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In various embodiments, the present invention provides T cells
genetically engineered with vectors designed to express CARs that
redirect cytotoxicity toward tumor cells. CARs are molecules that combine antibody-based
specificity for a target antigen (e.g., tumor antigen) with a T cell receptor-activating
intracellular domain to generate a chimeric protein that exhibits a specific anti-tumor cellular immune activity.
The CARs contemplated herein comprise an extracellular domain that binds to a specific target antigen (also referred to
as a binding domain or antigen-specific binding domain), a transmembrane domain and an intracellular signaling domain. Libraries of
TCRs may be screened for their selectivity to particular target antigens.
The T cell manufacturing methods contemplated are particularly
useful for expanding T cells modified to express
high affinity T cell receptors (engineered TCRs) or chimeric antigen receptors (CARs) without a concomitant
increase in the differentiation of these modified T cells.
In one embodiment, the T cell is genetically modified to express one ore more engineered TCRs or
CARs. The modified T cells are then able to express
one or more chains of a TCR (and preferably two chains) encoded by the transduced nucleic acid or nucleic acids.
In preferred embodiments, the engineered TCR is an exogenous TCR because it is introduced into T cells that do not normally express the particular TCR.


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