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Principal Investigator: Ryan Sowell
Organization: STRAND THERAPEUTICS INC
Fiscal Year: 2021
Award: $399,508
Funding agency: National Cancer Institute
PROJECT SUMMARY
While major strides have been made in the development of therapies for melanoma, cases continue to rise, with
more diagnoses occurring at an early stage where surgery is indicated for patients. However, even with standard
of care anti-PD-1 adjuvant immunotherapy, patients still have a high risk of relapse (3-year relapse-free survival
is 50-60%). Neoadjuvant anti-PD-1/anti-CTLA-4 immunotherapy has emerged as a potentially more efficacious
alternative to adjuvant immunotherapy, however, widespread usage in these non-metastatic patients would be
precluded due to significant toxicities. Therefore, there is a great unmet need to improve outcomes for
locally/regionally advanced surgically resectable melanoma patients. Cytokine therapies such as interleukin (IL)-
12 and IL-15 have shown promise in pre-clinical in vitro and in vivo studies, however, when delivered systemically
in bolus, their clinical utility is limited due to serious adverse effects as well as suboptimal pharmacokinetics and
pharmacodynamics. Thus, we need to find novel ways to locally modulate the immune system early to limit
toxicity and reduce the risk of recurrence. To address this challenge in melanoma in this NIH Phase I SBIR,
Strand Therapeutics is proposing to engineer a tunable and programmable small molecule-regulated
self-replicating mRNA (repRNA)-based combinatorial cytokine immunotherapy that mimics the
physiological expression kinetics of IL-12 (expressed early) and IL-15 (expressed later). In doing so, this
programmable repRNA immunotherapy is designed to enhance the patient’s own immune system to combat
melanoma tumors and provide durable immune surveillance and remission with limited toxicity. In Aim 1, we will
construct the mRNA circuit and validate expression kinetics of our programmed mRNAs using surrogate
luciferase reporters, which will allow us to assess in vivo expression kinetics in real-time in a mouse model of
melanoma. In Aim 2, we will encode IL-12 and IL-15 in the circuit validated in Aim 1 and assess expression
kinetics and tunability of IL-12/IL-15 expression in a mouse model of melanoma. In Aim 3, we will test if our
engineered circuit can eliminate tumors in vivo in mouse models of melanoma, and benchmark against non-
circuit IL-12/IL-15 delivery approaches such as recombinant cytokines and constitutive expression from mRNAs.
Successful completion of these studies will lead to a novel programmable circuit with IL-12/IL-15 for the treatment
of melanoma. Through this project, we intend to program the natural kinetics of IL-12/IL-15, which will induce
stronger and longer-lasting anti-cancer immune responses and increase the efficacy of anti-PD-1/PD-L1
therapies, without the side-effects linked to systemically delivered cytokines.
Terms: <Abscopal effect><Address><Adjuvant><Adjuvant Therapy><Adverse Experience><Adverse effects><Adverse event><American><Animals><Benchmarking><Best Practice Analysis><Biological><Bolus><Bolus Infusion><Cancers><Cell Body><Cells><Clinical><Data><Diagnosis><Disease remission><Distal><Dose><Doxycycline><Edodekin Alfa><Engineering><FDA approved><Feedback><Fireflies><Gene Expression><Half-Life><IL-12><IL-15><IL12><IL15><IL15 Protein><Immune Surveillance><Immune mediated therapy><Immune response><Immune system><Immunity><Immunologic Surveillance><Immunologic Surveillances><Immunological Surveillance><Immunological Surveillances><Immunological response><Immunologically Directed Therapy><Immunomodulation><Immunosurveillance><Immunotherapy><In Vitro><Incidence><Induction Therapy><Injections><Interleukin-12><Interleukin-15><Interleukin-15 