A5086534343- CAR-T cell therapy research
- Immunotherapy and Immune Responses
- Monoclonal and Polyclonal Antibodies Research
- Cancer Research and Treatments
- Cancer Immunotherapy and Biomarkers
- Immune Response and Inflammation
- T-cell and B-cell Immunology
- Biosimilars and Bioanalytical Methods
- Click Chemistry and Applications
- Cancer Cells and Metastasis
- interferon and immune responses
- Immune Cell Function and Interaction
- Viral Infectious Diseases and Gene Expression in Insects
- Cytokine Signaling Pathways and Interactions
- Melanoma and MAPK Pathways
- CRISPR and Genetic Engineering
- Polyamine Metabolism and Applications
- Systemic Lupus Erythematosus Research
- Neuroblastoma Research and Treatments
- Rheumatoid Arthritis Research and Therapies
- Chemokine receptors and signaling
- Viral Infections and Immunology Research
- Enzyme function and inhibition
- NF-κB Signaling Pathways
- Cell Adhesion Molecules Research
Biogen (United States)
2013-2018
Yale University
2010-2016
Johns Hopkins Medicine
2013
Johns Hopkins University
2013
Autoantibodies from rheumatoid arthritis patients augment the function of PAD4 by decreasing its calcium requirement.
Extrafollicular (EF) B-cell responses are increasingly being recognized as an alternative pathway of activation, particularly in autoimmunity. Critical cellular interactions required for the EF response unclear. A key question autoimmunity, which Toll-like receptor (TLR) signals costimulatory and could be sufficient is whether T cells response. This pivotal, because autoreactive B considered antigen-presenting cells, but where such occur has not been identified. Here, using AM14...
Adoptive cell therapies (ACT) have shown reduced efficacy against solid tumor malignancies compared to hematologic malignancies, partly due the immunosuppressive nature of microenvironment (TME). ACT may be enhanced with pleiotropic cytokines that remodel TME; however, their expression needs tightly controlled avoid systemic toxicities. Here we show T cells can armored membrane-bound surface regulated using drug-responsive domains (DRDs) developed from 260-amino acid protein human carbonic...
Abstract Background: TIL cell therapy can induce durable disease regression in solid tumors. engineered with regulatable mbIL15 (cytoTIL15TM cells) demonstrate interleukin 2-independent expansion and function (Burga SITC 2023) lead to clinical responses (Amaria ASCO 2024). Furthermore, co-regulated expression of LIGHT show enhanced efficacy fibroblast-containing, immunologically cold tumors (Koscso AACR Chondrosarcomas are often mesenchymal stem-cell origin similar transcriptional signature...
Combining a phenotypic screen with chemoproteomics reveals CDK12 as potential therapeutic target to inhibit noncanonical NF-κB in inflammation and cancer.
Abstract Introduction: We have previously shown the successful engineering of membrane-bound IL15 (mbIL15)-expressing tumor-infiltrating lymphocytes (TIL; cytoTIL15™ cells) from solid tumors such as melanoma, which are CD8+ enriched TIL exhibiting enhanced persistence and anti-tumor activity compared with unengineered (SITC 2022, 2023; clinical candidate OBX-115: NCT05470283). The mbIL15 expressed by cytoTIL15 cells is regulated via a carbonic anhydrase 2 (CA2) drug-responsive domain, allows...
Abstract Introduction: Adoptive cellular therapies (ACT) have encountered challenges in solid tumors due part to the immunosuppressive tumor microenvironment (TME). We developed OBX-115, TIL engineered express mbIL15 regulatable using cytoDRiVE® platform, which allows for expansion, persistence, and anti-tumor efficacy under control of FDA-approved small-molecule ligand, acetazolamide (ACZ), eliminating need co-administration IL2 (NCT05470283). LIGHT, a necrosis factor family member,...
Abstract Tumor infiltrating lymphocyte (TIL) therapy has shown promising results in the treatment of metastatic melanoma. However, TIL conventionally required co-administration IL2, which is associated with toxicity patients. We previously showed that melanoma TILs engineered to express membrane-bound IL15 (mbIL15) under control ligand acetazolamide (ACZ) can achieve IL2-independent expansion during manufacturing, antigen-independent persistence vitro and anti-tumor efficacy vivo. In current...
<h3>Background</h3> Non-engineered tumor-infiltrating lymphocyte (TIL) cell therapy has demonstrated antitumor activity in metastatic NSCLC.<sup>1 2</sup> Historically, surgical tumor tissue procurement been required to manufacture TIL, but surgery is a barrier treatment for many patients with NSCLC. TIL engineered regulatable membrane-bound IL15 (cytoTIL15<sup>TM</sup> cells) demonstrate IL2-independent expansion and preclinical functionality using multiple solid types, including...
<h3>Background</h3> TIL engineered to express the Th1-polarizing cytokine interleukin IL12 (IL12) have potential be a powerful cell therapy for recalcitrant solid tumors. modified secrete upon antigen stimulation showed promising response rate in patients with metastatic melanoma receiving low doses of TIL, but also unacceptable cytokine-related systemic toxicities,<sup>1</sup> highlighting need additional means regulating expression. We developed membrane-bound (mbIL12) enhanced regulation...
