Costimulation by chimeric antigen receptors revisited the T cell antitumor response benefits from combined CD28-OX40 signalling.
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.
Clinic I Internal Medicine Tumorgenetics, University Hospital Cologne, Cologne, Germany.
Andreas A
AA
Hombach
Hinrich
H
Abken
D000818:Animals; D018106:CD28 Antigens / Q000378:metabolism*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D004274:DNA, Recombinant; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D053262:Receptors, OX40 / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
D018106:CD28 Antigens; D004274:DNA, Recombinant; D011948:Receptors, Antigen, T-Cell; D053262:Receptors, OX40