Pharmacodynamic and clinical activity of RGX-104, a first-in-class immunotherapy targeting the liver-X nuclear hormone receptor (LXR), in patients with refractory malignancies.

Mita, Monica; Mita, Alain C.; Chmielowski, Bartosz; Hamilton, Erika; Pant, Shubham; Waltzman, Roger J.; Rowinsky, Eric K.; Szarek, Michael; Gonsalves, Foster C.; Kurth, Isabel; Andreu, Celia; Busby, Robert; Darst, David Martin; Tavazoie, Sohail F.; Tavazoie, Masoud; Postow, Michael A.

doi:10.1200/jco.2018.36.15_suppl.3095

Cited by 10 publications

(16 citation statements)

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“…In particular RGX-104 is able to deplete myeloid derived suppressor cells (MDSCs), stimulates dendritic cells and activates cytotoxic lymphocytes. The immunologic and anti-tumor activity of this drug has been demonstrated in patients with advanced refractory solid tumors and now a dose-escalation phase with nivolumab has started [80].…”

Section: New Partners For Icismentioning

confidence: 99%

Immunotherapy in small-cell lung cancer: from molecular promises to clinical challenges

Pavan¹,

Attili²,

Pasello³

et al. 2019

j. immunotherapy cancer

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Management of small cell lung cancer (SCLC) has not changed over the last decades. In more recent years, alterations of DNA repair machinery and other molecular pathways have been identified in SCLC and preclinical data suggest that dysregulation of these pathways might offer new therapeutic opportunities. While immune checkpoint inhibitors (ICIs) have had a major impact on the clinical outcome of several solid tumors, including non-small cell lung cancer, the potential role of ICIs is currently under investigation in SCLC and some promising data are available. However, several clinical and biological hurdles have to be overcome and predictive markers are still eagerly needed. Knowledge of molecular pathways specifically involved in SCLC growth and treatment resistance is essential for a more rational planning of new combinations including ICIs. The present manuscript summarizes the current clinical evidence on immunotherapy in SCLC, describes the molecular bases underlying treatment resistance and discusses the potentialities and the rationale of different therapeutic combinations.

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Section: New Partners For Icismentioning

confidence: 99%

Immunotherapy in small-cell lung cancer: from molecular promises to clinical challenges

Pavan¹,

Attili²,

Pasello³

et al. 2019

j. immunotherapy cancer

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“…RGX-104 is being studied as monotherapy or in combination with docetaxel in a phase I clinical trial in patients with advanced solid or hematologic malignancies (NCT02922764). Preliminary results were published in an abstract [ 52 ]. Among 12 patients who received monotherapy, the DCR was 42%.…”

Section: Stimulatory Pathwaysmentioning

confidence: 99%

“…Among 12 patients who received monotherapy, the DCR was 42%. There were 5 confirmed cases of SD after 8 weeks of treatment and 1 unconfirmed PR [ 52 ]. One patient with a neuroendocrine tumor had a 53% reduction in the metastatic load [ 52 ].…”

Section: Stimulatory Pathwaysmentioning

confidence: 99%

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Immunotherapies targeting stimulatory pathways and beyond

et al. 2021

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Co-stimulatory and co-inhibitory molecules play a critical role in T cell function. Tumor cells escape immune surveillance by promoting immunosuppression. Immunotherapy targeting inhibitory molecules like anti-CTLA-4 and anti-PD-1/PD-L1 were developed to overcome these immunosuppressive effects. These agents have demonstrated remarkable, durable responses in a small subset of patients. The other mechanisms for enhancing anti-tumor activities are to target the stimulatory pathways that are expressed on T cells or other immune cells. In this review, we summarize current phase I/II clinical trials evaluating novel immunotherapies targeting stimulatory pathways and outline their advantages, limitations, and future directions.

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“…In addition to the gemcitabine studies, the novel small molecule RGX-104 that targets the liver-X receptor is being tested in combination with existing ICIs or chemotherapeutics (NCT02922764). This agent has been shown to deplete MDSCs by apoptosis in non-small cell lung cancer ( 81 , 82 ). The tri-specific anti-CD16/IL-15/CD33 fusion protein GTB-3550 is being explored as a potential intervention for MDSC depletion by antibody-dependent cellular cytotoxicity (NCT03214666) ( 83 ).…”

Section: Anti-mdsc-targeted Therapies In Human Cancersmentioning

confidence: 99%

Granulocytic Myeloid-Derived Suppressor Cells as Negative Regulators of Anticancer Immunity

Kramer

Abrams

2020

Front. Immunol.

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The immune system plays a critical role in cancer progression and response to therapy. However, the immune system can be compromised during the neoplastic process. Notably, the myeloid lineage, which gives rise to granulocytic cells, including neutrophils, is a well-recognized target of tumor-mediated immune suppression. Ordinarily, granulocytic cells are integral for host defense, but in neoplasia the normal process of granulocyte differentiation (i.e., granulopoiesis) can be impaired leading instead to the formation of granulocytic (or PMN)-myeloid-derived suppressor cells (MDSCs). Such cells comprise various stages of myeloid differentiation and are defined functionally by their highly pro-tumorigenic and immune suppressive activities. Thus, considerable interest has been devoted to impeding the negative contributions of PMN-MDSCs to the antitumor response. Understanding their biology has the potential to unveil novel therapeutic opportunities to hamper PMN-MDSC production in the bone marrow, their mobilization, or their effector functions within the tumor microenvironment and, therefore, bolster anticancer therapies that require a competent myeloid compartment. In this review, we will highlight mechanisms by which the neoplastic process skews granulopoiesis to produce PMN-MDSCs, summarize mechanisms by which they execute their pro-tumorigenic activities and, lastly, underscore strategies to obstruct their role as negative regulators of antitumor immunity.

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Pharmacodynamic and clinical activity of RGX-104, a first-in-class immunotherapy targeting the liver-X nuclear hormone receptor (LXR), in patients with refractory malignancies.

Cited by 10 publications

References 0 publications

Immunotherapy in small-cell lung cancer: from molecular promises to clinical challenges

Immunotherapy in small-cell lung cancer: from molecular promises to clinical challenges

Immunotherapies targeting stimulatory pathways and beyond

Granulocytic Myeloid-Derived Suppressor Cells as Negative Regulators of Anticancer Immunity

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