title: Ipilimumab (Yervoy) and the TGN1412 catastrophe.
abstract: The development of the anti-CTLA-4 antibody (ipilimumab; marketed as Yervoy) immune regulatory therapy was based on the premise that "Abrogation of the function of CTLA-4 would permit CD28 to function unopposed and might swing the balance in favor of immune stimulation, tolerance breakdown and tumor eradication…" (Weber, 2009). By now, the vast majority of data collected from more than 4000 patients proves that this prediction was entirely correct. Paradoxically, the successful blockade of immune checkpoints raises the question whether an anti-CTLA-4 antibody could ever become an important therapy against cancer. T cells lost their ability to discriminate between self and non-self. Thus, tolerance to self tissues was broken in ∼70% of the patients. In the recent industry-sponsored phase III clinical trial of ipilimumab, 147 (38.7%) of the patients experienced severe adverse events and 6.8% suffered dose-limiting events (8.4%, in the ipilimumab-alone group). There were 14 deaths related to the study drugs and 7 of these were associated with immune-related adverse events. In contrast, the complete response rate was only 0.2%, in one patient out of 403 who received ipilimumab plus a peptide vaccine. Promoters of ipilimumab appear to be unmindful of the clinical trial catastrophe in London. Then, a humanized "superagonist" anti-CD28 monoclonal antibody, TGN1412, which "preferentially" activated regulatory T cells, at a higher dose, also activated all CD28 positive T cells. This precipitated a "cytokine storm" leading to life-threatening multiple organ failure in the six healthy human volunteers. Neither anti-CD28 nor anti-CTLA-4 therapies rely on antigen-specificity. Both release free antibody into the body against common molecular targets that are expressed on the targeted as well as on the non-targeted T cells. At lower antibody doses specific T cells are preferentially activated. With increasing antibody dose, however, the kinetics of the interaction is pushed in favor of widespread non-specific T cell expansion. Using the law of mass action we calculated that the vast majority of the CTLA-4 receptors on all activated T cells (including melanoma specific T cells) in the phase III clinical trial of ipilimumab will have been saturated. This would explain the runaway immune response observed. The conclusions drawn by the authors of the ipilimumab trial paper could bear an independent inspection and reassessment concerning the validation of the blockade of immune checkpoints as an important therapeutic strategy against cancer.
authors.affiliation: Department of Probability, Alfred Renyi Institute of Mathematics, Hungarian Academy of Sciences, Realtanoda utca 13-15, H-1053 Budapest, Hungary. bakacs.tibor@upcmail.hu
authors.forename: Tibor
authors.initials: T
authors.lastname: Bakacs
authors.forename: Jitendra N
authors.initials: JN
authors.lastname: Mehrishi
authors.forename: Ralph W
authors.initials: RW
authors.lastname: Moss
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology; D017326:Clinical Trials, Phase III as Topic; D000939:Epitopes; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D007116:Immunization, Passive / Q000379:methods*; D000074324:Ipilimumab; D008213:Lymphocyte Activation / Q000187:drug effects; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D012878:Skin Neoplasms / Q000276:immunology / Q000628:therapy*; D017211:Treatment Failure
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; D000939:Epitopes; D000074324:Ipilimumab; C509303:TGN-1412