An Update on Calcineurin Inhibitor-Free Regimens: The Need Persists, but the Landscape has Changed

Transplantation. 2016 Apr;100(4):836-43. doi: 10.1097/TP.0000000000000872.

Abstract

Calcineurin inhibitors (CNIs) have failed to improve long-term renal allograft survival. Their association with cardiovascular morbidity in addition to their suboptimal inhibition of a chronic alloimmune response has shifted investigative efforts toward CNI-free regimens. Sotrastaurin, a small molecule targeting protein kinase C isoforms, failed to provide adequate immunosuppression, whereas the Janus kinase 3 inhibitor tofacitinib's success in the treatment of rheumatoid arthritis led to biopharma's abandonment of it as a transplant agent. Like tofacitinib, tocilizumab, a biologic targeting the IL-6 pathway, has been approved for use in rheumatoid arthritis and interest in transplantation has been confined to several investigator-initiated trials. Belatacept, a second-generation, higher avidity variant of CTLA4Ig (abatacept), was approved by the Food and Drug Administration for prophylaxis of transplant rejection in 2011. Long-term follow-up of recipients on belatacept has demonstrated superior glomerular filtration rates as compared with CNIs, albeit with an increased risk of early and histologically severe rejection. Focus on optimizing belatacept-inclusive regimens has led to studies using lymphocyte depletion as induction and maintenance therapy with target of rapamycin inhibitors. ASKP1240, the most advanced of the anti-CD40 antibodies targeting the CD40/CD154 costimulatory pathway has just completed a phase II trial with a CNI-free arm. Animal models suggest that its highest efficacy may be in combination with belatacept. Finally, nonagonistic CD28 antibodies, which would allow CTLA4 and PD-LI binding of CD80/CD86 and activation of inhibitory pathways, have re-emerged with 2 anti-CD28 candidates in preclinical development. A reliable nontoxic CNI-free regimen may ultimately require the combination of biologic agents that provide efficacy as well as safety.

Publication types

  • Review

MeSH terms

  • Abatacept / therapeutic use
  • Animals
  • Calcineurin Inhibitors / adverse effects
  • Calcineurin Inhibitors / therapeutic use*
  • Drug Therapy, Combination
  • Graft Rejection / immunology
  • Graft Rejection / metabolism
  • Graft Rejection / prevention & control*
  • Graft Survival / drug effects*
  • Humans
  • Immunosuppressive Agents / adverse effects
  • Immunosuppressive Agents / therapeutic use*
  • Molecular Targeted Therapy
  • Organ Transplantation* / adverse effects
  • Piperidines / therapeutic use
  • Pyrimidines / therapeutic use
  • Pyrroles / therapeutic use
  • Quinazolines / therapeutic use
  • Risk Assessment
  • Risk Factors
  • Signal Transduction / drug effects
  • Time Factors
  • Treatment Outcome

Substances

  • Calcineurin Inhibitors
  • Immunosuppressive Agents
  • Piperidines
  • Pyrimidines
  • Pyrroles
  • Quinazolines
  • Abatacept
  • sotrastaurin
  • tofacitinib