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Gregory J. Riely, MD, PhD
Gregory J. Riely, MD, PhD
Posted: Monday, March 31, 2025
PD-1/PD-L1 blockade following concurrent platinum-based chemoradiotherapy (cCRT), has emerged as the standard of care for patients with stage III unresectable non–small cell lung cancer (NSCLC), with the landmark PACIFIC trial confirming the regimen’s efficacy. However, challenges related to resistance mechanisms and treatment response prompted researchers to explore novel combination strategies, including targeting the CD73/adenosine pathway, reported Lena Gockeln, PhD, of the Institute of Cell Biology, University Hospital Essen, Germany, and colleagues.
CD73 Inhibition
The CD73 enzyme plays a pivotal role in the purinergic signaling pathway by converting extracellular adenosine monophosphate into adenosine, which exerts immunosuppressive effects in the tumor microenvironment. In NSCLC, heightened CD73 expression is linked to immune evasion, resistance to therapy, and poor prognosis. Suppressing CD73 has the potential to enhance antitumor immunity by sustaining cytotoxic T-cell activity while reducing regulatory T-cell expansion, noted investigators. However, this pathway also plays a crucial role in mitigating inflammation and preserving lung tissue integrity, raising concerns about immune-related adverse events (irAEs), particularly radiation pneumonitis.
Radiotherapy elicits an immune response through adenosine triphosphate (ATP) release, acting as a damage-associated molecular pattern. However, CD73 counteracts this process by degrading ATP into immunosuppressive adenosine. This has led to the hypothesis that inhibiting CD73 may enhance the immunogenic effects of radiotherapy, boosting the efficacy of combined radioimmunotherapy.
Despite these benefits, CD73's protective role in lung tissue complicates its inhibition. While its suppression may improve tumor control, it could also impair the resolution of inflammation, exacerbating radiation pneumonitis. Preclinical studies indicated that CD73 inhibition mitigates radiation-induced fibrosis but disrupts pulmonary immune homeostasis, potentially increasing acute and subacute toxicities.
The PACIFIC trial cemented durvalumab consolidation therapy as the preferred post-cCRT approach in this patient population, improving overall and progression-free survival. However, an elevated risk of pneumonitis was observed in the study; real-world data further reinforced this concern, with pneumonitis rates surpassing 80% in high-risk groups.
Subsequent trials have explored novel approaches to enhance efficacy. The phase II COAST trial assessed the addition of the anti-CD73 monoclonal antibody oleclumab to durvalumab. Initial findings demonstrated improved response rates but also an uptick in low-grade radiation pneumonitis cases. The ongoing phase III PACIFIC-9 trial (ClinicalTrials.gov identifier NCT05221840) aims to further evaluate this combination in a broader patient cohort to determine its long-term safety and benefits.
As research progresses, optimizing patient selection and treatment protocols remains essential to balancing efficacy with safety. Key strategies include:
Targeting the CD73/adenosine pathway offers a promising avenue for enhancing radioimmunotherapy outcomes in patients with NSCLC, wrote the study authors. However, the potential for increased pulmonary toxicity necessitates a careful, balanced approach to treatment design. The results of ongoing studies like PACIFIC-9 will provide critical insights into the feasibility of integrating CD73 inhibition into standard care. In the meantime, a multidisciplinary approach—combining clinical, radiological, and molecular assessments—will be instrumental in refining strategies to maximize treatment efficacy while mitigating risks in NSCLC management.
“By understanding these dynamics, we aim to inform future strategies for optimizing radio-immunotherapy regimens, ensuring effective cancer control while preserving pulmonary integrity and patient quality of life,” noted Dr. Gockeln and colleagues.
Disclosure: The study authors reported no conflicts of interest.
Frontiers in Cell and Developmental Biology
