Towards a mechanistic understanding of patient response to neoadjuvant SBRT with anti-PDL1 in human HPV-unrelated locally advanced HNSCC: Phase I/Ib trial results (Part 1)

ABSTRACT: Five-year survival for HPV-unrelated head and neck squamous cell carcinomas (HNSCC) remains below 50%. We assessed the safety of administering combination hypofractionated stereotactic body radiation therapy (SBRT) with anti-PDL-1 neoadjuvantly followed by adjuvant anti-PDL-1 with standard of care therapy (n=21). The primary endpoint of the study was safety, which was met. Secondary endpoints included radiographic, pathologic, and objective response, locoregional control (LRC), progression-free survival (PFS), and overall survival (OS). Among evaluable patients at early median follow-up of 16 months (448 days), OS was 83.3%, LRC and PFS were 83.3%, and major pathological response (MPR) or complete response (CR) was 75%. Circulating CD8/Treg ratio, CD4 effector memory T cells, and TCR repertoire emerged as biologic correlates of response to therapy. Using high-dimensional multi-omics and spatial data as well as biological correlatives pre- and post-treatment, three major changes were noted in responders within the tumor microenvironment (TME) (and within the blood) post-treatment: 1) an increase in effector T cells; 2) a decrease in immunosuppressive cells; and 3) an increase in antigen presentation. Non-responders appeared to fail due to a lack of one of these three identified steps needed for priming and maintaining activation of T cells. Multiple correlates for response, along with subsets of non-responders that may benefit from additional or alternative immunotherapies, were identified. This treatment is being tested in an ongoing phase II trial with a similar design, where we hope to confirm and expand on our understanding of the mechanisms underlying resistance to therapy.

ORGANISM(S): Human Homo Sapiens

TISSUE(S): Blood

DISEASE(S): Cancer

SUBMITTER: Rachel Culp-Hill  

PROVIDER: ST002109 | MetabolomicsWorkbench | Wed Mar 09 00:00:00 GMT 2022

REPOSITORIES: MetabolomicsWorkbench