<h3>Background</h3> Non-engineered TIL cell therapy requiring co-administration of high-dose IL2 has shown promising activity, but concerning safety, in melanoma. To develop IL2-independent TIL, cytoTIL15<sup>TM</sup> cells are engineered to express regulatable membrane-bound IL15 (mbIL15) using an FDA-approved small-molecule drug, acetazolamide (ACZ), which binds the drug-responsive-domain (DRD) carbonic anhydrase 2 (CA2), driving expansion, persistence, and antitumor activity (OBX-115:...
Abstract Standard tumor-infiltrating lymphocyte (TIL) therapy requires IL-2 administration to support TIL expansion and survival, but this cytokine is associated with T cell exhaustion can result in severe toxicities that limit patient eligibility (1). To end, we genetically engineered express membrane-bound IL-15 (mbIL15) under the control of Obsidian’s cytoDRIVE® technology (cytoTIL15࣪), which allows regulation protein expression via a drug-responsive domain upon acetazolamide (ACZ)...
<h3>Background</h3> Adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) has demonstrated tremendous promise in clinical trials for patients solid or metastatic tumors.<sup>1</sup> However, current TIL requires systemic administration of IL-2 to promote survival, and IL-2-associated toxicities greatly limit patient eligibility reduce the long-term benefit therapy.<sup>2 3</sup> Unlike IL-2, which promotes T exhaustion, IL-15 maintains antigen-independent persistence through...
<h3>Background</h3> The clinical impact of tumor infiltrating lymphocytes (TIL) cell products is currently limited by suboptimal persistence and potency, as well the need for high-dose adjuvant IL-2 treatment, which associated with severe toxicities. Thus, we engineered an IL-2-independent TIL product, based on regulated expression interleukin 15 (cytoTIL15<sup>TM</sup> cells), has shown anti-tumor efficacy in human melanoma PDX models. Since immuno-suppressive microenvironment (TME) hinders...
Abstract Tumor infiltrating lymphocytes (TIL) have shown promising efficacy in immunologically “hot” solid tumors that a high level of T cell infiltration, such as melanoma. However, current treatment regimens require dose IL-2 administration to support TIL survival, which limits their clinical applications due related toxicity. Obsidian Therapeutics is engineering with membrane bound IL-15 (mbIL15) eliminate the dependence on exogenous IL-2, potentially enhancing tolerability therapies....
<h3>Background</h3> We have previously demonstrated the successful generation of membrane-bound IL15 (mbIL15) engineered TIL (cytoTIL15™ therapy) from solid tumors, and acetazolamide (ACZ)-driven regulated expression mbIL15 resulted in persistence an antigen-independent preclinical model (SITC 2021, 2022). Here, we evaluated function pharmacologically tunable setting chronic antigen stimulation by melanoma tumor-associated antigens (TAAs), such as MART1. <h3>Methods</h3> CytoTIL15 cells were...
Abstract Adoptive cell therapy with chimeric antigen receptor (CAR) modified T cells has demonstrated remarkable clinical efficacy in the treatment of certain B malignancies and more recently multiple myeloma. However, solid tumors, CAR-T been far less successful, likely due to lack robust expansion, immunosuppressive microenvironment, clonal heterogeneity within these tumors. The trafficking tumor sites provides an opportunity for selective delivery cargo that can enhance activity at site...
Abstract Cytokines are messenger molecules that act as regulators of innate and adaptive immunity by propagating cell-cell immune signaling. Several cytokines have been approved for the treatment metastatic renal cell cancer, advanced melanoma, hairy leukemia (HCL) can be particularly effective when combined with adoptive therapy. However, systemic delivery or constitutive expression even at moderate levels potentially lead to significant toxicity. These hurdles enabling cytokine-enhanced...
Abstract Adoptive cell therapy with chimeric antigen receptor (CAR) modified T cells has demonstrated remarkable clinical efficacy in the treatment of certain B malignancies, and more recently multiple myeloma. However, CAR-T been less successful treating solid tumors due to obstacles, including lack robust expansion, immunosuppressive tumor microenvironment, escape loss targeted antigen. Engineering produce immunomodulatory factors such as Interleukin 12 (IL12) Cluster Differentiation 40...
Adoptive cell therapy with chimeric antigen receptor (CAR) modified T cells has demonstrated remarkable clinical efficacy in the treatment of certain B malignancies, and more recently multiple myeloma. However, CAR-T been less successful treating solid tumors due to obstacles, including lack robust expansion, immunosuppressive tumor microenvironment, escape loss targeted antigen. Engineering produce immunomodulatory factors such as Interleukin 12 (IL12) Cluster Differentiation 40 Ligand...
Abstract Interleukin 12 (IL12) is an attractive cancer immunotherapeutic known to be extremely potent against solid tumors preclinically. However, the clinical utility of IL12 has been limited by toxicities stemming from high systemic cytokine exposure. Thus, armoring cellular therapies such as chimeric antigen receptor T cells (CAR-Ts) or tumor infiltrating lymphocytes (TILs) with will require technologies that provide tight control expression and localization. Herein, we describe a tightly...
<h3>Background</h3> Solid tumors remain a challenging frontier for adoptive cellular therapies (ACT). Armoring T-cells with cytokines, such as interleukin 12 (IL-12), to remodel the tumor microenvironment (TME) has demonstrated preclinical efficacy against solid tumors. However, clinical utility of IL-12 is limited by systemic toxicities, requiring tight control expression. Herein, we show that armored small molecule-controlled membrane bound (mbIL-12) drives regulation pharmacodynamic...