Biomarker-driven immunotherapy for sarcoma

In this thesis we demonstrated the significant immunological and genomic heterogeneity between pAS and sAS, which has clear implications for patient tailored treatment strategies. Our findings support the universal distinction between AS subgroups based on etiology rather than anatomical location. We have prospectively shown that a subset of sAS patients, previously thought unlikely to benefit from ICI, can obtain durable responses to ICI treatment. In the current era of ICI and targeted therapies, identifying patients who are likely to respond to treatment is crucial to avoid subjecting non-responding patients to ineffective treatments and experiencing unnecessary toxicity. We have identified several predictive biomarkers associated with treatment response to ICI in AS, including T-cell density, TMB-H, the gut microbiome, and ctDNA levels. These findings allow for further exploration of these biomarkers in future clinical trials.
Finally, based on the results of this thesis, we propose specific treatment strategies for future clinical trials, emphasizing the role of ICI in both advanced and (neo)adjuvant settings for sAS. Additionally, we recommend studies using combination therapies incorporating DDRi and ICI to enhance therapeutic efficacy. Our findings represent a significant step forward in the development of personalized, biomarker-driven treatment approaches, with the potential to improve patient outcomes and reshape therapeutic strategies for patients with rare sarcoma.