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Inclusion of an IgG1-Fc Spacer Abrogates Efficacy of CD19 CAR T Cells in a Xenograft Mouse Model

Inclusion of an IgG1-Fc Spacer Abrogates Efficacy of CD19 CAR T Cells in a Xenograft Mouse Model

H Almåsbak, E Walseng, A Kristian, M R Myhre, E M Suso, L A Munthe, J T Andersen, M Y Wang, G Kvalheim, G Gaudernack, J A Kyte

Gene Ther. 2015 May;22(5):391-403.

PMID: 25652098

Abstract:

Cancer therapy with T cells expressing chimeric antigen receptors (CARs) has produced remarkable clinical responses in recent trials, but also severe side effects. Whereas most protocols use permanently reprogrammed T cells, we have developed a platform for transient CAR expression by mRNA electroporation. This approach may be useful for safe clinical testing of novel receptors, or when a temporary treatment period is desirable. Herein, we investigated therapy with transiently redirected T cells in vitro and in a xenograft mouse model. We constructed a series of CD19-specific CARs with different spacers and co-stimulatory domains (CD28, OX40 or CD28-OX40). The CAR constructs all conferred T cells with potent CD19-specific activity in vitro. Unexpectedly, the constructs incorporating a commonly used IgG1-CH2CH3 spacer showed lack of anti-leukemia activity in vivo and induced severe, partly CD19-independent toxicity. By contrast, identical CAR constructs without the CH2-domain eradicated leukemia in vivo, without notable toxicity. Follow-up studies demonstrated that the CH2CH3-spacer bound soluble mouse Fcγ-receptor I and mediated off-target T-cell activation towards murine macrophages. Our findings highlight the importance of non-signalling CAR elements and of in vivo studies. Finally, the results show that transiently redirected T cells control leukemia in mice and support the rationale for developing an mRNA-CAR platform.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42412948	TRAIL, Soluble mouse			Price

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