Journal
CLINICAL CANCER RESEARCH
Volume 27, Issue 13, Pages 3757-3771Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-20-2487
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Funding
- National Natural Science Foundation of China [81472521, 81402251, 81502350, 81672676, 81772890]
- Guangdong Science and Technology Development Fund [2021A1515012355, 2015A030313181, 2016A030313352, 2017A030311011]
- Science and Technology Program of Guangzhou [201607010108, 201803010060]
- Fundamental Research Funds for the Central Universities [16ykpy10, 19ykzd20]
- National Clinical Key Specialty Construction Project for Department of Oral and Maxillofacial Surgery
- Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-sen University [KLB09001]
- Key Laboratory of Malignant Tumor Molecular Mechanism and Translational Medicine of Guangzhou Bureau of Science and Information Technology [(2013)163]
- NIH [R01DE028172, R03CA216114, R03CA223886, R03CA231766, R03CA239193]
- DOD [W81XWH-20-1-0315]
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The study demonstrated that the combination of SAHA and B7-H3.CAR T cells enhances the therapeutic efficacy against solid cancers, especially those with increased B7-H3 expression at the transcriptional level.
Purpose: The limited efficacy of chimeric antigen receptor (CAR) T-cell therapies with solid malignancies prompted us to test whether epigenetic therapy could enhance the antitumor activity of B7-H3.CAR T cells with several solid cancer types. Experimental Design: We evaluated B7-H3 expression in many human solid cancer and normal tissue samples. The efficacy of the combinatorial therapy with B7-H3.CAR T cells and the deacetylase inhibitor SAHA with several solid cancer types and the potential underlying mechanisms were characterized with in vitro and ex vivo experiments. Results: B7-H3 is expressed in most of the human solid tumor samples tested, but exhibits a restricted expression in normal tissues. B7-H3.CAR T cells selectively killed B7-H3 expressing human cancer cell lines in vitro. A low dose of SAHA upregulated B7-H3 expression in several types of solid cancer cells at the transcriptional level and B7-H3.CAR expression on human transgenic I-cell membrane. In contrast, the expression of immunosuppressive molecules, such as ClIA-4 and TET2, by T cells was downregulated upon SAHA treatment. A low dose of SAHA significantly enhanced the antitumor activity of B7-H3.CAR T cells with solid cancers in vitro and ex vivo, including orthotopic patient-derived xenogra ft and metastatic models treated with autologous CAR T-cell infusions. Conclusions: Our results show that our novel strategy which combines SAHA and B7-H3.CAR T cells enhances their therapeutic efficacy with solid cancers and justify its translation to a clinical setting.
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