Kim et al. Page 3452

MOXR0916 is an agonist antibody that targets the OX40 receptor. Ligation of OX40 provides costimulatory signals to effector T cells and functional inhibition of regulatory T cells. Here, Kim and colleagues demonstrated the safety of MOXR0916 in patients with solid tumors with no dose-limiting toxicities observed. Serial tumor biopsies demonstrated limited evidence of immune activation in a heterogeneous population. Minimal antitumor activity was observed in indication-specific expansion cohorts enrolled at the recommended dose of 300 mg every 3 weeks selected based on projected tumor OX40 receptor saturation. Therefore, clinical proof-of-concept for OX40 agonism was not demonstrated by this phase I study. Whether combination with established agents with complementary mechanisms of action, such as anti-PD-L1, or whether an alternative approach to targeting the OX40 receptor can achieve more compelling efficacy remains to be determined.

Leddon et al. Page 3464

Outcomes for patients with locally recurrent head and neck squamous cell carcinoma (HNSCC) remain poor. Although salvage surgery is currently the standard of care, surgery fails to achieve disease control in more than half of patients. To date, no adjuvant therapy has been shown to provide survival benefit after salvage resection. Here, Leddon and colleagues report the results of a phase II open-labeled trial of adjuvant nivolumab after salvage resection for recurrent HNSCC. They found that adjuvant nivolumab was well tolerated. Two-year disease-free survival after following adjuvant nivolumab was 71.4%, which is significantly longer than a historical control sample with similar baseline characteristics. Further study in randomized controlled trials is warranted to establish clinical efficacy.

Batsios et al. Page 3526

Telomere maintenance is essential for uncontrolled tumor proliferation. Most tumors maintain telomere length via reactivation of telomerase reverse transcriptase (TERT) expression. Identifying clinically translatable imaging biomarkers of TERT has the potential to enable noninvasive assessment of tumor proliferation and response to therapy. Batsios and colleagues utilized deuterium metabolic imaging following administration of deuterated pyruvate to noninvasively monitor TERT expression in tumor-bearing mice in vivo. Importantly, lactate production from deuterated pyruvate is a biomarker of early response to therapy, prior to anatomical alterations, thereby providing clinicians with a novel tool for assessment of tumor proliferation and treatment response in cancer.

Schmitd et al. Page 3557

Perineural invasion (PNI) occurs frequently in oral squamous cell carcinoma. However, diagnostic criteria of PNI vary and its role as an independent predictor of prognosis has not been established. Schmitd and colleagues reveal that PNI is an important predictor of prognosis among patients with no lymph node metastasis. Moreover, patients with nerves closer to the tumor have poor outcomes even if diagnosed as PNI-negative using current criteria. Consistent with clinical findings, spatial transcriptomic analysis of nerves in sections of human tumors shows a gradient of gene expression that is dependent on nerve-tumor distance. Together, these findings support broadening the definition of PNI to make it more clinically relevant. Moreover, the transcriptomic data reveal an injury response to the tumor; mechanisms involved in response to stress and growth are upregulated in nerves proximal to cancer. Understanding how these mechanisms contribute to clinical outcomes is crucial for developing new treatment strategies that reduce tumor recurrence.