BOXR1030, an anti-GPC3 CAR with exogenous GOT2 expression, shows enhanced T cell metabolism and improved anti-cell line derived tumor xenograft activity

The solid tumor microenvironment (TME) drives T cell dysfunction and inhibits the effectiveness of immunotherapies such as chimeric antigen receptor-based T cell (CAR T) cells. Early data has shown that modulation of T cell metabolism can improve intratumoral T cell function in preclinical models. W...

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Bibliographic Details
Published in:PloS one 2022-05, Vol.17 (5), p.e0266980-e0266980
Main Authors: Hickman, Taylor L, Choi, Eugene, Whiteman, Kathleen R, Muralidharan, Sujatha, Pai, Tapasya, Johnson, Tyler, Parikh, Avani, Friedman, Taylor, Gilbert, Madaline, Shen, Binzhang, Barron, Luke, McGinness, Kathleen E, Ettenberg, Seth A, Motz, Greg T, Weiss, Glen J, Jensen-Smith, Amy
Format: Article
Language:English
Subjects:
Analysis
Antibodies
Anticancer properties
Antigens
Antitumor activity
Biology and Life Sciences
Biopsy
Cell culture
Cell differentiation
Cell Line, Tumor
Cell surface
Chimeric antigen receptors
Complications and side effects
Cytokines
Design of experiments
Diagnosis
Evaluation
Experimental design
Genetic aspects
Glucose
Glypicans - genetics
Glypicans - metabolism
Good Manufacturing Practice
Heparan sulfate proteoglycans
Hepatocellular carcinoma
Heterografts
Humans
Hypoxia
Immunotherapy
Immunotherapy, Adoptive - methods
Liposarcoma
Liver cancer
Liver Neoplasms - pathology
Lung cancer
Lung carcinoma
Lung diseases
Lymphocytes
Lymphocytes T
Medicine and Health Sciences
Metabolism
Patient outcomes
Phenotypes
Plasmids
Protein expression
Receptors, Chimeric Antigen
Research and Analysis Methods
Solid tumors
T cells
T-Lymphocytes
Transaminase
Tumor Microenvironment
Tumors
Xenograft Model Antitumor Assays
Xenografts
Xenotransplantation
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Summary:The solid tumor microenvironment (TME) drives T cell dysfunction and inhibits the effectiveness of immunotherapies such as chimeric antigen receptor-based T cell (CAR T) cells. Early data has shown that modulation of T cell metabolism can improve intratumoral T cell function in preclinical models. We evaluated GPC3 expression in human normal and tumor tissue specimens. We developed and evaluated BOXR1030, a novel CAR T therapeutic co-expressing glypican-3 (GPC3)-targeted CAR and exogenous glutamic-oxaloacetic transaminase 2 (GOT2) in terms of CAR T cell function both in vitro and in vivo. Cell surface expression of tumor antigen GPC3 was observed by immunohistochemical staining in tumor biopsies from hepatocellular carcinoma, liposarcoma, squamous lung cancer, and Merkel cell carcinoma patients. Compared to control GPC3 CAR alone, BOXR1030 (GPC3-targeted CAR T cell that co-expressed GOT2) demonstrated superior in vivo efficacy in aggressive solid tumor xenograft models, and showed favorable attributes in vitro including an enhanced cytokine production profile, a less-differentiated T cell phenotype with lower expression of stress and exhaustion markers, an enhanced metabolic profile and increased proliferation in TME-like conditions. Together, these results demonstrated that co-expression of GOT2 can substantially improve the overall antitumor activity of CAR T cells by inducing broad changes in cellular function and phenotype. These data show that BOXR1030 is an attractive approach to targeting select solid tumors. To this end, BOXR1030 will be explored in the clinic to assess safety, dose-finding, and preliminary efficacy (NCT05120271).
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0266980