The past few years have witnessed something of a renaissance in the field of cancer immunotherapy relating largely to the clinical advances that have been associated with the development of monoclonal antibodies Dipsacoside B targeting the immune inhibitory co-receptors CTLA-4 and PD-1 and to the pursuit of genetically modified antigen-redirected adoptive T-cell therapies. signaling has been instrumental to recent advances in the development of genetically modified antigen-specific adoptive cellular therapies an increasing awareness of the ability of tumours to subvert multiple immune inhibitory pathways effectively blunting the development or expansion of any anti-tumour immunity is fostering the development of novel therapies that appear active as monotherapies but may achieve their greatest impact in combinatorial regimens. This mini-review will focus on attempts to target co-inhibitory members of the immunoglobulin superfamily. Rabbit Polyclonal to p15 INK. cooperate to inhibit the development of spontaneous and carcinogen-induced tumours in mice genetically engineered to lack a functional immune system (RAG-2?/?; Shankaran provides one possible mechanism by which peripheral tissues might be protected from the collateral damage that could ensue from T-cell activation in the context of infection providing a localised ‘molecular shield’ inhibiting activated T cells from targeting surrounding host tissues. The phenotype of PD-1 or PD-L1 knockout mice is less severe than that of CTLA-4-deficient mice (Nishimura and markedly enhances tumour growth and invasiveness was detected at the interface of PD-L1+ tumours and TILs whereas none was found Dipsacoside B in PD-L1? tumours suggesting that TILs may actually trigger their own inhibition by secreting cytokines that drive tumour PD-L1 expression a form of adaptive resistance mediating immune escape. In other tumours PD-L1 expression appears to be driven by constitutively active oncogenic signaling pathways (Parsa when expressed on either regulatory or effector T cells (Wing agents culminating in two successful phase III studies with the fully human anti-CTLA-4 monoclonal antibody ipilimumab. The first of these trials Dipsacoside B documented outcomes in 676 patients with previously treated advanced melanoma (Hodi 13.7%) appeared encouraging and while Dipsacoside B patient numbers with longer follow-up were small overall survival at 4 years appeared similar in the ipilimumab group (approximately 20%). Much effort is now being directed at identifying biomarkers that correlate with response/outcome to allow appropriate targeting of treatment to those likely to gain most benefit both to avoid exposure to potentially harmful side effects in those unlikely to gain benefit and to manage the financial cost associated with therapy. Such insights might also allow development of strategies to enhance activity in those who are unlikely to profit from ipilimumab monotherapy. One possible avenue for investigation in this regard is the tumour microenvironment before therapy. A subset of patients with melanoma display an inflamed tumour microenvironment associated with more effective recruitment of CD8+ effector T cells. It is tempting to speculate that the patients gaining clinical benefit from ipilimumab are among those who have an ongoing immune interaction between the tumour and the host immune system in a similar way as can be predicted for those responding to anti-PD-1 or anti-PD-L1. Such considerations are also of importance to contextualise these data with respect to the results of adoptive T-cell therapies in melanoma. These have been dramatic in many cases with response rates of up to 50% (Dudley 9.1 months) with higher survival rates in the ipilimumab-dacarbazine group at 1 year (47.3% 36.3%) 2 years (28.5% 17.9%) and 3 years (20.8% 12.2%). Grade 3-4 adverse events occurred in 56.3% of patients Dipsacoside B treated with ipilimumab plus dacarbazine as compared with 27.5% treated with dacarbazine and placebo (P<0.001). No drug-related deaths occurred in the ipilimumab-dacarbazine group. The results therefore mirror those of the study in more advanced disease establishing a role for ipilimumab in treatment-naive patients. Once again the benefits were relatively modest in terms of prolongation of median overall survival but a minority of patients achieved what appeared to be more durable responses. Arguably confirmation of durability of responses in this group will ultimately offer the best insights into the true impact of ipilimumab in patients with melanoma. PD-1/PD-L1: denting the molecular shield In contrast to CTLA-4 the major role of PD-1 is thought to be the limitation of activity of T cells in peripheral tissues at the time of an inflammatory response to infection and Dipsacoside B to limit autoimmunity..