It is the objective of WP-1 to most optimally educate ESR in research-related and transferable skills that guarantee optimal implementation of the training plan by organizing and monitoring all the training activities and the secondments. For details see sections 1.2, 1.3, 1.4, 2.1, 2.2 and 3.1.1.
WP-2: Management & Dissemination
It is the objective of this WP-2 to manage the project and to ensure that the project achieves its research training objectives and complies with all relevant guidelines concerning financial management, recruitment, gender balance, research ethics, and practice. In addition, it will coordinate the work of the “Dissemination & Outreach Board” (DOB) that guarantees the performance of all dissemination of all results to the appropriate audience. For details see sections 2.3.1 and 3.2.2.
WP-3: Developing novel biologicals that can target cell populations with unprecedented specificity
Currently, antibody-based targeting of cell populations is based on cell-type specific markers. In many cases, however, a specific cell-type marker is expressed by more than one specific cell type – hampering its therapeutic targeting substantially. In this WP, antibodies will be established that recognize specific cell types by their expression of two different cell-type markers that in their combination are specific for the specific cell-type.
Antibody specificity is based on the multimeric binding of an antigen. While a single head antibody binds its target with relatively low affinity, its avidity for the antigen increases exponentially the more binding sites the antibody has. Based on this effect, a low-affinity pentameric IgM antibody can have a similar avidity to an antigen as a high-affinity monomeric IgG antibody. Also, a bi-specific antibody construct can bind with low avidity to cells that express only one of the targeted antigens, but with high avidity to cells that express two antigens. This mechanism allows to construct a bi-specific antibody that is specific for two antigens of which either of them is commonly expressed, but in their combination are cell-type specific – which in our case will be either Treg-specific (IRP-1) or specific for cancerous but not healthy tissue (IRP-2).
WP-4: Specifically engaging particular cell types of the innate immune system
After market approval of the “check-point inhibitor” IpilimuMab, experiments in mouse models of cancer indicated that at least part of the mode-of-action and efficacy of IpilimuMab could be ascribed to tumour-selective depletion of Treg cells. This mode-of-action was mediated by the specific IgG subclass used in the case of Ipilimumab and the capacity of this IgG subclass to activate specific cells of the innate immune system within tumours. Another CTLA-4 targeting antibody, TremelimuMab, which used another IgG subclass, entirely failed to show efficacy despite being able to block CTLA-4 with even higher affinity. Currently, it remains unknown whether this is due to a potentially critical role for cells of the human innate immune system for the anti-tumour activity of monoclonal antibody-based tumour therapy. Nevertheless, the appropriate interaction between tumour-targeted antibodies and tumour-resident leukocytes could appear to be a critical factor influencing therapeutic success.
WP-5: Targeting known immune-modulating cytokines / check-point inhibitors directly into established tumours
Pro-inflammatory cytokines have in general been supposed to support tumour immunotherapy. Due to their ability to activate NK cells as well as T-cells, have for instance IL2 or IL-12 for a long time been assumed to be ideal candidates for support of tumour immunotherapy. Nevertheless, cytokine-based therapies had rather disappointing clinical antitumor efficacy and were accompanied by unacceptable levels of adverse effects. Similarly, cancer therapy using monoclonal antibodies that enhance immune responses or block the immune cell-intrinsic “check-point inhibitors” have found wide clinical applications. However, their application is associated with substantial levels of adverse effects. Thus, in this WP, methods are developed aiming at targeting these cytokines and monoclonal antibodies directly towards immune cells within the tumour micro-environment. Such an approach could substantially increase the efficacy of such treatment while diminishing side effects.