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Genetic modification of T cells redirected toward CS1 enhances eradication of myeloma cells.

ABSTRACT: Our goal is to test whether CS1 could be targeted by chimeric antigen receptor (CAR) T cells to treat multiple myeloma (MM).We generated a retroviral construct of a CS1-specific CAR and engineered primary human T cells expressing the CAR. We then tested the capacity of CS1-CAR T cells to eradicate human MM tumor cells in vitro, ex vivo, and in vivo using orthotopic MM xenograft mouse models.In vitro, compared with mock-transduced T cells, upon recognizing CS1-positive MM cells, CS1-CAR-transduced T cells secreted more IFN-? as well as interleukin (IL)-2, expressed higher levels of the activation marker CD69, showed higher capacity for degranulation, and displayed enhanced cytotoxicity. Ectopically forced expression of CS1 in MM cells with low CS1 expression enhanced recognition and killing by CAR T cells. Ex vivo, CS1-CAR T cells also showed similarly enhanced activities when responding to primary MM cells. More importantly, in orthotopic MM xenograft mouse models, adoptive transfer of human primary T cells expressing CS1-CAR efficiently suppressed the growth of human MM.1S and IM9 myeloma cells and significantly prolonged mouse survival.CS1 is a promising antigen that can be targeted by CAR-expressing T cells for treatment of MM.

SUBMITTER: Chu J

PROVIDER: S-EPMC4119545 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Genetic modification of T cells redirected toward CS1 enhances eradication of myeloma cells.

Chu Jianhong J He Shun S Deng Youcai Y Zhang Jianying J Peng Yong Y Hughes Tiffany T Yi Ling L Kwon Chang-Hyuk CH Wang Qi-En QE Devine Steven M SM He Xiaoming X Bai Xue-Feng XF Hofmeister Craig C CC Yu Jianhua J

Clinical cancer research : an official journal of the American Association for Cancer Research 20140327 15

<h4>Purpose</h4>Our goal is to test whether CS1 could be targeted by chimeric antigen receptor (CAR) T cells to treat multiple myeloma (MM).<h4>Experimental design</h4>We generated a retroviral construct of a CS1-specific CAR and engineered primary human T cells expressing the CAR. We then tested the capacity of CS1-CAR T cells to eradicate human MM tumor cells in vitro, ex vivo, and in vivo using orthotopic MM xenograft mouse models.<h4>Results</h4>In vitro, compared with mock-transduced T cell ...[more]

PMID: 24677374

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Project description:Genetic modification has been used to create dairy cattle without horns and with increased resistance to disease; applications that could be beneficial for animal welfare, farm profits, and worker safety. Our aim was to assess how different stated purposes were associated with public attitudes toward these two applications using a mixed methods approach. Using an online survey, U.S. participants were randomly assigned to one of ten treatments in a 2 (application: hornless or disease-resistant) x 5 (purposes: improved animal welfare, reduced costs, increased worker safety, all three purposes, or no purpose) factorial design. Each participant was asked to read a short description of the assigned treatment (e.g. hornlessness to improve calf welfare) and then respond to a series of questions designed to assess attitude toward the treatment using 7-point Likert scales (1 = most negative; 7 = most positive). Responses of 957 participants were averaged to creative an attitude construct score. Participants were also asked to explain their response to the treatment. Qualitative analysis of these text responses was used to identify themes associated with the participants' reasoning. Participant attitudes were more favorable to disease resistance than to hornlessness (mean ± SE attitude score: 4.5 ± 0.15 vs. 3.7 ± 0.14). In the 'disease-resistance' group participants had more positive attitudes toward genetic modification when the described purpose was animal welfare versus reduction of costs (contrast = 1.00; 95% CI = 0.12-1.88). Attitudes were less favorable to the 'hornless' application if no purpose was provided versus when the stated purpose was either to improve animal welfare (contrast = 0.95; 95% CI = 0.26-1.64) or when all purposes were provided (contrast = 0.88; 95% CI = 0.19-1.58). Similarly, attitudes were less positive when the stated purpose was to reduce costs versus either improving animal welfare (contrast = 0.86; 95% CI = 0.09-1.64) or when all purposes were provided (contrast = 0.79; 95% CI = 0.02-1.56). Quantitative and qualitative analysis indicated that both the specific application and perceived purpose (particularly when related to animal welfare) can affect public attitudes toward genetic modification.

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Genetic modification of T cells redirected toward CS1 enhances eradication of myeloma cells.

Publications

Genetic modification of T cells redirected toward CS1 enhances eradication of myeloma cells.

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