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Costimulation by chimeric antigen receptors revisited the T cell antitumor response benefits from combined CD28‐OX40 signalling
Author(s) -
Hombach Andreas A.,
Abken Hinrich
Publication year - 2011
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.25960
Subject(s) - cd28 , cd137 , chimeric antigen receptor , t cell , microbiology and biotechnology , biology , cytotoxic t cell , cancer research , cd8 , il 2 receptor , immunology , antigen , immune system , in vitro , biochemistry
The therapeutic success of adoptive therapy with chimeric antigen receptor (CAR) engineered T cells depends on the appropriate costimulation of CD3ζ to induce full T cell activation. Costimulatory endodomains of the CD28 family are therefore fused with CD3ζ in a dual signalling CAR. Serious adverse events in two most recent trials; however, highlight the need to analyse in more detail the impact of each costimulatory endodomain on individual effector functions of redirected T cells. We therefore performed a thoroughly controlled side‐by‐side comparison of the most frequently used endodomains with respect to their impact on CD4 + and CD8 + T cell effector functions. CD28 reinforced T cell proliferation and is mandatory to induce IL‐2. In the absence of added IL‐2, CD28 and OX40 (CD137) but not 4‐1BB (CD134) enhanced specific cytolysis. While CD28, 4‐1BB and OX40 similarly improved pro‐inflammatory cytokine secretion, OX40 most efficiently prevented activation induced cell death of CD62L − effector memory T cells. CD28 was superior to initiate the T cell response, OX40 and 4‐1BB sustained the response in long term with OX40 being most effective. We consequently combined the beneficial functions in a 3rd generation CD28‐OX40 CAR which substantially improved the antitumor response without loosing specificity.