Abstract
The widespread application of immune-checkpoint blockade (ICB) has resulted in unprecedented response rates in patients with immunogenic cancers, such as melanoma and lung cancer. However, sub-groups of patients with these indications do not respond to ICB, and the same applies to patients with other cancer types. Mechanisms of resistance to ICB include low tumor immunogenicity associated with low T cell infiltration (‘cold' tumors), suppression of anti-tumor immunity by immunosuppressive cells in the tumor microenvironment (TME), lack of antigen-presentation and immune escape (e.g. by downregulation of MHC-I on tumor cells) as well as oncologic pathways that suppress immune responses. Combination strategies, involving cytostatic drugs, harbor the potential to overcome refractoriness to immunotherapy. However, suppression of immune cell function by cytostatic drugs may limit the efficacy. In our study, we show that combination treatment of targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) and agonist immunostimulatory anti-CD40 antibody (Ab) is particularly suitable in counteracting aforementioned ICB resistance mechanisms (Fig. 1).
Highlights
IDENTIFYING SUITABLE CYTOSTATIC DRUGS FOR COMBINATORIAL IMMUNOTHERAPY The main dilemma in finding combinations of cytostatic and immunostimulatory drugs that act synergistically is as follows
We show that combination treatment of targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) and agonist immunostimulatory anti-CD40 antibody (Ab) is suitable in counteracting aforementioned immune-checkpoint blockade (ICB) resistance mechanisms (Fig. 1)
This implies that in the in vivo immunization setting signals downstream of CD40-ligation can overcome this inhibitory effect on T cells, possibly through T cell costimulatory signals provided by activated dendritic cell (DC) (Fig. 2A)
Summary
IDENTIFYING SUITABLE CYTOSTATIC DRUGS FOR COMBINATORIAL IMMUNOTHERAPY The main dilemma in finding combinations of cytostatic and immunostimulatory drugs that act synergistically is as follows. * Corresponding Author: Rienk Offringa, Department of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center Heidelberg, Heidelberg, Baden-Wuerttemberg, 69120, Germany; E-mail: r.offringa@dkfz.de
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
