Abstract 5559
Background
Immunotherapy with nivolumab, an anti-PD-1 blocking antibody, is clinically approved for the management of recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) but it benefits only a minority of patients. The phosphodiesterase (PDE) 5 inhibitor tadalafil was found to lower intratumoral myeloid-derived suppressor cells and regulatory T cells in SCCHN patients. Here we describe exploratory analyses of immune-related gene expression correlates of nivolumab with or without concurrent administration of tadalafil administered for 4 weeks before planned surgical resection in the context of a completed randomized, window-of-opportunity trial.
Methods
RNA-seq was performed on pre- and post-treatment tumor tissues from 28 patients receiving either nivolumab alone (n = 12) or nivolumab and tadalafil (n = 16). RNA was sequenced (NextSeq 500) using 75bp paired-end chemistry at a depth of ∼50 million reads.
Results
Consistent with previous work, pretreatment biopsies of HPV(+) SCCHN (n = 19) were more strongly immune infiltrated when compared to HPV(-) (n = 9) cancers. Preliminary principal component analysis of pretreatment gene expression suggests that select transcripts related to T cells and inflammation were predicitve of clinical outcomes in HPV(+) SCCHN. Nivolumab treatment enhanced expression of a broad range of immune-related genes in both HPV(+) and HPV(-) SCCHNs and this signature was amplified by tadalafil. Whereas transcript patterns consistent with enhanced myeloid cell infiltration after treatment were observed in both, HPV(+) and HPV(-) HNSCCs, T cell gene expression signatures were more pronounced in HPV(+) cancers.
Conclusions
These results point to diverse intratumoral immune states triggered by nivolumab/tadalafil in HPV(+) when compared to HPV(-) SCCHNs. They challenge the notion that increased presence of intratumoral T lymphocytes alone is associated with favorable therapeutic responses to PD1 inhibition in SCCHN. Yet, select pretreatment transcripts associated with innate and/or adaptive immune responses may have prognostic relevance.
Clinical trial identification
NCT 03238365.
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Bristol-Myers Squibb.
Disclosure
All authors have declared no conflicts of interest.
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