Research

Remarkably, there has been significant progress in treatment outcome with the introduction of therapies targeting tumor-specific genetic alterations, and immunotherapy against the PD-1 axis, which boosts the immune system to combat cancer. Unfortunately, a considerable fraction of lung cancer patients still relapses. Thus, there is a clear need to identify new molecular targets for therapeutic intervention to overcome disease recurrence.

Here, we propose that IL-7R, which is expressed in immune cells and required for their differentiation and anti-tumor function, can be co-opted by lung cancer cells to promote tumor development, metastasis, and resistance to immunotherapy. Consequently, we also propose to generate therapeutic tools to counteract these features, by developing novel bispecific antibody formats to selectively target IL-7R on cancer cells in order to improve treatment efficacy.

---

Abstract

Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small-cell lung cancer (NSCLC) is the major lung cancer subtype, accounting for 85% of all cases. Immunotherapy based on PD-1 axis blockade transformed the therapeutic landscape of advanced NSCLC in recent years. However, resistance can emerge and constitutes a significant challenge. Another clinical hurdle stems from >50% primary tumors metastasizing. Interleukin (IL)-7 and its receptor (IL-7R) are critical for T-cell development, survival of naïve T-cells, and generation and maintenance of memory T-cells, being essential for efficient immune anti-tumor responses.

However, they can be subverted to promote cancer progression: IL-7 accelerates leukemia development and IL7R is a bona fide lymphoid oncogene. There is also evidence that IL-7R can be aberrantly expressed in solid tumors and contribute to tumor expansion and resistance to therapy. Based on our preliminary data indicating that IL-7 promotes NSCL proliferation in vitro and tumor expansion in vivo and that high levels of IL-7R expression in cancer cells associate with poor response to anti-PD-1 treatment, we propose to:

1) Dissect the role of IL-7/IL-7R in NSCLC development and metastasis;

2) Confirm whether IL-7R is a biomarker of resistance to anti-PD-1 axis therapy and explore the mechanisms by which IL-7R may mediate resistance to immune checkpoint inhibition;

3) Develop novel antibody-based approaches to target IL-7R expression specifically in tumor cells, decrease tumor burden and prevent resistance to immunotherapy. These studies, combining our expertise in IL-7R biology (Barata), lung cancer and PD-1 inhibition (Zugazagoitia) and antibody engineering (Álvarez-Vallina), and making use of clinical data, patient specimens and unique animal models, have the ambition to reveal critical new facets of NSCLC biology and to translate into the establishment of new therapeutic tools that help circumvent current treatment limitations.

---

Aim

As stated above, the IL-7-IL-7R axis acting on immune cells is critical for antitumor activity, including in the context of immunotherapy involving PD-1 axis inhibition, but we hypothesize that the same axis acting on lung cancer cells promotes tumor development, metastasis and resistance to PD-1 axis inhibition. Our proposal will dissect and integrate these two opposing facets into a coherent pathophysiological model that can be exploited therapeutically.

Our specific aims are to:

1) Dissect the role of IL-7/IL-7R in NSCLC development and metastasis;

2) Confirm whether IL-7R is a biomarker of resistance to anti-PD-1 axis therapy and explore the
mechanisms by which IL-7R may mediate resistance to immune checkpoint inhibition;

3) Develop novel antibody-based approaches to specifically target IL-7R expressed in tumor cells, decrease tumor burden and prevent resistance to PD-1 axis blockade.

These aims will be pursued using complementary methodologies and tools, including clinical data, our established lung cancer PDX samples and models, and our unique IL-7R-related mouse models.