Search

Purpose: 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., Experimental Design: 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., Results: 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., Conclusions: 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)., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: TLH is an employee of Takeda Pharmaceuticals, a former employee of Unum Therapeutics, has ownership interest in Unum Therapeutics (now Cogent Biosciences), and has issued patents: PCT/US18/00028 and PCT/US2018/015999-all outside the submitted work. EC is an employee of Catamaran Bio, Inc, a former employee of Unum Therapeutics; has ownership interest in Unum Therapeutics (now Cogent Biosciences) and Catamaran Bio, Inc; and has issued patents: PCT/US2010/0041032A1, PCT/US2019/0153061A1, PCT/US2019/0105348A1, and PCT/US2019/0284298A1-all outside the submitted work. KRW is an employee of SOTIO Biotech Inc., a former employee of Unum Therapeutics; has ownership interest in Unum Therapeutics (now Cogent Biosciences) and has issued patents: PCT/US2012/0282175A1 and PCT/US2010/0028346A1 all outside the submitted work. SM is an employee of SOTIO Biotech Inc., a former employee of Kiniksa Pharmaceuticals. TP is an employee of Novartis and a former employee of Unum therapeutics. TJ is an employee of Novartis, a former employee of Unum Therapeutics, and has ownership interest in Unum Therapeutics (now Cogent Biosciences). TF is an employee of Biogen and a former employee of Unum therapeutics. MG is an employee of Arrakis Therapeutics and a former employee of Unum therapeutics. BS is an employee of Tango Therapeutics, a former employee of Unum Therapeutics, and has issued patents: US9464333, US9388422, US9303250, WO2014055778A2, WO2016069774A1, and WO2017049094A1-all outside the submitted work. LB is an employee of Catamaran Bio, Inc. and a former employee of Unum therapeutics. KEM is an employee of Arrakis Therapeutics, a former employee of Unum Therapeutics, and a consultant for SOTIO Biotech Inc.; has ownership interest in Unum Therapeutics (now Cogent Biosciences), and ownership interests in Baxter International and Takeda Pharmaceutical Co. outside the submitted work; is an inventor multiple patents PCT/US2019/046550, PCT/US2019/050013, PCT/US2019/040346, and PCT/US2019/060287 related to the submitted work; and US 8,252,913, US 8,461,318, US 8,598,327, US 10,144,770, PCT/US2019/044512, PCT/US2018/015999, PCT/US2017/023064, PCT/US2010/023599-outside of the submitted work. SAE is an employee of BlueRock Therapeutics, a former employee of Unum Therapeutics, has ownership interest in Unum Therapeutics (now Cogent Biosciences), and is a co-inventor on patents filed related to this work. GTM is an employee of BlueRock Therapeutics, a former employee of Unum Therapeutics; has ownership interest in Unum Therapeutics (now Cogent Biosciences), and is a named inventor on many CAR-T patents. GJW is an employee of SOTIO Biotech Inc., a former employee of Unum Therapeutics; reports personal fees from Spring Bank Pharmaceuticals, Imaging Endpoints II, MiRanostics Consulting, Gossamer Bio, Paradigm, International Genomics Consortium, Angiex, IBEX Medical Analytics, GLG Council, Guidepoint Global, Genomic Health, Rafael Pharmaceuticals, SPARC-all outside this submitted work; has ownership interest in Unum Therapeutics (now Cogent Biosciences), and ownership interests in MiRanostics Consulting, Exact Sciences, Moderna, Agenus, Aurinia Pharmaceuticals, and Circulogene-outside the submitted work; and has issued patents: PCT/US2008/072787, PCT/US2010/043777, PCT/US2011/020612, and PCT/US2011/037616-all outside the submitted work and is an inventor on a patent filed related to this work. AJS is an employee of SOTIO Biotech Inc.; a former employee of bluebird bio; has ownership interest in bluebird bio, Pfizer, Regeneron, Exelixis, Bristol Myers Squibb, Celgene, and Alkermes-all outside the submitted work. All other authors have no other competing interests related to this work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.