inflammatory cues facilitate turning a “cold” TME to one that will respond to anti-PD-1 therapy.
In this proposal, we will determine whether tumoral injection of repRNA IL-12-lumican can effectively overcome
insufficient immune activation in the TME and augment responses to anti-PD-1 therapy in TNBC. In Aim 1 we
will demonstrate that in TNBC cells repRNAs have more sustained transgene expression and greater type I IFN
induction than modRNAs. In Aim 2 we will demonstrate that repRNAs in human cell line-derived xenograft (CDX)
and patient-derived xenografts (PDX) have greater sustained expression than modRNAs. In Aim 3 we will
demonstrate efficacy and superiority of repRNA IL-12-lumican over modRNA IL-12-lumican treatment (in
combination with anti-PD-1) in vivo in syngeneic mouse models of TNBC and ex vivo in primary explants from
TNBC patients. These studies will provide proof of concept data that Strand Therapeutics’ approach using self-
replicating mRNA encoding IL-12 in combination with PD-1 antibody blockade is effective at reducing TNBC
tumor volume.
Terms: <(IFN) α><(IFN)-α><(IFN)α><4T1><Adjuvant><Alferon><Alpha Virus><Alphavirus><Anzatax><Asotax><B7-H1><B7H1><Binding><Binding Proteins><Breast Cancer Cell><Breast Cancer Patient><Breast Cancer cell line><Breast Tumor Patient><Breast tumor cell line><Bristaxol><CD274><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cell Body><Cell Culture Techniques><Cell Line><CellLine><Cells><Checkpoint inhibitor><Chimera Protein><Chimeric Proteins><Clinical Trials><Collagen><Combined Modality Therapy><Cues><Cytotoxic cell><Data><Development><EC 2.7.7.48><ELISA><Edodekin Alfa><Encapsulated><Engineering><Ensure><Enzyme-Linked Immunosorbent Assay><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Fusion Protein><Gene Transcription><Genetic Transcription><Group A Arboviruses><Heterograft><Heterologous Transplantation><Human><Human Cell Line><IFN><IFN Alpha><IFN α><IFN-α><IFNa><IFNα><IL-12><IL12><IVIS SpectrumCT><IVIS imaging><IVIS optical imaging><IVIS spectral imaging><IVIS spectrum><IVIS system><Immune Cell Activation><Immune checkpoint inhibitor><Immune mediated therapy><Immunologically Directed Therapy><Immunotherapy><In Vitro><In complete remission><Induction Therapy><Inflammatory><Injections><Interferon Alfa-n3><Interferon Type I><Interferon-alpha><Interferon-α><Interferons><Interleukin-12><K lymphocyte><Keytruda><Kinetics><Lesion><Leukocyte Interferon><Ligand Binding Protein><Ligand Binding Protein Gene><Luciferase Immunologic><Luciferases><Lymphoblast Interferon><Lymphoblastoid Interferon><Malignant Melanoma><Mammalian Cell><Measures><Messenger RNA><Mice><Mice Mammals><Modern Man><Molecular Interaction><Multimodal Therapy><Multimodal Treatment><Murine><Mus><NEOADJ><NK Cells><NKSF><Natural Killer Cell Stimulatory Factor><Natural Killer Cells><Neoadjuvant><Neoadjuvant Therapy><Neoadjuvant Treatment><Non-Polyadenylated RNA><Oncolytic><PD 1><PD-1><PD-1 antibody><PD-1 antibody therapy><PD-1 therapy><PD-L1><PD-L1 blockade><PD1><PD1 antibody><PD1 antibody therapy><PD1 based treatment><PDL-1><PDL1><PDL1 blockade><PDX model><Paclitaxel><Paclitaxel (Taxol)><Pathologic><Patient derived xenograft><Patients><Pattern recognition receptor><Praxel><Prognosis><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Protein Binding><RNA><RNA Expression><RNA Gene Products><RNA Replicase><RNA replication><RNA-Dependent RNA Polymerase><RNA-Directed RNA Polymerase><Regimen><Reporter><Reporter Genes><Ribonucleic Acid><Risk><Staining method><Stains><Strains Cell Lines><T8 Cells><T8 Lymphocytes><TNBC><Taxol><Taxol A><Taxol Konzentrat><Therapeutic><Transcription><Tumor Burden><Tumor Load><Tumor Volume><Virus><Xenograft><Xenograft procedure><Xenotransplantation><aPD-1><aPD-1 therapy><aPD-1 treatment><aPD1><aPD1 therapy><aPD1 treatment><adaptive immunity><anti programmed cell death 1><anti-PD-1><anti-PD-1 Ab><anti-PD-1 antibodies><anti-PD-1 monoclonal antibodies><anti-PD-1 therapy><anti-PD-1 treatment><anti-PD-L1 blockade><anti-PD1><anti-PD1 Ab><anti-PD1 antibodies><anti-PD1 monoclonal antibodies><anti-PD1 therapy><anti-PD1 treatment><anti-programmed cell death 1 therapy><anti-programmed cell death protein 1><anti-programmed cell death protein 1 antibodies><anti-programmed cell death protein 1 therapy><anti-tumor immune response><antiPD-1><antiPD1><antitumor immune response><base><bound protein><breast tumor cell><cancer microenvironment><cell culture><chemotherapy><combination therapy><combined modality treatment><combined treatment><complete response><cultured cell line><cytokine><developmental><flow cytophotometry><imager><immune activation><immune check point inhibitor><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunogenic apoptosis><immunogenic cell death><immunogenicity><improved><in vivo><in vivo imaging system><lipid nanoparticle><lumican><mRNA><manufacturing process><meetings><melanoma><mouse model><multi-modal therapy><multi-modal treatment><murine model><nano particle delivery><nanoparticle delivered><nanoparticle delivery><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><patient derived xenograft model><patient response><patient specific response><patient subgroups><patient subpopulations><patient subsets><patient subtypes><pembrolizumab><programmed cell death 1><programmed cell death ligand 1><programmed cell death protein 1><programmed cell death protein 1 therapy><programmed cell death protein ligand 1><programmed death 1><response><responsive patient><sle2><standard of care><synergism><systemic lupus erythematosus susceptibility 2><systemic toxicity><transgene expression><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor><tumor microenvironment><xeno-transplant><xeno-transplantation><αPD-1><αPD1>