Targeting immunosuppressive adenosine in patients with metastatic non-small cell lung cancer

SUMMARY/ABSTRACT
Immune checkpoint inhibitors (ICIs) have transformed the management of patients with metastatic non-small cell
lung cancer (NSCLC). Unfortunately, over 50% of patients do not respond to these therapies. Combination
strategies with chemotherapy-ICIs show progress, but long-term responses remain rare, pointing to the role for
other tumor-associated mechanisms affecting functionality of immune cells. Adenosinergic signaling has recently
emerged as a powerful immuno-metabolic regulator within the tumor microenvironment (TME) exploited by
tumors to promote their growth and suppress immunity. Preclinical studies on interference with adenosine
generation or signaling through A2A and A2B adenosine receptors (A2BAR) have demonstrated efficacy in relieving
this immunosuppression by reducing stress in the TME and decreasing expression of key adenosine-generating
enzymes, thereby enhancing efficacy of immune checkpoint inhibition. A2BAR blockade in particular enhanced
anti-tumor immunity through both a reduction in myeloid-derived suppressor cell differentiation and an
enhancement of the capacity of dendritic cells to evoke anti-tumor T cell responses. These findings provide
strong rationale for clinical applications of A2BAR antagonists in combination with current ICIs. To determine
whether disruption of A2BAR signaling has the potential to improve upon single agent PD-1 immunotherapy, we
propose a phase Ib clinical trial testing the A2BAR antagonist PBF-1129 in combination with nivolumab in
patients with metastatic NSCLC. The primary objective of the clinical study is to evaluate the safety and
tolerability of combination PBF-1129 with nivolumab; preliminary evidence of efficacy will be evaluated in an
expansion cohort. Analysis of pre- and on- treatment blood and tumor samples will be conducted to evaluate the
correlation between and immunological parameters and adenosine generation and signaling, and to evaluate
the efficacy of PBF-1129 in targeting adenosine-mediated immunosuppression. Finally, we intend to further
elucidate mechanisms of metabolic TME and immune regulation by adenosine in pre-clinical cancer models and
test the combined PBF-1129/anti-PD-1 approach to ameliorate metabolic TME using a novel imaging modality.
Together, we expect that A2BAR antagonist treatment combined with nivolumab will be a safe, effective
approach targeting different mechanisms of immunosuppression and tumor growth in metastatic
NSCLC patients, that we will uncover immunological profiles reflective of adenosinergic signaling
disruption in these patients, and that we will demonstrate the utility of a novel combined imaging
approach for evaluation of adenosine targeting in the TME.

Grant Number: 5R01CA248741-05
NIH Institute/Center: NIH
Principal Investigator: DAVID CARBONE