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. 2013 Jun 5:4:135.
doi: 10.3389/fimmu.2013.00135. eCollection 2013.

Young T Cells Age During a Redirected Anti-Tumor Attack: Chimeric Antigen Receptor-Provided Dual Costimulation is Half the Battle

Andreas A Hombach  1 , Hinrich Abken
Affiliations

Young T Cells Age During a Redirected Anti-Tumor Attack: Chimeric Antigen Receptor-Provided Dual Costimulation is Half the Battle

Andreas A Hombach et al. Front Immunol. .

Abstract

Adoptive therapy with chimeric antigen receptor (CAR)-redirected T cells showed spectacular efficacy in the treatment of leukemia in recent early phase trials. Patient's T cells were ex vivo genetically engineered with a CAR, amplified and re-administered to the patient. While T cells mediating the primary response were predominantly of young effector and central memory phenotype, repetitive antigen engagement irreversible triggers T cell maturation leaving late memory cells with the KLRG1(+) CD57(+) CD7(-) CCR7(-) phenotype in the long-term. These cells preferentially accumulate in the periphery, are hypo-responsive upon TCR engagement and prone to activation-induced cell death. A recent report indicates that those T cells can be rescued by CAR provided CD28 and OX40 (CD134) stimulation. We discuss the strategy with respect to prolong the anti-tumor response and to improve the over-all efficacy of adoptive cell therapy.

Keywords: CD28; OX40; adoptive cell therapy; chimeric antigen receptor; memory T cells.

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Figures

Figure 1
Figure 1
T cell maturation is accompanied by altered functional properties. CAR engineered T cells progress in maturation when the CAR repetitively engages cognate antigen as physiologically occurs upon TCR/CD28 signaling. While CAR engineered “young” memory T cells are transferred to the patient, the cells expand and undergo further differentiation leaving effector memory T cells at the tumor lesion which require additional signals for being protected from anergy and activation-induced cell death. On the other hand, those more matured cells have increased cytolytic potential making them highly effective in the anti-tumor attack. Engineering T cells with a combined CD28-OX40 CAR which prevents apoptosis of matured CCR7− T cells is one of the upcoming strategies to solve the situation and to improve the anti-tumor efficacy in the long-term.
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