A recently published study examines the effectiveness of neoadjuvant immunotherapy efficacy in treating head and neck squamous cell carcinoma (HNSCC). It compares three treatment regimens: anti-PD-1 monotherapy (nivolumab), nivolumab combined with anti-CTLA-4 (ipilimumab), and nivolumab paired with anti-LAG-3 (relatlimab). The combination therapies exhibited higher pathologic response rates than monotherapy. Nivolumab plus relatlimab reprogrammed tumor-infiltrating CD8+ T cells into effector and resident memory phenotypes, increasing therapeutic efficacy. Each therapy showcased unique T cell modulation mechanisms, indicating promising avenues for personalized immunotherapy strategies.

HNSCC represents a significant cancer burden worldwide, with ~890,000 new cases yearly. Traditional treatments often cause functional impairments, spurring interest in neoadjuvant immunotherapy to shrink tumors before surgery, preserving speech and swallowing. Immune checkpoint inhibitors (ICIs), like anti-PD-1 nivolumab, are transforming cancer immunotherapy. However, they often show limited efficacy alone, necessitating combination strategies. CD8+ cytotoxic T cells are crucial for anti-tumor immunity. Research emphasizes maintaining functional memory T cells and combating exhaustion to improve outcomes.

Key Insights into Treatment Mechanisms

1. Distinct Mechanisms of Action:
   • Nivolumab combined with relatlimab reprogrammed exhausted CD8+ T cells through a type-I interferon (IFN-I) response. This transformed them into functional effector memory (TEM) and tissue-resident memory (TRM) cells, enhancing immune surveillance and diversity. In contrast, nivolumab plus ipilimumab expanded pre-existing TEM and TRM CD8+ T cells without reprogramming exhausted cells, resulting in a different anti-tumor strategy.
2. Pathologic Response and Survival Enhancement:
   • The combination therapies yielded significantly higher pathologic response rates (>50% tumor reduction). These correlated with improved 3-year disease-free and overall survival rates compared to monotherapy. Tumor-reactive CD8+ T cells persisted post-treatment, suggesting ongoing immune surveillance and potential long-term benefits.
3. Identification of Biomarker-Driven Therapies:
   • The lymphocyte activation gene 3 (LAG-3) gene served as a predictive biomarker for responses to nivolumab combined with relatlimab. CTLA-4 markers correlated with better outcomes in patients treated with nivolumab plus ipilimumab. The diversity of T cell receptors (TCR) and CD8+ T cell transcriptional profiles emerge as promising biomarkers for individualized therapies.

Implications for Health Economics and Outcomes Research (HEOR)

Biomarker-guided selection of ICIs, like LAG-3 for nivolumab + relatlimab, can optimize efficacy while minimizing costs from ineffective therapies. Enhanced patient stratification through predictive biomarkers has significant implications for precision oncology reimbursement.

Higher pathologic response rates and improved survival may enhance patient quality of life and reduce long-term costs via lower recurrence. Triple-agent regimens (nivolumab + relatlimab + ipilimumab) may improve responses but require cost-effectiveness analyses weighing outcomes against toxicities and costs. Successful neoadjuvant therapies may also enable less invasive surgeries, reducing long-term functional impairments and rehabilitation costs.

Conclusion: A New Era in Cancer Treatment

The study highlights neoadjuvant combination immunotherapy’s potential to transform cancer treatment. The distinct CD8+ T cell dynamics pave the way for biomarker-driven, patient-tailored approaches. These findings impact clinical practice, pricing, market access, and reimbursement in oncology. Integrating genomic and immune signatures into HEOR can promote equitable access to these therapies. For more insights, see the original article.