Box 1. Revving up T cells.

Michel 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").

"Having 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.

In 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.

PSCA also 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 brush border.

In mice 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