Use of EGF-R antagonists for the treatment of infections and tumour growth

Immune responses play a central role in the protection against infections and tumor growth. At the same time can uncontrolled immune responses cause severe tissue damage. Local immune responses, therefore, have to be tightly regulated to prevent immune-mediated pathology. A subset of CD4 T-cells, so called regulatory T-cells, has been shown to constitute an important component of local immuno-regulation. Thus, on the one hand these regulatory T-cells are necessary to ensure a well-balanced immune response. On the other hand has it been shown that pathogens and tumours that co-evolved with the immune system have found ways to use regulatory T-cells to dampen local immune responses and to induce tolerance. Thus, translated into a clinical setting, the targeted interference with regulatory T-cell function could substantially enhance the pathogen-/tumor-specific immune response in patients suffering from infections or of cancer.
Unfortunately, little is known about the regulation of regulatory T-cell function at the site of inflammation and, as a consequence, there is a high unmet medical need for treatments that specifically could interfere with regulatory T-cell function in a therapeutic setting.
We recently discovered a mechanism by which regulatory T-cell function is controlled; which is via the expression of the growth factor receptor, EGF-R. Inhibitors of this receptor are already in wide clinical use for the treatment of some tumours, and in an experimental setting it was shown that these inhibitors enhance immune responses during viral infections. These findings suggest that these inhibitors may function, at least in part, via the suppression of regulatory T-cell function. Such a suppression of immune regulation could also explain for the severe side-effects, such as skin rashes, stomatitis or diarrhea, that are experienced by cancer patients treated with EGF-R inhibitors.

In this proposal, we would like to show that EGF-R inhibitors that are already used in the clinic, enhance anti-viral and antitumor immune responses by suppressing the functionality of regulatory T-cells in vivo. Based on that knowledge, we will further develop inhibitors that will interfere with regulatory T-cells specifically, while keeping other functions of this growth factor receptor untouched. We would expect such novel inhibitors to be more effective than the current generation of inhibitors and to induce less side effects, which would allow their further application also in cancer patients that at this moment would not be considered for treatment with EGF-R inhibitors, or in patients suffering from chronic infections.

We recently have found that activated regulatory T-cells (Tregs) require the expression of the EGF-R for their optimal functioning. So lack for example Tregs that fail to express the EGF-R the capacity to prevent the development of colitis in a T-cell transfer-based mouse model; and can treatment with EGF-R antagonists induce the clearance of a tumour by tumour-specific immune responses. In this project, we would like to determine how Tregs limit the success of tumour immuno-therapy and how they contribute to persistence of chronic infections.
Our hypothesis is that EGF-R antagonists diminish Treg function and thereby substantially enhance the efficiency of both tumour- and pathogen-specific immune responses. We will test this proposition in the context of i) genetic defects in EGF-R expression in the regulatory T cell lineage, ii) lack of Tregs and iii) in context of treatment with EGF-R antagonists. Based on our findings, we will develop a new type of EGF-R inhibitor that specifically targets Tregs. In this way, we establish an EGF-R inhibitor that most optimally modulates immune responses, while keeping the function of the EGF-R for other physiological functions, such as tissue homeostasis, intact.
We expect that the outcome of these studies could contribute to a wider application of EGF-R inhibitors, in particular in combination with tumour immunotherapies, to enhance clinical response rates and could create novel possibilities to treat diseases, such as chronic viral infections, for which yet no treatments exist at all.

The here proposed project is fundamental and hypothesis-derived in character. Nevertheless, its impact beyond the scientific field could, in particular due to its potential applicability for clinical interventions, be quite substantial. The proposal is based on a novel and entirely unexpected finding in the field of immune regulation, i.e. that cells of the innate immune system not only initiate immune responses, but that they also are important for the efficient resolution of local inflammation and the induction of immunological tolerance. The immune system thereby utilizes the evolutionary ancient signalling pathway of the epidermal growth factor (EGF) receptor to regulate the functionality of local regulatory T-cells (Tregs).

Impact for our understanding of Treg function
Tregs have in recent years been shown to be of critical importance to regulate local immune responses in a way that ensure efficient clearance of pathogens, while at the same time limiting the damage pathogen-specific immune responses may cause at the site of inflammation. How Tregs are regulated in their functionality is thereby only partially understood. However, a better understanding could also lead to improved treatments of immune mediated diseases, such as auto-immune diseases, allergies or the induction of tolerance in the context of organ transplantation.

Impact for the targeting of Treg function in a clinical setting
Both, pathogens and tumours, have co-evolved with the immune system and often have found ways to use Treg function to diminish local immune responses and to induce immunological tolerance against their antigens. So has it in recent years become apparent that the immune system plays a critical role in the success and failure of many tumour treatments (Zitvogel L., et al. J Clin Invest. 2008) and several tumour immune therapies, such as in the form of depleting antibodies (e.g. RetuxiMab), have substantially improved our quality of life, as they allow now-a-days to cure patients suffering of specific cancers for which a couple of decades ago clinicians would have had little means of helping. In the course of these studies, it became apparent that Tregs play a central role in the success or failure of many tumour treatments (Zou W. Nat Rev Immunol. 2006 & Yao X., et al., Blood. 2012), and tumour treatments that directly target cell surface proteins that function as T-cell regulators, such as the CTLA-4 or PD-1 blocking monoclonal antibodies, have shown substantial clinical successes. However, they are also often associated with very severe side-effects (Yang JC., et al. J Immunother. 2007); so severe that during early clinical trials some patients succumbed to the effects of treatment (Hodi FS., et al. N Engl J Med. 2010). Thus, complementary and alternative treatments appear warranted.
The novel, by us revealed mechanism of how Treg functionality is regulated, i.e. signalling via the EGF-R, is already targeted by drugs that are in wide clinical use. Given these EGF-R inhibitors could improve the efficacy of tumour therapy, such as of chemo- or ACT therapy, then such a treatment could substantially improve the efficacy of a several other experimental tumour therapies in a way that they might become applicable in the clinic. In addition, would such a finding also warrant the testing of their applicability to treat so far un-treatable chronic infections, such as HCMV or HSV. In particular, given we succeed in developing new types of EGF-R inhibitors that directly target Treg function, while diminishing the side-effect, then such novel drugs could substantially improve the acceptance of treatment and could move it into a much wider field of applications.