Impact
The overall aim of the present proposal is to validate tumor cell IL-7R overexpression as a novel therapeutically amenable mechanism of lung tumor progression and resistance to immune checkpoint blockade in NSCLC. To address this, we have structured a complete reverse translational research plan that integrates and aligns the expertise of three unique research groups.
i) At the scientific level, we propose to validate a novel hypothesis where IL-7R, an essential component for normal lymphoid development, is subverted and co-opted by solid tumor cells to promote tumor progression and immunotherapy resistance.
ii) At the technological level, this project has the potential to incorporate novel profiling technologies into the clinic and to develop novel scientifically rigorous diagnostic tests based on quantitative and automated methods. We also anticipate the possibility to implement more broadly the use of human patient derived xenograft models as suitable in vivo tools to test experimentally the anti-tumor efficacy of novel drugs with immunomodulatory properties for future translational studies. This could greatly increase the capacity to pre-clinically screen the most effective therapies for clinical development. Ultimately, all these features make this project of great interest for biotechnology, diagnostic and pharmaceutical companies.
iii) At the clinical level, this project could be transformative for lung cancer patient care. In the context of PD-1 axis blockade for NSCLC, there is medical need to develop biomarkers with high negative predictive value of response, as only a small minority of NSCLC patients truly derive long-term survival benefit from PD-1 axis inhibitors. Ideally, these biomarkers should be easily assessed in the clinic, and should identify subsets of patients amenable for alternative effective therapeutic interventions. IL-7R is a surface molecule that can be easily detected with protein-based assays, and thus could be rapidly scalable to clinical settings. Furthermore, IL-7R could be therapeutically targetable with engineered antibody-based molecules for selective and efficient.
IL-7R blockade in tumor cells as those proposed in this project. These innovative prodrugs would also transform IL-7R blockade into recruitment points of T cell effector functions or PD-L1 blockade, with potential synergistic anti-tumor effect.
