Interesting possibilities to improve the safety and efficacy of ipilimumab (Yervoy)

Anti-CTLA-4 therapy may have mechanisms similar to those occurring in inherited human CTLA4 haploinsufficiency

“…This is entirely consistent with a recent finding that inherited human CTLA4 haploinsufficiency plays a critical quantitative role for CTLA-4 in governing T and B lymphocyte homeostasis (Kuehn et al, 2014). Our theoretical proposition, therefore, needs to be validated as it has important clinical consequences (Bakacs et al, 2012;Slavin et al, 2014).…”

“…The reality, albeit somewhat inconvenient, is that despite the dramatic therapeutic effects of ipilimumab in a subgroup of metastatic melanoma patients, the majority suffered autoimmune-related adverse events (irAEs) some of these being life-threatening or even fatal (Bakacs et al, 2012;Slavin et al, 2014). Therefore, the question as to how anti-CTLA-4 works to improve the tumor immune response in humans still remains unclear.…”

“…In the face of a pan-lymphocytic activation the task is not desperately trying to put the genie back in the bottle by immune-suppressive treatments, but exploiting the immense forces liberated by the anti-CTLA-4 antibody blockade (Bakacs et al, 2012). Based on a proof-of-principle paper (Bashey et al, 2009) (demonstrating augmented graft-versus-malignancy (GVM) effect reversing the relapse of malignancy without worsening the GVHD by a CTLA-4 blockade), we suggested exploiting rather than suppressing the drug-induced non-specific, polyclonal T cell stimulation (Bakacs et al, 2012).…”

“…Therefore, we have every reason to hope that a finely tuned, low dose ipilimumab therapy in MRD, could induce a safe and effective auto-GVHD without compromising the long lasting objective to eradicate tumors throughout the body (Slavin et al, 2014). While our pretargeting approach would enable a high dose ipilimumab therapy (Bakacs et al, 2012), which is essentially a focused auto-GVHD (without transplantation of course), hopefully, with tolerable collateral damage. Then it might not be difficult to recruit patients even with high tumor burden for anti-CTLA-4 treatment.…”

Overview of cancer vaccines

“…This suggests that tumor regression is associated with the development of autoimmunity and does imply that enhanced efficacy with anti-CTLA-4 and selectivity cannot be achieved. 45 Notwithstanding, with various safety warnings and precautions introduced into the product label and risk minimisation steps proposed by the applicant as a part of risk management plan, overall the benefitrisk balance was viewed favorably. 44 Experience with these submissions and parallel development of FDA guidance on clinical considerations for therapeutic cancer vaccines issued in 2011 triggered an addition of the trial, the company changed the primary endpoint in a sequential design from "overall survival" to "time to death or re-intervention," which is prone to bias by treating physicians.…”