title: An Update on Calcineurin Inhibitor-Free Regimens: The Need Persists, but the Landscape has Changed.
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.
authors.affiliation: 1 Kidney Transplant Service, University of California San Francisco, San Francisco, CA.
authors.forename: Allison B
authors.initials: AB
authors.lastname: Webber
authors.forename: Flavio
authors.initials: F
authors.lastname: Vincenti
mesh_terms: D000069594:Abatacept / Q000627:therapeutic use; D000818:Animals; D065095:Calcineurin Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D058990:Molecular Targeted Therapy; D016377:Organ Transplantation / Q000009:adverse effects; D010880:Piperidines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use; D011799:Quinazolines / Q000627:therapeutic use; D018570:Risk Assessment; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; D011799:Quinazolines; D000069594:Abatacept; C543528:sotrastaurin; C479163:tofacitinib