Adoptive therapy of cancer with genetically redirected T cells showed spectacular efficacy in recent trials. A body of preclinical and clinical data indicate that young effector and central memory T cells perform superior in a primary antitumor response; repetitive antigen engagement, however, drives T-cell maturation to terminally differentiated cells associated with the loss of CCR7, which enables T cells to persist in peripheral tissues. In this work, we explored the antitumor efficacy of CCR7⁻ T cells when redirected in an antigen-dependent fashion by a chimeric antigen receptor (CAR) toward tumors in the periphery. CAR-engineered CCR7⁻ T cells more efficiently accumulated at the tumor site, secreted more IFN-γ, expressed higher amounts of cytotoxic molecules, and showed superior tumor cell lysis compared to the younger CCR7⁺ cells. CCR7⁻ T cells, however, were more prone to spontaneous and activation-induced cell death, which could be counteracted by simultaneous CD28 and OX40 (CD134) costimulation. Consequently, the combined CD28-ζ-OX40 signaling CAR rescued CCR7⁻ T cells from apoptosis, which then produced more efficient antitumor efficacy than CCR7⁺ T cells redirected by the same CAR. Data suggest that T-cell therapy will benefit from combined CD28-ζ-OX40 stimulation in the long-term by rescuing continuously generated CCR7⁻ T cells for an antitumor attack.