Precursor><Intravenous><Kinetics><Lampyridae><Lesion><Link><Luciferase Immunologic><Luciferases><MGC9721><Malignant Melanoma><Malignant Neoplasms><Malignant Tumor><Measurement><Messenger RNA><Metastasis><Metastasis to the Lung><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Neoplasm to the Lung><Metastatic Tumor><Metastatic Tumor to the Lung><Mice><Mice Mammals><Modeling><Murine><Mus><NEOADJ><NIH><NKSF><National Institutes of Health><Natural Killer Cell Stimulatory Factor><Neoadjuvant><Neoadjuvant Therapy><Neoadjuvant Treatment><Neoplasm Metastasis><Non-metastatic><Nonmetastatic><Operative Procedures><Operative Surgical Procedures><PD-1 antibody therapy><PD-1 blockade><PD-1 therapy><PD-L1 therapy><PD-L1 treatment><PD1 antibody therapy><PD1 based treatment><PD1 blockade><PDL1 therapy><PDL1 treatment><PK/PD><Pathway interactions><Patient risk><Patients><Pharmacodynamics><Phase><Physiologic><Physiological><Population><Program Development><Proloprim><Recombinant Cytokines><Recurrence><Recurrent><Regimen><Relapse><Remission><Renilla><Reporter><Resectable><Risk><SBIR><Sea Pansy><Secondary Neoplasm><Secondary Tumor><Small Business Innovation Research><Small Business Innovation Research Grant><Surgical><Surgical Interventions><Surgical Procedure><T cell response><T memory cell><T-Cells><T-Lymphocyte><Testing><Therapeutic><Time><Toxic effect><Toxicities><Trimethoprim><Trimpex><Tumor Burden><Tumor Load><United States National Institutes of Health><Vibramycin><aCTLA-4><aCTLA4><aPD-1><aPD-1 therapy><aPD-1 treatment><aPD-L1 therapy><aPD-L1 treatment><aPD1><aPD1 therapy><aPD1 treatment><abscopal activity><abscopal response><adaptive immune response><allergic/immunologic body system><allergic/immunologic organ system><alpha-6-Deoxyoxytetracycline><anti programmed cell death 1><anti programmed cell death ligand 1 therapy><anti programmed cell death ligand 1 treatment><anti programmed cell death protein ligand 1 therapy><anti programmed cell death protein ligand 1 treatment><anti-CTLA-4><anti-CTLA4><anti-PD-1><anti-PD-1 blockade><anti-PD-1 therapy><anti-PD-1 treatment><anti-PD-1/PD-L1><anti-PD-L1 therapy><anti-PD-L1 treatment><anti-PD1><anti-PD1 blockade><anti-PD1 therapy><anti-PD1 treatment><anti-PDL1 therapy><anti-PDL1 treatment><anti-cancer><anti-programmed cell death 1 therapy><anti-programmed cell death protein 1><anti-programmed cell death protein 1 therapy><anti-tumor immune response><antiPD-1><antiPD1><anticancer><antitumor immune response><base><cancer metastasis><cancer microenvironment><combat><combinatorial><cytokine><cytokine therapy><design><designing><develop therapy><high risk><host response><immune modulation><immune regulation><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunogenicity><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><improved outcome><in vivo><innovate><innovation><innovative><intervention development><lipid nanoparticle><lumican><lung metastasis><mRNA><mRNA Expression><malignancy><manufacturing process><melanoma><memory T lymphocyte><metastasize to the lung><mouse model><murine model><nano particle delivery><nanoparticle delivered><nanoparticle delivery><neoplasm/cancer><new approaches><novel><novel approaches><novel strategies><novel strategy><objective response rate><pathway><pharmacokinetics and pharmacodynamics><pre-clinical><pre-clinical study><preclinical><preclinical study><programmed cell death protein 1 therapy><programs><prototype><pulmonary metastasis><relapse risk><side effect><small molecule><standard of care><subcutaneous><subdermal><success><surgery><synthetic biology><therapy development><thymus derived lymphocyte><treatment development><tumor><tumor cell metastasis><tumor growth><tumor microenvironment><α-CTLA-4><α-CTLA4><αCTLA-4><αCTLA4><αPD-1><αPD-L1 therapy><αPD-L1 treatment><αPD1>