Purpose: Inducible costimulator (ICOS) on T cells enhances basic T cell responses to foreign antigen, and increased ICOS expression is detected in association with pathogenic alloimmunity in αCD40-treated non-human primate (NHP) recipients of cardiac (and renal) allografts. We asked whether ICOS-Ig treatment timed to anticipate ICOS upregulation prolongs survival or attenuates pathogenic alloimmunity in a NHP cardiac model.

Methods: Cynomolgus heterotopic cardiac allograft recipients were treated with αCD40 (2C10R4, n=9). ICOS-Ig was given to three recipients (αCD40+ICOS-Ig) Q3-4 days at 5-10 mg/kg IV from D63 (ICOS expression is detected in graft T cells with 2C10R4 treatment) until D90-110. Acute rejection (ISHLT score) and chronic allograft vasculopathy (CAV score) severity were quantified in protocol biopsies and explanted grafts using published scoring systems. Both antidonor alloantibody production and peripheral blood T effector memory (EM: CD8⁺CD28^–) phenotype were characterized using flow cytometry.

Results: Allograft median survival time (MST) was similar with αCD40+ICOS-Ig (120 days, range 120-125) and αCD40 monotherapy (124, 89-178, p=0.6). Peak ICOS-Ig levels generally exceeded a 100 [micro]g/mL target, although trough ICOS-Ig levels were unexpectedly low (<1 [micro]g/mL) despite progressive dose escalation. αCD40 and αCD40+ICOS-Ig had similar kinetics of alloantibody production, ISHLT (1.2±0.4 vs 1.7±0.6 at 3 months), and CAV scores (1.19±0.6 vs 1.34±0.33 at 3 months). Graft rejection was consistently associated with both IgM and IgG alloantibody production. From D63-D110, the number of CD8⁺ T_EM cells were similar with αCD40+ICOS-Ig (466±67) and αCD40 (570±82, p=0.3).

Conclusions: The addition of the ICOS-Ig reagent as used here did not yield synergy with αCD40 or modulate surrogate markers of pathogenic alloimmunity, confirming prior observations in an NHP renal allograft model using an induction approach. Our findings suggest that alternative strategies to target pathogenic features of the ICOS/ICOS-L pathway should be prioritized in transplant models.

CITATION INFORMATION: O'Neill N, Zhang T, Cheng X, Sun W, Braileanu G, Tatarov I, Hassanein W, Azimzadeh A, Pierson R. Does Blockade of ICOS/ICOS-L Pathway Act Synergistically with αCD40 Costimulation Pathway Blockade? Am J Transplant. 2017;17 (suppl 3).

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