Regulated intratumoral expression of IL-12 using a RheoSwitch Therapeutic System® (RTS®) gene switch as gene therapy for the treatment of glioma

Barrett, John; Cai, Hongliang; Miao, John; Khare, Pranay D.; Gonzalez, Paul; Dalsing-Hernandez, Jessica; Sharma, Geeta; Chan, Tim; Cooper, Laurence J.N.; Lebel, François

doi:10.1038/s41417-018-0019-0

Cited by 82 publications

(73 citation statements)

References 48 publications

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“…Furthermore, dasatinib does not completely remove CAR-T from circulation, rather it suppresses activity. In addition, the ligand-inducible RheoSwitch Therapeutic System has been evaluated in animal models [90] and people for regulation of interleukin-12 delivered by an Ad vector [91,92]. Building on these studies from the gene therapy and CAR-T fields, additional study of gene safety switches in skeletal muscle would be useful for pDNA-mAb platforms.…”

Section: Understanding the Genomic Impact Of Mrna And Dna Deliverymentioning

confidence: 99%

In Vivo Delivery of Nucleic Acid-Encoded Monoclonal Antibodies

2020

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Antibody immunotherapy is revolutionizing modern medicine. The field has advanced dramatically over the past 40 years, driven in part by major advances in isolation and manufacturing technologies that have brought these important biologics to the forefront of modern medicine. However, the global uptake of monoclonal antibody (mAb) biologics is impeded by biophysical and biochemical liabilities, production limitations, the need for cold-chain storage and transport, as well as high costs of manufacturing and distribution. Some of these hurdles may be overcome through transient in vivo gene delivery platforms, such as non-viral synthetic plasmid DNA and messenger RNA vectors that are engineered to encode optimized mAb genes. These approaches turn the body into a biological factory for antibody production, eliminating many of the steps involved in bioprocesses and providing several other significant advantages, and differ from traditional gene therapy (permanent delivery) approaches. In this review, we focus on nucleic acid delivery of antibody employing synthetic plasmid DNA vector platforms, and RNA delivery, these being important approaches that are advancing simple, rapid, in vivo expression and having an impact in animal models of infectious diseases and cancer, among others. Key PointsDirect in vivo delivery of synthetic nucleic acidencoded antibodies employing plasmid DNA [plasmid DNA-encoded monoclonal antibodies (pDNA-mAbs)] and messenger RNA-encoded monoclonal antibodies (mRNA-mAbs) platforms represent new approaches for the in vivo delivery of antibody-like biologics.While there are more preclinical data using pDNA-mAbs, both platforms have made significant progress and are demonstrating promising efficacy in infectious disease and cancer studies in small and large animal models.These platforms have advantages such as rapid product development and simpler manufacturing processes, yet they represent different strategies for deployment, with unique advantages and challenges.

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Section: Understanding the Genomic Impact Of Mrna And Dna Deliverymentioning

confidence: 99%

In Vivo Delivery of Nucleic Acid-Encoded Monoclonal Antibodies

2020

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“…14 Various methods to improve IL-12-based therapy by controlling gene expression have also been proposed, including the use of an NFAT promoter 16 28 or a smallmolecule gene-activation system. 29 The advantages of this system include use of a relatively small genetic construct and the absence of a requirement for systemic administration of a gene-activating small molecule. A disadvantage to this system is that the levels of iaIL-12 gene expression are not precisely controlled, and there is a measure of basal iaIL-12 expression ( figure 6B).…”

Section: Ail-12 Enhanced Human T-cell-mediated Tumor Regression In a mentioning

confidence: 99%

Enhanced efficacy and limited systemic cytokine exposure with membrane-anchored interleukin-12 T-cell therapy in murine tumor models

