Abstract 2184: BOXR1030: A first-in-class CAR T-cell therapy co-expressing GOT2 enhances T-cell metabolic function for the treatment of GPC3-positive solid tumors

Abstract

GPC3 is an oncofetal tumor antigen that is an attractive target for CAR T-cell therapy due to its highly restricted expression on normal tissue and high prevalence in several adult and pediatric solid tumors, including hepatocellular carcinoma and squamous cell lung carcinoma. However, solid tumors create an unfavorable microenvironment that restricts critical nutrients, drives T-cell dysfunction, and inhibits the effectiveness of cellular therapies. BOXR1030 is a first-in-class engineered cell therapy identified from a screen of > 100 bolt-on transgenes, composed of a humanized GPC3-targeting CAR and glutamic-oxaloacetic transaminase 2 (GOT2) mitochondrial enzyme to enhance T-cell metabolic function. GOT2 plays a central metabolic role, linking multiple pathways involved in biosynthesis and cellular energy production, and addition of the GOT2 bolt-on leads to increased amino acid uptake and improved antioxidant capacity of BOXR1030 T cells. As the first product candidate from the BOXR platform, BOXR1030 represents a novel approach to modulate T-cell metabolism, specifically engineered to overcome immunosuppressive challenges that limit conventional CAR T cells. In preclinical studies across tumor microenvironment (TME) conditions including hypoxia, nutrient restriction, and exhaustion driven by chronic stimulation, BOXR1030 T cells had improved function relative to control CAR T cells lacking the GOT2 bolt-on. These functional changes result in superior in vivo anti-tumor activity without altering target specificity. BOXR1030 activity is target-dependent with no evidence of off-target cytotoxicity or cytokine release in the presence of GPC3-negative cell lines. Binding specificity of BOXR1030 T cells was evaluated against > 5000 human membrane and secreted proteins, and no off-target CAR interactions were identified. In tumor-bearing NSG mice, no abnormalities in hematology, clinical chemistry, or gross pathology were observed with BOXR1030 treatment. In addition, no evidence for target-independent proliferation of BOXR1030 T cells was observed in vivo. These preclinical data demonstrate the robust activity and specificity of BOXR1030 and support clinical investigation. BOXR1030 has potential application in GPC3-positive solid tumor indications with significant unmet medical need. IND-enabling studies are currently in progress to support a future first-in-human trial in subjects with GPC3-positive tumors. Citation Format: Eugene Choi, Kathleen Whiteman, Tapasya Pai, Taylor Hickman, Tyler Johnson, Taylor Friedman, Avani Parikh, Madaline Gilbert, Binzhang Shen, Glen J. Weiss, Seth Ettenberg, Kathleen E. McGinness, Greg Motz. BOXR1030: A first-in-class CAR T-cell therapy co-expressing GOT2 enhances T-cell metabolic function for the treatment of GPC3-positive solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2184.

Expression of GOT2 Is Epigenetically Regulated by DNA Methylation and Correlates with Immune Infiltrates in Clear-Cell Renal Cell Carcinoma

“…Moreover, a correlation observed between increased clusters with the signature CD8_6 (CD8 + T-cells) and TAM_3 (macrophages) showed a better prognosis. In another study, a first-in-class CAR T-cell therapy co-expressing GOT2 enhanced T-cell metabolic function for treating GPC3-positive solid tumors, supporting the progress of a future first-in-human trial in subjects with GPC3-positive tumors [ 78 ]. Considering this context, we argue that GOT2 is likely to play distinct roles at different stages of T-cell exhaustion and might potentially be modulated by the spectrum of changes in TME conditions of KIRC patients, including tumor metabolism, hypoxia, nutrient restriction, and exhaustion driven by chronic stimulation, thus strengthening the potential application of synergic modulation of the GOT2 and T cell exhaustion markers in non-responsive KIRC patients to boost antitumor and immune responses.…”