2010
DOI: 10.1038/gt.2010.91
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Adoptive immunotherapy with genetically engineered T cells: modification of the IgG1 Fc ‘spacer’ domain in the extracellular moiety of chimeric antigen receptors avoids ‘off-target’ activation and unintended initiation of an innate immune response

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Cited by 193 publications
(206 citation statements)
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“…cause activation of macrophages expressing the Fc receptor and compromise the antitumor activity of CARTs (20)(21)(22). Modifications of our current κ.CAR cassette to include the 4-1BB motif and remove the long spacer may enhance in vivo CART persistence and, therefore, the therapeutic effects of our proposed κ.CART therapy.…”
Section: Discussionmentioning
confidence: 99%
“…cause activation of macrophages expressing the Fc receptor and compromise the antitumor activity of CARTs (20)(21)(22). Modifications of our current κ.CAR cassette to include the 4-1BB motif and remove the long spacer may enhance in vivo CART persistence and, therefore, the therapeutic effects of our proposed κ.CART therapy.…”
Section: Discussionmentioning
confidence: 99%
“…We observed incremental gains of function in signaling outputs based on in vitro assays as spacer size increased from the short IgG4 hinge spacer, to an intermediate hinge:CH3, to the full-length IgG4-hinge:Fc spacer. Because prior studies have revealed reduced survival of LS CAR T cells due to interaction between FcgR þ cells in the lung and the Fc portion of the CAR after intravenous injection (14,35), we used for in vivo testing a direct intratumoral route of CD8 þ CTL administration to study the direct effect of spacer length on CAR T cells within a solid tumor that provides IL2 locally, as a surrogate for infusional IL2 and/or codelivery of CD4 þ Th1 T cells. Unexpectedly, the antitumor potency of intratumorally injected CAR-CD8 þ CTLs was inversely correlated to spacer size (i.e., SS>MS>>LS) and in vitro functional potency.…”
Section: Discussionmentioning
confidence: 99%
“…5 The length, flexibility, and origin of the hinge domain is also an important variable in the design of CARs. [6][7][8] A major challenge to the field is that it is currently necessary to empirically test these design variables as there are no general rules guiding CAR design for target molecules.…”
Section: Anatomy Of Cars and Car T-cell Productsmentioning
confidence: 99%
“…Most investigators are using the hinge and transmembrane domains of CD8a or CD28; hinge domains derived from Fc regions have also been investigated and modified in length 6 and have also been reported to engage Fc receptors and activate innate immune cells. 7,8 Investigators in the field are using a variety of methods to introduce their CAR constructs into T cells. 9 Each has advantages and disadvantages with regard to cost, safety, and level of expression.…”
Section: Anatomy Of Cars and Car T-cell Productsmentioning
confidence: 99%