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Program Number: B181
Session Name: Poster Session

Timing Matters: Investigating the Impact of Immunotherapy Start Time on Clinical Outcomes and Gene Expression in Head and Neck Squamous Cell Carcinoma

Hani Samarah, BS; Kalena Liu, BS; Sonali Persaud, BS; Kelly Bridgham, MD; Pablo Llerena, BS; Alban Linnenbach, PhD; Adam Luginbuhl, MD; Thomas Jefferson University

Background: Immune checkpoint inhibitors (ICIs) are an approved treatment option for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). However, response rates remain modest. There is evidence in the literature suggesting that aligning immunotherapy with circadian rhythms, a concept known as chronotherapy, may influence treatment response. This study explores the potential association between the timing of neoadjuvant immunotherapy and treatment response.  

Objective: This study investigates the association between the start time of neoadjuvant immunotherapy and treatment response in HNSCC patients, while also evaluating gene expression profiles using gene set enrichment analysis (GSEA). 

Methods: This secondary analysis includes 69 patients from two clinical trials who received either nivolumab plus tadalafil (Trial 1) or nivolumab plus an IDO inhibitor (Trial 2). Patients received two infusions of immunotherapy. Patient responses were prospectively classified as responders (R) or non-responders (NR) based on a pathologic treatment effect (pTE) cut-off of 20%. A decision-tree analysis evaluated the relationship between treatment start time and response rates. Mean pTE was compared between patients who received immunotherapy infusions before and after 1 PM (Figure 1a). GSEA was performed using both unsupervised and supervised approaches to identify enriched immune pathways based on treatment timing (Figure 1b). 

Results: Patients initiating immunotherapy before 1:00 PM had a higher response rate (74%, 21/29) than those starting after 1:00 PM (52%, 36/69). Those receiving both infusions before 1:00 PM showed the highest mean pTE, significantly higher than those with discordant or later infusion timing (p = 0.049) (Figure 1a). Unsupervised GSEA showed enrichment of Hallmark pathways, including WNT/β-catenin, Notch, and estrogen response, supporting a link between treatment timing and gene expression. Supervised GSEA revealed that pre-treatment circadian gene expression did not differ significantly across timing groups but diverged post-treatment (Figure 1b). Specifically, patients treated before 1:00 PM showed a normalized enrichment score (NES) of -1.6 (FDR q-val = 0.007) in pre- vs. post-treatment comparisons, while those treated after 1:00 PM had an NES of 1.35 (FDR q-val = 0.043) in the same comparison (Figure 1b). Whole blood parameter comparisons (e.g., neutrophils, lymphocytes, NLR) showed no significant differences between timing groups (all p > 0.05), indicating no timing-related effects on blood composition. 

Conclusion: These findings suggest that the timing of immunotherapy may influence response rates in HNSCC, with earlier administration linked to improved pathologic treatment outcomes. The significant enrichment of circadian-related pathways in gene set analysis supports the need for further investigation into the role of chronotherapy in optimizing immunotherapy efficacy. Further analysis of the tumor microenvironment, peripheral cytokine, and whole blood samples is under way to provide additional insights into the mechanisms driving this timing-based variation in treatment response. 

 

 

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