Zhang

Davies

Serna

et al. 2020

J Immunother Cancer

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BackgroundInterleukin-12 (IL-12) is a potent, proinflammatory cytokine that holds promise for cancer immunotherapy, but its clinical use has been limited by its toxicity. To minimize systemic exposure and potential toxicity while maintaining the beneficial effects of IL-12, we developed a novel IL-12-based therapeutic system that combines tumor-specific T-cell-mediated delivery of IL-12 with membrane-restricted IL-12 localization and inducible IL-12 expression.MethodsTherapeutic T cells targeting a tumor antigen were genetically engineered to express membrane-anchored IL-12 (aIL-12). Expression, function, and shedding of the aIL-12 molecule was assessed in vitro. Tumor treatment efficacy was assessed in vivo with T cell receptor (TCR) transgenic murine tumor models and a tumor xenograft model. Key outcomes were change in tumor size, circulating levels of IL-12 and other cytokines, and survival. Toxicity was assessed via change in body weight. Tumor growth curve measurements were compared using repeated-measures two-way analyses of variance.ResultsRetroviral gene transfer resulted in cell membrane expression of aIL-12 by transduced T cells. In each of two transgenic murine tumor models, tumor-specific T cells constitutively expressing aIL-12 demonstrated increased antitumor efficacy, low circulating IL-12 and interferon-γ, and no weight loss. Expression of aIL-12 via aNFAT-inducible promoter resulted in coordinate expression of aIL-12 with T cell activation. In an OT-I TCR transgenic murine tumor model, theNFAT-inducible aIL-12 molecule improved tumor treatment and did not result in detectable levels of IL-12 in serum or in weight loss. In a human tumor xenograft model, theNFAT-inducible aIL-12 molecule improved antitumor responses by human T cells coexpressing a tumor-specific engineered TCR. Serum IL-12 levels were undetectable with theNFAT-inducible construct in both models.ConclusionExpression of aIL-12 by tumor-targeting therapeutic T cells demonstrated low systemic exposure and improved efficacy. This treatment strategy may have broad applications to cellular therapy with tumor-infiltrating lymphocytes, chimeric antigen receptor T cells, and TCR T cells.

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“…Also, while not investigated further in this work, the observation of synergy between blinatumomab and recombinant IL-12 is significant in that the former is currently approved to treat relapsed/refractory and minimal residual disease positive (MRD + ) B-ALL in both adults in children. And while IL-12 therapies have not advanced to phase III trials due to poor circulation and toxicity, several novel IL-12 drug candidates currently under investigation may benefit from combination with blinatumomab including adenoviral, 33 plasmid, 34 mRNA, 35 and affinity-targeted 24, 25 IL-12.…”

Section: Il-12 Enhances Bispecific T Cell Engager Activitymentioning

confidence: 99%

Rapid Assembly and Screening of Multivalent Immune Cell-Redirecting Therapies for Leukemia

Do¹,

Perdue²,

Chyong³

et al. 2020

Preprint

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Therapies that bind with immune cells and redirect their cytotoxic activity towards diseased cells represent a promising and versatile approach to immunotherapy with applications in cancer, lupus, and other diseases; traditional methods for discovering these therapies, however, are often time-intensive and lack the throughput of related target-based discovery approaches. Inspired by the observation that the cytokine, IL-12, can enhance antileukemic activity of the clinically approved T cell redirecting therapy, blinatumomab, here we describe the structure and assembly of a chimeric immune cell-redirecting agent which redirects the lytic activity of primary human T cells towards leukemic B cells and simultaneously co-targets the delivery of T cell-stimulating IL-12. We further describe a novel method for the parallel assembly of compositionally diverse libraries of these bispecific T cell engaging cytokines (BiTEokines) and their high-throughput phenotypic screening, requiring just days for hit identification and the analysis of structure-function relationships. Using this approach, we identified CD19 x CD3 x IL12 compounds that exhibit ex vivo lytic activity comparable to current FDA-approved therapies for leukemia and correlated drug treatment with specific cell-cell contact, cytokine delivery, and leukemia cell lysis. Given the modular nature of these multivalent compounds and their rapid assembly/screening, we anticipate facile extension of this therapeutic approach to a wide range of immune cells, diseased cells, and soluble protein combinations in the future.

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Regulated intratumoral expression of IL-12 using a RheoSwitch Therapeutic System® (RTS®) gene switch as gene therapy for the treatment of glioma

Cited by 82 publications

References 48 publications

In Vivo Delivery of Nucleic Acid-Encoded Monoclonal Antibodies

In Vivo Delivery of Nucleic Acid-Encoded Monoclonal Antibodies

Enhanced efficacy and limited systemic cytokine exposure with membrane-anchored interleukin-12 T-cell therapy in murine tumor models

Rapid Assembly and Screening of Multivalent Immune Cell-Redirecting Therapies for Leukemia

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