期刊
MOLECULAR IMMUNOLOGY
卷 85, 期 -, 页码 293-304出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.molimm.2017.03.017
关键词
Ovarian cancer; Immunotherapy; Cytokine induced killer cells; Chimeric antigen receptor; Folate receptor-alpha
资金
- National Natural Science Foundation of China [81301963]
- Outstanding Youth Science Foundation of Henan university [yqpy20140036]
- Natural Science Foundation of Henan Province [162300410040]
- Science and Technology Development Program of Henan Province [132300410274]
- Key Project of Scientific and Technological Research of Henan Educational Committee [13B320917]
Folate receptor alpha (FR alpha) 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 FRa 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 FR alpha-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 FR alpha-positive (FR alpha*) or FR alpha-negative (FR alpha-) targets. However, all three generations of CAR -modified CIK cells showed enhanced antitumor activity against FRa* targets, but not FRa- targets. First -generation zeta-CAR-CIK cells increased production of IFN gamma, enhanced short-term cytotoxicity against FRa* ovarian cancer cells, and showed modest and shortterm suppression of established tumors; while second -generation 28 zeta-and third -generation 28BK zeta CAR-CIK cells showed significant proliferation, enhanced secretion of IL-2, eliminated the FRa* 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 28BB zeta-CAR was more potent in the modification of CIK cells than 28 zeta-CAR both in vitro and in vivo. Moreover, CAR-OK 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 FRa-specific CARs enhances their antitumor immunity to FRa* ovarian cancers. The third -generation 28BB-zeta CAR containing 4-1BB co-stimulation was more efficient in modification of CIK cells than either first -generation zeta -CAR or second -generation CD28 zeta CAR. (C) 2017 Elsevier Ltd. All rights reserved.
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