Targeting Bcl-2 in CLL: cui bono?

ing this work to humans. First, we do not know whether the molar concentration of CD3 is similarly limiting for the expression of transgenic human TCRs. If CD3 is indeed limiting, then the enhanced expression and functionality we achieve by cotransfection of CD3 and TCRs may be accompanied by enhanced toxicity. Thus, enhanced expression may increase the risk of mispairing of endogenous and transgenic TCRs, and increase the risk of unwanted gain of function. It is, however, encouraging that the autoreactivity observed with such gain-of-function mispairing6 has yet to be observed in clinical trials,7,8 and indeed was absent in Ahmadi et al’s murine studies. Even without gain-of-function mispairing, however, T cells with transgenic TCRs may produce on-target antigen but offtarget organ toxicities, such as the damage to melanin-expressing cells in the inner ear and the retina observed using MART1-specific TCRs9 and the severe colitis observed in recipients of T cells expressing transgenic CEAspecific TCRs.4 These toxicities may become more frequent and more severe if we simply increase overall TCR expression. The above concerns notwithstanding, there will undoubtedly be much interest in exploring whether CD3-mediated “easing” of TCR expression really will benefit human T-cell therapies of cancer. Conflict-of-interest disclosure: The author declares no competing financial interests. ■