Thursday, January 16, 2014
Box 1. Revving up T cells.
Sadelain, director of the Memorial
Sloan Kettering Cancer Center's Center for Cell Engineering,
previously teamed with researchers from the Dresden University
of Technology to design co-stimulatory chimeric receptors
(CCRs) that ramp up T cell function when encountering on-target cells while
sparing off-target cells.2 Similar to the newly reported inhibitory
chimeric antigen receptors (iCARs), the goal is to have T cells express two
different receptors that eliminate cancer cells and spare normal cells (see
Figure 1, "Putting the brakes or gas on T cell function").
two approaches to achieve tumor selectivity in the absence of a tumor-unique
target is very valuable, but both will require a balance of finely tuned
signaling," said Sadelain.
proof-of-concept studies, the MSKCC-Dresden group focused on prostate stem cell antigen (PSCA) and prostate-specific membrane antigen (PSMA; FOLH1; GCPII). Both targets are highly expressed
in metastatic prostate cancer, although neither antigen is absolutely specific
to prostate tissue.
is expressed in the renal pelvis, ureter, urinary bladder and urethra. PSMA is
expressed in type II astrocytes, the kidney proximal tubule and the intestinal
with PSCA+/PSMA+, PSCA+/PSMA- and PSCA-/PSMA+ tumors, T cells expressing an
attenuated, PSCA-specific CAR and a PSMA-specific CCR eradicated the
double-antigen tumors but not the single-antigen tumors. The findings confirmed
that T cell cytotoxicity took place in the presence of on-target tissues while
sparing off-target tissues. -TB