Research strategy and objectives
There is significant attraction to make agonist IS-Abs available for patient treatment in addition to the antagonist IS-Abs (checkpoint blockers) that are already in the clinic, first of all because there is ample evidence from pre-clinical tumor models that this approach can be at least as efficacious. In line with the notion that these IS-Ab classes represent two conceptually distinct ways of mobilizing immunity, the efficacy of agonist and antagonist IS-Abs differs between the mouse models studied. Furthermore, analyses of human tumors revealed that different mechanism of immune suppression underlie immune failure in cancer (sub-)types. Consequently, there is a clear need for multiple treatment options/drugs to overcome immune failure in human cancer (personalized medicine).
Pioneering pre-clinical work has been performed in Europe, including that by several IACT partners. Moreover, one of our partners (University of Southampton) has recently concluded a successful phase I study with an agonist anti-CD40 IS-Ab (ChiLob7/4) and, with support from Cancer Research UK, is also developing lead agonist Abs targeting the stimulatory receptors OX40 and 4-1BB. The availability of these clinical antibodies to the IACT consortium, together with the long-standing expertise of our team in this area of research, create a unique opportunity for European academia and industry to bring this promising class of drugs into the clinic and thereby develop new treatment options for cancer patients.
These considerations inspired the three-pronged IACT research strategy, which encompasses the following main objectives:
|1.||To drive further clinical development and testing of the available lead IS-Abs through:|
|obtaining clinical proof of concept for the efficacy of anti-CD40 IS-Ab ChiLob7/4 in combination with chemotherapy in pancreatic cancer|
|obtaining clinical proof of concept for the efficacy of anti-CD40 IS-Ab ChiLob7/4 with antigen-specific vaccination in human papillomavirus type 16 (HPV16+) head and neck cancer|
|selecting lead anti-OX40 and 4-1BB IS-Abs for first in human testing|
|2.||To optimally support the successful development of IS-Ab drugs through|
|the identification of pharmacodynamics (PD) biomarkers that are related to therapeutic efficacy, and the development of validated, harmonized assays for their measurement in the context of clinical trials|
|the development of validated, harmonized in vitro and in vivo models to guide the pre- clinical development of IS-Ab drugs and their best possible application in clinical trials|
|3.||To set up a pipeline for the development of 2nd-generation IS-Abs with improved therapeutic index along four innovative approaches that are based on the latest insights in IS-Ab function as well as on proprietary technologies of our SME partners.|