Drug concept

During the past 5 years, the clinical approval of so-called checkpoint inhibitors, antibodies that mobilize the anti-tumor T-cell response by neutralizing immunosuppressive signals, have marked a breakthrough in cancer therapy. In spite of promising clinical results, it is also evident that a broader array of immunostimulatory drugs will be needed to counter the diversity of cancers and cancer subtypes, and that selected combinations of cytostatic drugs and immunotherapeutics are likely to provide the best therapeutic window.

The IACT project focuses on the clinical development of agonist immunostimulatory antibodies, drugs that activate and/or reprogram immune cells by delivering stimulatory signals to their activatory receptors. There is significant attraction to make agonist IS-Abs available for patient treatment in addition to the checkpoint inhibitors that are already in the clinic, because there is ample evidence from pre-clinical tumor models that this approach can be at least as efficacious. Furthermore, analyses of human tumors revealed that different mechanism of immune suppression underlie immune failure in cancer (sub-)types, pointing at the need for multiple treatment options/drugs to overcome immune failure in human cancer (personalized medicine). This need is supported by the notion that clinical results for these checkpoint blockers differ between individual patients and cancer types. Finally, combining agonist and antagonist IS-Abs in mice often work synergistically, pointing at the merit of exploring this approach in the clinic.

In spite of this strong rationale, clinical development of agonist IS-Abs has been stalled for several years. This is mainly due to an incident in the U.K. in 2006, in which administration of a highly potent agonist Ab against  the  immunostimulatory  receptor  CD28  (TGN1412)  to  healthy  volunteers  resulted  in  a  life threatening cytokine-release syndrome, due to the uncontrolled activation of immune cells. Importantly, it is now generally agreed that this clinical study was not conducted in an appropriate manner, while the underlying pre-clinical studies offered insufficient conceptual basis for the intended aim of suppressing – rather than enhancing – immunity by an agonist IS-Ab. With resolution of these concerns, the clinical development of agonist IS-Abs as cancer therapeutics is currently regaining momentum.