The success of checkpoint blockade therapy revolutionized cancer treatment. However, we need to increase the fraction of responding patients and overcome acquired resistance to these therapies.... Show moreThe success of checkpoint blockade therapy revolutionized cancer treatment. However, we need to increase the fraction of responding patients and overcome acquired resistance to these therapies. Recently, the inhibitory receptor NKG2A received attention as a new kid on the block of immune checkpoints. This receptor is selectively expressed on cytotoxic lymphocytes, including natural killer cells and CD8 T cells, and NKG2A+ T cells are preferentially residing in tissues, like the tumor microenvironment. Its ligand, HLA-E, is a conserved non-classical HLA class I molecule that binds a limited peptide repertoire and its expression is commonly detected in human cancer. NKG2A blockade as a standalone therapy appears poorly effective in mouse tumor models, however in the presence of activated T cells, for example induced by PD-1/PD-L1 blockade or cancer vaccines, displays strongly enhanced efficacy. Clinical trials demonstrated safety of the humanized NKG2A-blocking antibody monalizumab and first results of phase II trials demonstrate encouraging durable response rates. Further development of this axis is clearly warranted. Show less
Bergstra, S.A.; Allaart, C.F.; Berg, R. van den; Chopra, A.; Govind, N.; Huizinga, T.W.J.; Landewe, R.B.M. 2017
In recent years combination therapies have become increasingly popular in most therapeutic areas. We present a qualitative and quantitative approach and elucidate some of the challenges and... Show moreIn recent years combination therapies have become increasingly popular in most therapeutic areas. We present a qualitative and quantitative approach and elucidate some of the challenges and solutions to a more optimal ther- apy. For tumor growth this involves the study of semi-mechanistic cell-growth/kill models with multiple sites of action. We introduce such models and analyze their dynamic properties using simulations and mathematical analysis. This is done for two specific case studies, one involving a single compound and one a combination of two compounds. We generalize the notion of Tumor Static Concentration to cases when two compounds are in- volved and develop a graphical method for determining the optimal combination of the two compounds, using ideas akin to those used in studies employing isobolograms. In studying the dynamics of the second case study we focus, not only on the different concentrations, but also on the different dosing regimens and pharmacokinet- ics of the two compounds. Show less
