title: Modification of cytokine-induced killer cells with folate receptor alpha (FRα)-specific chimeric antigen receptors enhances their antitumor immunity toward FRα-positive ovarian cancers.
abstract: Folate receptor alpha (FRα) is aberrantly expressed in ovarian cancers but largely absent in normal tissues, and therefore represents an attractive target for immunotherapy. In recent years, modification of T cells with chimeric antigen receptor (CAR) targeting FRα has been reported to improve antitumor immunity of T cells. However, there are limited data regarding CAR-modified cytokine-induced killer (CAR-CIK) cells. In the present study, we modified CIK cells with FRα-specific CARs and investigated their antitumor immunity against ovarian cancers. We found that both non-transduced and mock CAR-transduced CIK cells showed only low antitumor activity against either FRα-positive (FRα+) or FRα-negative (FRα-) targets. However, all three generations of CAR-modified CIK cells showed enhanced antitumor activity against FRα+targets, but not FRα-targets. First-generation ζ-CAR-CIK cells increased production of IFN-γ, enhanced short-term cytotoxicity against FRα+ovarian cancer cells, and showed modest and short-term suppression of established tumors; while second-generation 28ζ- and third-generation 28BBζ-CAR-CIK cells showed significant proliferation, enhanced secretion of IL-2, eliminated the FRα+ovarian cancer cells in long-term co-culture, and showed dramatic and long-term inhibition of tumor growth and prolonged survival of xenograft-bearing mice. It is noteworthy that the 28BBζ-CAR was more potent in the modification of CIK cells than 28ζ-CAR both in vitro and in vivo. Moreover, CAR-CIK cells showed more efficient anticancer activity compared with CAR-T cells in vitro, but less efficient than CAR-T cells in vivo. According to these results, we conclude that modification of CIK cells with FRα-specific CARs enhances their antitumor immunity to FRα+ovarian cancers. The third-generation 28BB-ζ CAR containing 4-1BB co-stimulation was more efficient in modification of CIK cells than either first-generation ζ-CAR or second-generation CD28-ζ-CAR.
authors.affiliation: Center for Translational Medicine, Huaihe Hospital of Henan University, Kaifeng, Henan Province 475001, China. Electronic address: zuosg@icloud.com.
authors.forename: Shuguang
authors.initials: S
authors.lastname: Zuo
authors.affiliation: Department of General Surgery, Huaihe Hospital of Henan University, Kaifeng, Henan Province 475001, China.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Wen
authors.affiliation: Department of General Surgery, Huaihe Hospital of Henan University, Kaifeng, Henan Province 475001, China.
authors.forename: Hean
authors.initials: H
authors.lastname: Panha
authors.affiliation: Department of General Surgery, Huaihe Hospital of Henan University, Kaifeng, Henan Province 475001, China.
authors.forename: Gongpeng
authors.initials: G
authors.lastname: Dai
authors.affiliation: Center for Translational Medicine, Huaihe Hospital of Henan University, Kaifeng, Henan Province 475001, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Wang
authors.affiliation: Center for Translational Medicine, Huaihe Hospital of Henan University, Kaifeng, Henan Province 475001, China; Department of General Surgery, Huaihe Hospital of Henan University, Kaifeng, Henan Province 475001, China.
authors.forename: Xuequn
authors.initials: X
authors.lastname: Ren
authors.affiliation: Center for Translational Medicine, Huaihe Hospital of Henan University, Kaifeng, Henan Province 475001, China; Department of General Surgery, Huaihe Hospital of Henan University, Kaifeng, Henan Province 475001, China. Electronic address: hhyyfkd@126.com.
authors.forename: Kanda
authors.initials: K
authors.lastname: Fu
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D055612:Cytokine-Induced Killer Cells / Q000276:immunology* / Q000637:transplantation*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D058975:Folate Receptor 1 / Q000276:immunology*; D016219:Immunotherapy, Adoptive / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010051:Ovarian Neoplasms; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000951:Antigens, Neoplasm; D058975:Folate Receptor 1; D011948:Receptors, Antigen, T-Cell
keywords: Chimeric antigen receptor; Cytokine induced killer cells; Folate receptor-alpha; Immunotherapy; Ovarian cancer