Thursday, June 26, 2014
Receptor expression and engagement of antigen. (I) T cell receptors
(TCRs) consist of a heterodimer of a- and b-chains
that associate with the g-, d-, e- and z-chains of the CD3 complex. The TCR
recognizes processed antigenic peptides presented by major histocompatibility complex class I
(MHC) molecules on the
surface of a tumor cell. The targets can thus be antigens derived from
intracellular or extracellular proteins as long as they are processed and
displayed as MHC complexes.
The first generation
of TCRs generally had low affinity and specificity for their targets because
the immune system naturally avoids making high-affinity TCRs against
self-proteins to prevent autoimmune reactions. Thus, second-generation TCRs
used endogenous, tumor-targeting TCRs as a starting point and were then
optimized for potency and cancer antigen affinity.
(II) Chimeric antigen receptors (CARs) are synthetic
receptors made up of a single-chain antibody variable fragment (scFv) linked
through a hinge domain to one or more T cell signaling domains capable of
activating the T cell response. CARs can target tumor-associated protein,
carbohydrate or glycolipid antigens presented in an MHC-independent manner on
the outside of cells.
The first generation of
CARs included only one T cell-activating signaling molecule and showed limited
antitumor effects owing to suboptimal T cell stimulation and proliferation.
breakthroughs occurred with second-generation CARs, which consist of two T cell
signaling domains that provide enhanced activation of T cells and produce
better T cell expansion, proliferation and persistence than first-generation
CARs. (Figure based on Figure 1 in Kershaw, M.H. et al., Nat. Rev. Cancer 13, 525-541; 2013.)