Tumor microenvironment changes after treatment with avelumab and immune-stimulating agent combinations in patients with advanced solid tumors.

Background: The use of immune checkpoint inhibitors (ICIs) has led to a paradigm change in cancer management. Many patients may have inherent primary resistance to ICIs or develop secondary resistance after initial response. The impact of using novel therapeutic combinations of checkpoint blockade (avelumab) with immune stimulating agonists such as anti-OX40 and/or anti-4-1BB on the tumor microenvironment and modulation of the immune response is an intriguing strategy to evaluate how these agents interact and whether the hypothetical rationale for combinations can be translated into augmentation of anti-tumor immunity in solid tumors. Methods: We performed whole exome sequencing (WES), bulk RNAseq, multiplex immunofluorescence (mIF) and chromogenic immunohistochemistry (IHC) on tumor tissue and flow cytometry of the peripheral blood to study longitudinal changes following the combination of avelumab with utomilumab (a 4-1BB agonist) (arm A), PF-04518600 (an OX40 agonist) (arm B), utomilumab and PF-04518600 (arm C) and utomilumab and radiotherapy (arm D) in phase I/II study (NCT03217747). Results: We observed low tumor mutation burden (TMB < 6) (median: 1.88), alteration of RTK-RAS, TP53, PI3K and WNT pathways across the cohorts. Mutations in Conclusions: Our findings, though limited, highlight genomic differences between histologic subsets and outcome as well as the need for combination strategies that drive the recruitment and/or priming of anti-tumor T cells and address low immune permissive tumor states in patients with advanced solid tumors. Clinical trial registration: This clinical trial was registered on clinicaltrials.gov NCT03217747.